2012 Breast Cancer Symposium Educational Summaries - American ...

2012 Breast Cancer Symposium
Educational Summaries
General Session I: Controversial Topics in Medical Oncology Management
Role of Chemotherapy for Small Triple-Negative and HER2-Positive Cancers
Robert W. Carlson, MD ....................................................................................................................................4
General Session II: Risk Assessment, Prevention, Detection, and Screening
Imaging Techniques for Breast Cancer Detection and Diagnosis: What Works and What Doesn’t
David Mankoff, MD, PhD ................................................................................................................................7
Surgical Risk Reduction for Atypical Ductal Hyperplasia, Lobular Carcinoma In Situ, and Ductal Carcinoma
In Situ
Todd M. Tuttle, MD ..........................................................................................................................................9
Prevention Strategies for Women at High Risk and for Those with Lobular or Ductal Carcinoma In Situ
Victor G. Vogel, MD, MHS .............................................................................................................................10
General Session III: Controversies in Diagnosis of Early-Stage Breast Cancer and
Management of Sentinel Nodes
Magnetic Resonance Imaging Debate: Con
Kathryn Evers, MD ........................................................................................................................................14
General Session IV: Controversies in Local/Regional Treatment
Debate on the Role of Local Radiation Therapy in Ductal Carcinoma In Situ: Pro
Shivani Duggal, DO, and Thomas B. Julian, MD .......................................................................................17
Targeted Intraoperative Radiotherapy: Analysis of a Randomized Trial—The TARGIT-A Trial
Jayant S. Vaidya, MBBS, MS, DNB, PhD ....................................................................................................19
Debate on the Role of Radiation Therapy in Ductal Carcinoma In Situ: Con
Abram Recht, MD ...........................................................................................................................................22
Intraoperative Radiation Therapy for Breast Cancer
Julia White, MD ..............................................................................................................................................25
General Session V: Genomics for the Clinician
PI3K in Breast Cancer
Toby M. Ward, PhD, Rebecca Olson, MS, Mark D. Pegram, MD, and Charles E. Geyer Jr., MD ........28
Role of Genomic Testing in Patients with Node-Positive Breast Cancer
Shaheenah Dawood, MRCP, MPH, and Ana M. Gonzalez-Angulo, MD, MSc ........................................31
Breast Cancer Whole Genome Sequencing
Matthew J. Ellis, MB BChir, PhD ................................................................................................................34
General Session VI: Health Care Delivery and Prevention
Breast Health Care Delivery in Context: The World Health Organization’s Initiative for Noncommunicable Diseases
Benjamin O. Anderson, MD ..........................................................................................................................36
1

Reducing Breast Cancer Risk: Progress toward Resolution
Rowan T. Chlebowski, MD, PhD ..................................................................................................................38
General Session VII: Survivorship
Inflammation in the Pathogenesis and Progression of Breast Cancer
Patrick G. Morris, MD, MSc, Kotha Subbaramaiah, PhD, Andrew J. Dannenberg, MD, and
Clifford A. Hudis, MD ....................................................................................................................................41
Managing Menopausal Symptoms in Patients with Breast Cancer
Patrick Neven, MD, and Anneleen Lintermans, MD ................................................................................44
The Transition from Active Treatment to Normal Life as a Survivor
Denise J. O’Neill, BS ......................................................................................................................................47
General Session VIII: The Future of Health Policy
What Are the Differences between Approving and Using New Drugs and New Devices in the United States?
Gary H. Lyman, MD, MPH ............................................................................................................................50
General Session IX: New Directions in Systemic Therapy for Advanced Disease
Hormone-Responsive Disease
Francisco J. Esteva, MD, PhD ......................................................................................................................53
Therapeutic Strategies Targeting ERBB2: An Update on ERBB2-Positive Breast Cancer
Mark D. Pegram, MD .....................................................................................................................................55
General Session XI: Debates on Current Controversies in Systemic Therapy
Bone Health and the Role of Biphosphonates in Early-Stage Breast Cancer: A Debate
Julie Gralow, MD, and Catherine Van Poznak, MD .................................................................................60
In Favor of the Use of Anthracyclines in Patients with HER2-Positive and HER2-Negative Breast Cancer
Clifford Hudis, MD .........................................................................................................................................62
Marker-Driven Personalized Therapy for Breast Cancer
Gabriel N. Hortobagyi, MD ...........................................................................................................................64
“Just Say No” to Anthracyclines for Early Breast Cancer
Stephen Jones, MD ........................................................................................................................................66
Reassessing Local Treatment in the Context of Increasingly Effective Systemic Therapy
Jay R. Harris, MD ...........................................................................................................................................68
2

GENERAL SESSION I:
Controversial Topics in Medical Oncology Management
CHAIR
Lori Goldstein, MD
Fox Chase Cancer Center
SPEAKERS
William John Gradishar, MD
Northwestern University
Robert W. Carlson, MD
Stanford Comprehensive Cancer Center
After this session, attendees should be able to
● Assess the role of mTOR inhibitors in the management of metastatic breast cancer and determine potential patient
benefits from targeting mTOR pathways
● Discuss the potential applications for the use of chemotherapy for small TN and HER2-positive cancers and evaluate how
this technique might be incorporated into treatment plans for specific patients

Role of Chemotherapy for Small Triple-Negative and
HER2-Positive Cancers
Breast cancers encompass a diverse group of biologic
subsets of disease that may be identified by biomarker
expression (e.g., estrogen receptor [ER]/progesterone receptor
[PR]/human epidermal growth factor receptor 2
[HER2]) and genetic microarray analysis. The biologic heterogeneity
among invasive breast cancers may be exploited
in the treatment decision-making process. Breast cancers
that are HER2-positive or triple-negative (ER-negative, PRnegative,
and HER2-negative) have a worse prognosis than
do the other subtypes. The HER2-positive breast cancers
are highly responsive to HER2-targeted therapy (e.g., trastuzumab)
and to selected chemotherapies (e.g., anthracyclines,
taxanes, platinoids). The triple-negative breast
cancers (TNBCs) also appear highly sensitive to selected
chemotherapies (e.g., anthracyclines, taxanes, and platinoids)
despite their overall relatively poor prognosis. 1
The prognosis in women with T1a/bN0M0 disease has
been the subject of multiple retrospective studies. The results
of these studies consistently demonstrate favorable
outcomes in women with T1a/bN0M0 disease as a group.
Subset analyses to identify favorable or unfavorable biologic
subsets within this cohort of patients have yielded inconsistent
and sometimes contradictory results. 2-6 Some studies
have found age and triple-negative status but not HER2
status to be prognostic; others have found HER2-positive,
endocrine receptor–negative disease or triple-negative status
to be unfavorable; others have found HER2 status to be
prognostic; and still others have found that HER2 status is
not predictive of poor outcome in this anatomic subset.
The activity of adjuvant trastuzumab added to chemotherapy
has been studied in a number of randomized
trials in high-risk women with HER2-positive early
breast cancer. These studies demonstrate an approximate
40% reduction in hazard of recurrence and 34%
reduction in hazard of death with the addition of trastuzumab
to adjuvant therapy. 7 In high-risk women with
Author’s Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Robert W. Carlson, MD
Stanford University, Stanford, CA
Consultant or
Advisory Role
TNBC, the use of anthracycline- and taxane-containing
adjuvant chemotherapy has demonstrated substantial
improvement in relapse-free and overall survival. Generally,
adjuvant therapy studies have been limited to
patients with either node-positive disease or high-risk
node-negative disease (grade 2 to 3, T � 1 cm). However,
there are no data demonstrating that the relative
risk reductions documented in high-risk populations
should not also apply to patients in lower-risk populations.
In the low-risk populations, the relative risk
reduction in recurrences or deaths from disease may be
large, while the absolute benefits may be small.
The use of adjuvant HER2-targeted therapy and of cytotoxic
chemotherapy is associated with acute and chronic
toxicity, reduced quality of life, and financial expense. Some
of the toxicities, such as second cancers, premature ovarian
failure, and cardiac toxicity may be permanent. While the
absolute efficacy benefits of the adjuvant therapies decrease
with decreasing disease risk, the toxicities of adjuvant therapy
are the same across all risk categories. The challenge is
to assess when the benefits of adjuvant therapy become too
small to justify the toxicity for the individual patient. In the
extreme, do patients with T1a/bN0M0 HER2-positive or
triple-negative disease derive sufficient benefit from adjuvant
therapy to justify adjuvant treatment?
The potential use of chemotherapy plus trastuzumab in
the treatment of HER2-positive disease and of chemotherapy
in the treatment of TNBC in women with T1a/bN0M0
disease must be considered in the context of inconsistent/
heterogeneous data on prognosis, absent clinical trials, and
the known toxicities of treatment. 8 Further investigation to
identify those patients most likely to experience recurrence
of disease and thus have a relatively more acceptable efficacy
to toxicity balance is required before definitive recommendations
regarding adjuvant cytotoxic or HER2-targeted
therapy may be made.
Stock
Ownership Honoraria
Research
Funding
Carlson, Robert W. AstraZeneca;
Genentech;
Sanofi
References
1. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to
paclitaxel in node-positive breast cancer. N Engl J Med. 2007;357:
1496-1506.
2. Curigliano G, Viale G, Bagnardi V, et al. Clinical relevance of
HER2 overexpression/amplification in patients with small tumor
size and node-negative breast cancer. J Clin Oncol. 2009;27:
5693-5699.
4
Expert
Testimony
Other
Remuneration
3. Fehrenbacher L, Shiraz P, Sattavat M, et al. T1abN0M0 HER2�
invasive breast cancer recurrence: Population-based cohort of
17,000� consecutive breast cancers 2000-2006 at Kaiser Permanente
Northern California (KPNC). J Clin Oncol. 2011;29:57s
(suppl; abstr 551).
4. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al. High risk of
recurrence for patients with breast cancer who have human epidermal
growth factor receptor 2-positive, node-negative tumors 1
cm or smaller. J Clin Oncol. 2009;27:5700-5706.

5. Chia S, Norris B, Speers C, et al. Human epidermal growth factor
receptor 2 overexpression as a prognostic factor in a large tissue
microarray series of node-negative breast cancers. J Clin Oncol.
2008;26:5697-5704.
6. Kwon J, Kim YJ, Lee KW, et al. Triple negativity and young age as
prognostic factors in lymph node-negative invasive ductal carcinoma
of 1 cm or less. BMC Cancer. 2010;10:557.
EDUCATIONAL SUMMARIES
7. Moja L, Tagliabue L, Balduzzi, et al. Trastuzumab containing regimens
for early breast cancer. Cochrane Database Syst Rev. http://
onlinelibrary.wiley.com/doi/10.1002/14651858.CD006243.pub2/
pdf. Accessed June 8, 2012.
8. Carlson RW, Allred DC, Anderson BO, et al. NCCN Clinical
Practice Guidelines: Breast Cancer. v1.2012. www.nccn.org. Accessed
June 8, 2012.
5

GENERAL SESSION II:
Risk Assessment, Prevention, Detection, and Screening
CHAIR
Banu Arun, MD
University of Texas M. D. Anderson Cancer Center
SPEAKERS
Claudine Isaacs, MD
Georgetown University
David A. Mankoff, MD, PhD
University of Pennsylvania
Todd M. Tuttle, MD, MS
University of Minnesota
Victor Vogel, MD, MHS
Geisinger Health System
After this session, attendees should be able to
● Appropriately use genetic testing to identify patients at high risk of cancer and employ strategies to clearly and
effectively communicate results to patients and assist them in making informed decisions about any recommended next
steps
● Compare and contrast imaging techniques used in screening patients for cancer and determine what patient populations
are most likely to benefit from each specific technique currently available
● Examine both positive and negative implications of using risk-reducing surgery for patients with premalignant lesions
and be able to clearly discuss all options with patients to assist them in making an informed decision
● Evaluate different medical management strategies for patients with ductal carcinoma in situ (DCIS) or lobular
carcinoma in situ (LCIS) as well as prevention strategies for women at risk, including pharmacologic interventions, such
as results from MAP.3; determine those strategies’ potential to improve prevention outcomes in breast cancer

Imaging Techniques for Breast Cancer Detection and
Diagnosis: What Works and What Doesn’t
T
he landscape for breast cancer detection and diagnosis
has become more complex in recent years in part due
to the introduction of new imaging methods. In addition to
mammography and ultrasound, tests that have wellestablished
roles in breast imaging, breast magnetic resonance
imaging (MRI) has become an accepted and widely
used tool for breast imaging. In addition, recent developments
in instrumentation designed for breast imaging have
led to interest in radionuclide breast imaging, namely
breast-specific gamma imaging (BSGI) and positron emission
mammography (PEM). In addition to breast cancer
detection and diagnosis, these modalities have been shown,
to varying degrees, to be helpful for defining the extent of
disease in the breast (local breast staging) and for detecting
regional nodal metastases (locoregional staging). This talk
will provide a brief overview of how the imaging modalities
particularly, the new modalities, work, and where they fit
into the detection, diagnosis, and staging of breast cancer in
current practice.
Breast MRI
Breast MRI works on the principle of imaging the magnetic
resonance of protons perturbed by radiofrequency signal in
the presence of a strong magnetic field. 1,2 Breast MRI uses
dedicate coils to provide high quality, high-resolution images
of the breast. MRI-guided biopsy methods have been
established and are now widely available in practices with
specialized breast imaging radiologists. 1,2 Detection and diagnosis
requires the use of gadolinium-based contrast magnetic
contrast; however, early work in diffusion-weighted
imaging 3 may offer the ability to identify breast tumors
without the need for contrast. Breast MRI has been most
widely used for screening in high-risk women 4 and for local
beast staging to guide surgical resection. 1 Some recent studies
have questioned the influence of breast MRI for the
David Mankoff, MD, PhD
University of Pennsylvania, Philadelphia, PA
Author’s Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Mankoff, David Bristol-Myers
Squibb; Pfizer
References
1. Lehman CD, Schnall MD. Imaging in breast cancer: magnetic
resonance imaging. Breast Cancer Res. 2005;7:215-219.
2. Morrow M, Waters J, Morris E. MRI for breast cancer screening,
diagnosis, and treatment. Lancet. 2011;378:1804-1811.
3. Partridge SC, Mullins CD, Kurland BF, et al. Apparent diffusion
coefficient values for discriminating benign and malignant
breast MRI lesions: effects of lesion type and size. AJR Am J
Roentgenol. 2010;194:1664-1673.
latter application, 5 and studies under development should
help further define its role in guiding breast surgery. 2
Radiotracer Imaging
Radiotracer imaging, also called nuclear medicine imaging,
provides images of regional radiopharmaceutical concentration.
Radiotracer imaging can use both standard gammaemitting
tracers, single-photon emission computed
tomography (SECT), and positron-emitting compounds
(positron emission tomography [PET]). Radiotracer imaging
plays an important role in the current care for patients
with breast cancer, thus far it has been largely focused on
staging for more advanced breast scans (bone scan and
18
F-fluorodexoyglucose [FDG] PET/computed tomography
[CT]) and for guiding nodal sampling in sentinel lymph
node biopsy. 6,7 Early studies of radiotracer breast imaging
showed that it was useful for imaging mass lesions and
evaluating response to therapy, 8,9 but had lower sensitivity
for smaller, earlier-stage breast cancer. 8 More recently, the
development of dedicated breast imaging devices for SPECT
(breast-specific gamma imaging, BSGI) or PET (positron
emission mammography, PEM) have shown promise detecting
smaller lesions. 10-12 However, unlike breast MRI,
the roles of BSGI and PEM in breast cancer diagnosis
remain unclear. Early data from smaller studies, and some
recent data from multicenter trials, point to reasonable and
high specificity 10,11 ; however, the role of radiotracer breastspecific
imaging methods vis-à-vis established methods such
as mammography, ultrasound, and breast MRI will need to
be defined. In the future, identification of molecular targets
for early breast cancer detection, and translation of these
targets into specific imaging probes, would greatly benefit
radiotracer breast imaging methods and very likely improve
upon the relatively nonspecific probes that are currently
used. 13
Stock
Ownership Honoraria
Research
Funding
Merck; Pfizer
Expert
Testimony
Other
Remuneration
4. Saslow D, Boetes C, Burke W, et al. American Cancer Society
guidelines for breast screening with MRI as an adjunct to mammography.
CA Cancer J Clin. 2007;57:75-89.
5. Turnbull L, Brown S, Harvey I, et al. Comparative effectiveness
of MRI in breast cancer (COMICE) trial: a randomised controlled
trial. Lancet. 2010;375:563-571.
6. Benard F, Turcotte E. Imaging in breast cancer: Single-photon
computed tomography and positron-emission tomography.
Breast Cancer Res. 2005;7:153-162.
7. Lee JH, Rosen EL, Mankoff DA. The role of radiotracer imaging
7

EDUCATIONAL SUMMARIES
in the diagnosis and management of patients with breast cancer:
part 1—overview, detection, and staging. J Nucl Med. 2009;50:
569-581.
8. Khalkhali I, Villanueva-Meyer J, Edell SL, et al. Diagnostic
accuracy of 99m Tc-sestamibi breast imaging: multicenter trial
results. J Nucl Med. 2000;41:1973-1979.
9. Mankoff DA, Dunnwald LK, Gralow JR, et al. Monitoring the
response of patients with locally advanced breast carcinoma to
neoadjuvant chemotherapy using [technetium 99m]-sestamibi
scintimammography. Cancer. 1999;85:2410-2423.
10. Berg WA, Madsen KS, Schilling K, et al. Breast cancer: comparative
effectiveness of positron emission mammography and MR
8
imaging in presurgical planning for the ipsilateral breast. Radiology.
2011;258:59-72.
11. Brem RF, Floerke AC, Rapelyea JA, et al. Breast-specific gamma
imaging as an adjunct imaging modality for the diagnosis of
breast cancer. Radiology. 2008;247:651-657.
12. Tadwalkar RV, Rapelyea JA, Torrente J, et al. Breast-specific
gamma imaging as an adjunct modality for the diagnosis of
invasive breast cancer with correlation to tumour size and grade.
Br J Radiol. 2012;85:e212–e216.
13. Mankoff DA, Dunnwald LK, Kinahan P. Are we ready for
dedicated breast imaging approaches? J Nucl Med. 2003;44:
594-595.

Surgical Risk Reduction for Atypical Ductal Hyperplasia,
Lobular Carcinoma In Situ, and Ductal Carcinoma In Situ
With wide-spread screening mammography, high-risk
breast lesions including atypical ductal hyperplasia
(ADH) and lobular carcinoma in situ (LCIS) are increasingly
diagnosed. These lesions are usually confirmed histologically
with image-guided–core-needle biopsy. About 15%
to 20% of patients with ADH or LCIS diagnosed using
core-needle biopsy will have ductal carcinoma in situ (DCIS)
or invasive cancer. 1 Because of this, excisional breast biopsy
is usually recommended after core-needle biopsy to exclude
a higher-stage lesion.
Although ADH and LCIS are associated with an increased
risk of breast cancer, surgical risk reduction is not frequently
performed. The most commonly performed riskreduction
procedure is bilateral skin-sparing mastectomy
with immediate reconstruction, which is associated with a
risk reduction of about 90%. 2 Surgical complications from
bilateral mastectomy occur in about 20% of patients. The
most common complications are infection, flap necrosis, and
loss of reconstruction. Survey studies indicate that most
patients are satisfied with their decision to undergo bilateral
mastectomy.
An increasing number of patients are undergoing surgical
risk reduction using bilateral nipple-sparing mastectomies
(NSM). Ideal candidates for NSM are younger patients,
nonsmokers, and nonobese patients. Generally, NSMs are
performed with either a radial or inframammary incision.
The ductal tissue beneath the nipple is excised and submitted
to pathology separately. If DCIS or invasive cancer is
identified in this tissue, the nipple-areolar complex is excised.
The cosmetic outcomes after NSM and reconstruction
are excellent. Nipple necrosis can occur in about 5% of
Author’s Disclosures of Potential Conflicts of Interest
Author
Tuttle, Todd M.*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
References
Todd M. Tuttle, MD
University of Minnesota, Minneapolis, MN
Consultant or
Advisory Role
1. Foster MC, Helvie MA, Gregory NE, et al. Lobular carcinoma
in situ or atypical lobular hyperplasia at core-needle biopsy: is
excisional biopsy necessary? Radiology. 2004;231:813-819.
2. Lostumbo L, Carbine NE, Wallace J. Prophylactic mastectomy for
the prevention of breast cancer. Cochrane Database Syst Rev.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002748.
pub3/abstract. Accessed June 25, 2012.
3. Fisher ER, Dignam J, Tan-Chiu E, et al. Pathologic findings from
the National Surgical Adjuvant Breast Project (NSABP) eightyear
update of Protocol B-17: intraductal carcinoma. Cancer.
1999;86:429-438.
patients. The occurrence of cancer in the nipple-areolar
complex after NSM is extremely rare.
Today, DCIS is usually detected by screening mammography
and diagnosed by image-guided–core-needle biopsy.
However, approximately 15% of patients with DCIS who are
diagnosed by core-needle biopsy will have invasive cancer
identified in the excision or mastectomy specimen. Local
treatment options for DCIS include breast-conserving surgery
(BCS) alone, BCS plus radiation, or mastectomy. Indications
for mastectomy include multicentric disease, a large
area of microcalcifications, inability to obtain negative surgical
margins, and contraindications to radiation therapy.
BCS without radiation therapy is primarily used for older
patients or those with other significant health problems.
Radiation therapy after breast-conserving surgery markedly
reduces the risk of local recurrence.
In NSABP B17, a negative surgical margin after BCS was
defined as no ink on tumor. 3 Retrospective, single-center
studies have reported lower local recurrence rates with
wider margins. 4 A recent meta-analysis found no advantage
with margins wider than 2 mm. 5 Presently, sentinel lymphnode
biopsy is not routinely recommended for patients with
DCIS; however, sentinel lymph-node biopsy should be considered
for patients with microinvasion, palpable masses, or
mastectomy treatment.
Surgical risk reduction for DCIS is performance of a
contralateral prophylactic mastectomy (CPM). For DCIS,
the annual risk of developing metachronous contralateral
breast cancer is about 0.5% to 0.6% per year. 6 The performance
of CPM will significantly reduce the risk of contralateral
breast cancer. The use of CPM in the United States for
DCIS has markedly increased during the past decade. 7
Stock
Ownership Honoraria
Research
Funding
Expert
Testimony
Other
Remuneration
4. Silverstein MJ, Lagios MD, Groshen S, et al. The influence of
margin width on local control of ductal carcinoma in situ of the
breast. N Engl J Med. 1999;340:1455-1461.
5. Dunne C, Burke JP, Morrow M, et al. Effect of margin status on
local recurrence after breast conservation and radiation therapy
for ductal carcinoma in situ. J Clin Oncol. 2009;27:1615-1620.
6. Gao X, Fisher SG, Emami B. Risk of second primary cancer in the
contralateral breast in women treated for early-stage breast cancer:
a population-based study. Int J Radiat Oncol Biol Phys.
2003;56:1038-1045.
7. Tuttle TM, Jarosek S, Habermann EB, et al. Increasing rates of
contralateral prophylactic mastectomy among patients with ductal
carcinoma in situ. J Clin Oncol. 2009;27:1362-1367.
9

Prevention Strategies for Women at High Risk and for Those
with Lobular or Ductal Carcinoma In Situ
Tamoxifen is a selective estrogen-receptor modulator
(SERM) and is approved by the U.S. Food and Drug
Administration for breast cancer risk reduction in both
premenopausal and postmenopausal women. Three phase
III randomized trials prospectively evaluated tamoxifen
compared with placebo for breast cancer risk reduction
(Table 1). The combined reduction in invasive breast cancer
and ductal carcinoma in situ (DCIS) with tamoxifen use
compared with placebo was 34% to 38%. There was no
reduction in the risk of estrogen receptor (ER)-negative
breast cancer, but the incidence of ER-positive breast cancer
decreased by 48%. Age had no apparent effect on the relative
degree of breast cancer risk reduction. For noninvasive
breast cancer occurring in the National Surgical Adjuvant
Breast and Bowel Project (NSABP) Breast Cancer Prevention
Trial (BCPT), the reduction in risk was 50%. Among
women with a history of lobular carcinoma in situ (LCIS),
the reduction in risk was 56%, and among women with a
history of atypical hyperplasia, the reduction in risk was
86%. 1-9
The STAR trial randomly assigned 19,747 postmenopausal
women with a 5-year increased risk of breast cancer
to tamoxifen or raloxifene for 5 years (Fig. 1). The primary
end point was a reduction in breast cancer risk. More than
Table 1. Summary of Tamoxifen Chemoprevention Trials
10
Trial
Breast Cancer
Prevention Trial
(BCPT, NSABP
P-1) 1,2
International Breast
Intervention
Study I 5
Italian Tamoxifen
Prevention
Study 4
All tamoxifen
prevention trials 3
Victor G. Vogel, MD, MHS
Geisinger Health System, Danville, PA
Subject
Characteristics Population
High breast cancer
risk (age � 60
years or a
combination of
risk factors using
the Gail model);
39% � 50 years
Women 35 to 70
years who were
at increased risk
for breast cancer
Women with
hysterectomy
(48% bilateral
oophorectomy);
median age 51
years
� 1.66% 5-year
risk
� two-fold
relative risk
Normal risk,
hysterectomy
32% of STAR participants had a history of breast LCIS or
atypical hyperplasia (AH) compared with 15% of NSABP-P1
participants. The incidence of invasive breast cancer in the
tamoxifen and raloxifene groups was not significantly
different. 10-13 Patients with a history of LCIS or AH have a
four-fold to 10-fold increased risk of subsequent invasive
disease, and in the initial STAR report, tamoxifen and raloxifene
were equally effective in reducing that risk. That is no
longer the case for those with a history of atypical hyperplasia
(relative risk [RR]: 1.48; 95% CI [1.06-2.09], comparing
raloxifene with tamoxifen), although results for the
LCIS group remain similar to those originally reported (RR:
1.13; 95% CI [0.76-1.69]).
In the PEARL trial, 8,556 postmenopausal women with
low-bone density and normal mammograms were randomly
assigned to lasofoxifene (0.25 mg and 0.5 mg) or placebo. 14
The primary endpoints of the PEARL trial were incidence of
ER-positive breast cancer and nonvertebral fractures at
5 years. Compared with placebo, 0.5 mg of lasofoxifene
reduced the risk of total breast cancer by 79% and ERpositive
invasive breast cancer by 83% (hazard ratio [HR]:
0.17; 95% CI [0.05-0.57]). One clinical trial examined the
effect of an aromatase inhibitor on the risk of developing
either invasive or noninvasive breast cancer. In the
Number
Randomized
Intended
Duration
of
Treatment
Breast Cancer
Risk Reduction
13,388 5 years Overall: 49%
Ductal carcinoma in
situ: 50%
With prior lobular
carcinoma in situ:
55%
With prior atypical
hyperplasia: 86%
7,152 5 years Overall: 32%
5,408 5 years Overall: no reduction;
in the high-risk
subset, 82%
28,442 Overall: 38%
Estrogen receptorpositive,
invasive:
48%

Fig. 1. Forest plots of the risk of breast cancer from
placebo-controlled trials of tamoxifen or raloxifene,
with pooled estimates overall and for each treatment
separately. 6
Author’s Disclosures of Potential Conflicts of Interest
Author
Vogel, Victor G.*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
References
Consultant or
Advisory Role
1. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for
prevention of breast cancer: Report of the National Surgical
Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer
Inst. 1998;90:1371-1388.
2. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the
prevention of breast cancer: current status of the National Surgical
Adjuvant Breast and Bowel Project P-1 Study. J Natl
Cancer Inst. 2005;97:1652-1662.
Canadian-based MAP3 trial, a total of 4,560 postmenopausal
women at an increased risk of developing breast
cancer were randomly assigned to either exemestane or
placebo. 15 At 35 months, there was a 65% relative reduction
in the annual incidence of invasive breast cancer, and the
annual incidence of invasive plus noninvasive (DCIS) breast
cancers was 0.35% on exemestane and 0.77% on placebo
(HR: 0.47; 95% CI [0.27-0.79]; p�0.004). Combined LCIS
and AH were reduced 64% in the exemestane group (HR:
0.36; 95% CI [0.11-1.12]).
ECOG study E5194 included 670 patients with DCIS
treated with surgical excision without irradiation. The
Oncotype DX assay was performed by quantitative reverse
transcription polymerase chain reaction using
formalin-fixed paraffin embedded tumor specimens
from 49% of the patients. Recurrence score was calculated
using the published algorithm. This multigene
assay may provide individualized selection of treatment
for patients with DCIS.
A number of other drugs including retinoids, statins,
NSAIDS, and COX-2 inhibitors are being investigated for
their potential use in the reduction of breast cancer risk
(including ER-negative disease), but none is yet approved
for use outside of a clinical trial.
Conclusion
The ASCO Clinical Practice Guideline Update on the Use of
Pharmacologic Interventions Including Tamoxifen, Raloxifene,
and Aromatase Inhibition for Breast Cancer Risk
Reduction published in 2009 recommends that tamoxifen
be offered to reduce the risk of invasive ER-positive breast
cancer in women who are at an increased risk for breast
cancer, with benefits for at least 10 years. 16 In postmenopausal
women, raloxifene may also be considered. Use of
aromatase inhibitors or other SERMs to lower breast cancer
risk is not recommended outside of a clinical trial. ASCO
believes that discussion of risks and benefits of preventive
agents by health providers is critical to patient decision
making. 17-20
Stock
Ownership Honoraria
Research
Funding
EDUCATIONAL SUMMARIES
Expert
Testimony
Other
Remuneration
3. Cuzick J, Powles T, Veronesi U, et al. Overview of the main
outcomes in breast-cancer prevention trials. Lancet. 2003;361:
296-300.
4. Veronesi, U, Maisonneuve P, Rotmensz N, et al. Tamoxifen for
the Prevention of Breast Cancer: late results of the Italian randomized
tamoxifen prevention trial among women with hysterectomy.
J Natl Cancer Inst. 2007;99:727-737.
5. Cuzick J, Forbes JF, Sestak I, et al. Long-term results of tamoxifen
prophylaxis for breast cancer: 96-month follow-up of the
randomized IBIS-I trial. J Natl Cancer Inst. 2007;99:272-282.
11

EDUCATIONAL SUMMARIES
6. Cummings SR, Tice JA, Bauer S, et al. Prevention of breast
cancer in postmenopausal women: approaches to estimating and
reducing risk. J Natl Cancer Inst. 2009;101:384-398.
7. Gail, MH, Costantino JP, Bryant J, et al. Weighing the risks and
benefits of tamoxifen treatment for preventing breast cancer.
J Natl Cancer Inst. 1999;91:1829-1846.
8. Freedman AN, Costantino JP, Gail MH, et al. A benefit/risk
assessment tool for breast cancer chemoprevention treatment.
J Clin Oncol. 2011; 29:2327-2333.
9. Goetz MP, Schaid DJ, Wickerham DL, et al. Evaluation of
CYP2D6 and efficacy of tamoxifen and raloxifene in women
treated for breast cancer chemoprevention: Results from the
NSABP P-1 and P-2 clinical trials. Clin Cancer Res. 2011;17:
6944-6951.
10. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen
vs raloxifene on the risk of developing invasive breast cancer
and other disease outcomes: The NSABP Study of tamoxifen and
raloxifene (STAR) P-2 Trial. JAMA. 2006;295:2727-2741.
11. Land SR, Wickerham DL, Costantino JP, et al. Patient-reported
symptoms and quality of life during treatment with tamoxifen or
raloxifene for breast cancer prevention: The NSABP study of
tamoxifen and raloxifene (STAR) P-2 trial. JAMA. 2006;295:
2742-2751.
12. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the
NSABP study of tamoxifen and raloxifene (STAR) P-2 Trial:
Preventing breast cancer. Cancer Prev Res. 2010;3:696-706.
13. Vogel VG, Costantino JP, Wickerham DL, et al. Carcinoma in
situ outcomes in National Surgical Adjuvant Breast and Bowel
12
Project Breast Cancer Chemoprevention Trials. J Natl Cancer
Inst Monographs. 2010;2010:181-186.
14. LaCroix AZ, Powles T, Osborne CK, et al. Breast cancer incidence
in the randomized PEARL trial of lasofoxifene in postmenopausal
osteoporotic women. J Natl Cancer Inst. 2010;102:
1706-1717.
15. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for
breast-cancer prevention in postmenopausal women. N Engl
J Med. 2011;364:2381-2391.
16. Visvanathan K, Chlebowski RT, Hurley P, et al. American Society
of Clinical Oncology practice guideline update on the use of
pharmacologic intervention including tamoxifen, raloxifene, and
aromatase inhibition for breast cancer risk reduction. J Clin
Oncol. 2009;27:3235-3258.
17. Vogel VG. Managing the risk of invasive breast cancer in women
at risk for breast cancer and osteoporosis: The role of raloxifene.
Clin Interv Aging. 2008;3:609-609.
18. Zon RT, Goss E, Vogel VG, et al. American Society of Clinical
Oncology Policy Statement: The Role of the Oncologist in Cancer
Prevention and Risk Assessment. J Clin Oncol. 2009;27:986-993.
19. Cuzick J. DeCensi A, Arun B, et al. Preventive therapy for breast
cancer: An international consensus statement. Lancet Oncol.
2011;12:496-503.
20. Rastogi P, Lo S, Vogel VG. Chemoprevention: clinical aspects. In:
Harris J, Lippman M, Morrow M, Osborne CK (eds). Diseases of
the Breast, 4th edition. Philadelphia, J.B. Lippincott, 2010;302-
319.

GENERAL SESSION III:
Controversies in Diagnosis of Early-Stage Breast Cancer and
Management of Sentinel Nodes
CO-CHAIRS
Jennifer Bellon, MD
Dana-Farber Cancer Institute
Richard Bleicher, MD
Fox Chase Cancer Center
SPEAKERS
Kathryn Evers, MD
Fox Chase Cancer Center
Constance D. Lehman, MD, PhD
Seattle Cancer Care Alliance
After this session, attendees should be able to
● Assess the pros and cons of routine breast magnetic resonance imaging use for the diagnosis and preoperative evaluation
of the non–high-risk patient with breast cancer
● Compare and contrast the Z0011 surgical and radiation approaches to nodal management of sentinel node positive
disease with MA.20, considering the unique patient characteristics that would impact management decisions

Magnetic Resonance Imaging Debate: Con
T
he role of magnetic resonance imaging (MRI) in the
diagnosis and evaluation of breast carcinoma continues
to evolve. Contrast-enhanced breast MRI is an extremely
sensitive tool for the diagnosis of carcinoma, and
the role of MRI in women at high risk for the development
of breast carcinoma is well established at this time. Additionally,
MRI is extremely useful in the scenario of proven
axillary metastasis with no primary tumor visible on mammography
or ultrasound. In this case, demonstration of
the primary lesion can potentially allow the patient to have
breast-conserving therapy. Similar benefits can be seen in
patients with Paget’s disease of the nipple. In women with
dense breasts, MRI is considerably more sensitive than
mammography.
For the evaluation of the patient with a new diagnosis
of breast carcinoma, the role of MRI remains considerably
more controversial. At this time in many practices, treatment
planning for patients with newly diagnosed carcinoma
is the most common reason for diagnostic breast MRI. 1 This
occurs despite the lack of strong evidence for the utility of
MRI in this setting.
There is good evidence that MRI is more accurate than
physical examination, mammography, or ultrasound for determining
tumor size. Additionally, the presence or absence
of invasion of the pectoralis muscle or the chest wall can be
accurately assessed. Skin thickening, which may be subtle
on physical examination, may be identified on breast MRI.
The fact that MRI is accurate at estimating tumor size has
been extended to mean that the use of MRI will allow a
decrease in close or positive surgical margins. Initially,
there was considerable enthusiasm for using MRI to increase
the rate of negative margins at lumpectomy and to
decrease the number of second procedures or conversions
to mastectomy required for patients scheduled for breastconserving
therapy.
Significant improvement in the rate of second procedures
for patients who are potential candidates for breastconserving
therapy is an ambitious undertaking, since historical
success rates for this procedure are 90% to 97%. 2,4
Several studies have found no significant improvement in
margin status in women undergoing preoperative MRI. 5,6 A
recent meta-analysis 7 reports that foci of disease visible only
on MRI are found in 16% of cases, with appropriate conversion
to more extensive surgery in approximately 11%
of cases (3% more extensive resection and 8% conversion
to mastectomy). Conversion to more extensive treatment
occurred in approximately 5% of patients based on MRI
findings where no additional malignancy was found at pathology.
The overall false–positive rate has been reported as
1% to 28%. Given these statistics, it is imperative that
additional findings on MRI be confirmed with core biopsy
prior to surgery (Fig. 1).
The largest prospective, randomized controlled trial evaluating
the effectiveness of MRI is the Comparative Effec-
14
Kathryn Evers, MD
Fox Chase Cancer Center, Philadelphia, PA
Fig. 1. Multiple areas of enhancement in a patient
with known breast carcinoma. Shown is a single
subtraction image of the initial postcontrast image
in a patient sent for surgical treatment planning.
The patient’s known primary tumor and a satellite
mass (arrows) in the upper right breast are shown.
A small enhancing mass in the lower right breast
(arrowhead) proved to be a fibroadenoma on core
biopsy.
tiveness of MRI in Breast Cancer (COMICE) trial, 8 which
was performed in Great Britain. In this trial, patients who
were scheduled for wide excisions for breast carcinoma were
randomly assigned to receive or not receive MRI preoperatively.
The results showed that patients in the MRI arm had
an equal number of re-excisions or conversion to mastectomy
as the patients in the non-MRI arm. Moreover, in 58
cases where there were abnormal results, 27.6% of patients
had a mastectomy that was felt to be avoidable based on
pathology results.
The Dutch MR Mammography of Nonpalpable Breast
Tumors (MONET) trial 9 randomly assigned patients with
suspicious imaging (BI-RADS 3, 4, and 5) to MRI and non-
MRI arms. The endpoint of this trial was the rate of additional
surgical procedures (re-excision and conversion to
mastectomy). In this trial, MRI was associated with an
increased re-excision rate for positive margins, although it
was not statistically significant. It has been noted that there
is an increased use of mastectomy, stage for stage, with the
use of MRI. This has been reported as a 20% to 30% unnecessary
mastectomy rate 10 or as a stage-specific likelihood of
undergoing mastectomy approximately 1.8 times more than
patients who did not have MRI. 11

Small foci of additional disease appear to be adequately
treated in patients who have had lumpectomy and wholebreast
radiation therapy because the recurrence and survival
rates are equivalent to that of patients treated with
mastectomy. Therefore, the utility of detecting additional
small foci of disease is unclear. The same is not true for
patients receiving accelerated partial-breast irradiation, as
additional small foci may not be adequately treated.
MRI is also capable of identifying occult carcinoma in the
contralateral breast. In 2007, Lehman 12 reported a 3.1%
rate of contralateral carcinoma found only by MRI. The
false–positive rate remains relatively high in this regard
as recommendations for biopsy in this setting range from
13% to 32%, 13 although this is somewhat lower in more
recent studies. Relapse in the contralateral breast is low,
reported as 2% to 4% over 5 years. A study by Solin in 2008 14
Author’s Disclosures of Potential Conflicts of Interest
Author
Evers, Kathryn*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
References
Consultant or
Advisory Role
1. Bassett LW, Dhaliwal SG, Eradat J, et. al. National trends and
practices in breast MRI. AJR Am J Roentgenol. 2008;191:332-
339.
2. Fisher B, Bauer M, Margolese R, et al. Five-year results of a
randomized clinical trial comparing total mastectomy and segmental
mastectomy with or without radiation in the treatment of
breast cancer. N Engl J Med. 1985;312:665-673.
3. Blichert-Toft M, Rose C, Andersen JA, et al. Danish randomized
trial comparing breast conservation therapy with mastectomy:
six years of life-table analysis. Danish Breast Cancer Cooperative
Group. J Natl Cancer Inst Monogr. 1992:11:19-25.
4. Morrow M, Strom E, Bassett LW, et al. Standard for breast
conservation therapy in the management of invasive breast carcinoma.
CA Cancer J Clin. 2002;52:277-300.
5. Bleicher RJ, Ciocca RM, Egleston BL, et al. Association of routine
pretreatment magnetic resonance imaging with time to surgery,
mastectomy rate and margin status. J Am Coll Surg. 2009;
209:180-187.
6. Pengel KE, Loo CE, Teertstra HJ, et al. The impact of preoperative
MRI on breast-conserving surgery of invasive cancer: a
comparative cohort study. Breast Cancer Res Treat. 2009;116:
161-169.
7. Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical
impact of magnetic resonance imaging in breast cancer staging:
Systematic review and meta-analysis in detection of multifocal
and multicentric cancer. J Clin Oncol. 2008;26:3248-3258.
8. Turnbull LW, Brown SR, Olivier C, et al. Multicentre randomised
controlled trial examining the cost-effectiveness of
showed no change in the contralateral breast cancer rate
of patients who have or have not had breast MRI. It is
unclear whether detection of these tumors will influence
survival.
To date, there is no evidence that the use of preoperative
MRI will result in improved survival. Solin 14 reported no
change in 8-year survival. A study 1 year later reported a
nonstatistically significant trend towards improved survival.
15 Neither of these trials demonstrate sufficient
follow-up that could evaluate whether or not MRI will effect
survival.
In conclusion, breast MRI is a powerful tool with numerous
indications. At this time, its usefulness in the setting
of newly diagnosed breast cancer is unproven with no demonstrable
benefit in decreasing reoperation or improving
survival.
Stock
Ownership Honoraria
Research
Funding
EDUCATIONAL SUMMARIES
Expert
Testimony
Other
Remuneration
contrast-enhanced high field magnetic resonance imaging in
women with primary breast cancer scheduled for wide local
excision (COMICE). Health Technol Asses. 2010;14:1-182.
9. Peters NH, van Esser S, van den Bosch MA, et al. Preoperative
MRI and surgical management in patients with nonpalpable
breast cancer: The MONET-Randomised controlled trial. Eur J
Cancer. 2011;42:879-886.
10. Bedrosian I, Mick R, Orel SG, et al. Changes in the surgical
management of patients with breast carcinoma based on preoperative
magnetic resonance imaging. Cancer. 2003;98:468-473.
11. Katipamula R ,Degnim AC, Hoskin T, et al. Trends in mastectomy
rates at the Mayo Clinic Rochester: effect of surgical year
and preoperative magnetic resonance imaging. J Clin Oncol.
2009;27:4082-4088.
12. Lehman CD, Gatsonis C, Kuhl CK, et al. MRI evaluation of the
contralateral breast in women with recently diagnosed breast
cancer. N Engl J Med. 2007;356:1295-1303.
13. Liberman L, Morris EA, Kim CM, et al. MR imaging findings in
the contralateral breast of women with recently diagnosed breast
cancer. AJR Am J Roentgenol. 2003;180:333-341.
14. Solin LJ, Orel SG, Hwang WT, et al. Relationship of breast
magnetic resonance imaging to outcome after breastconservation
treatment with radiation for women with earlystage
invasive breast carcinoma or ductal carcinoma in situ.
J Clin Oncol. 2008;26:386-391.
15. Hwang WT, Schiller DE, Crystal P, et al. Magnetic resonance
imaging in the planning of initial lumpectomy for invasive breast
carcinoma: its effect on ipsilateral breast tumor recurrence after
breast-conservation therapy. Ann Surg Oncol. 2009;16:3000-
3009.
15

GENERAL SESSION IV:
Controversies in Local/Regional Treatment
CO-CHAIRS
Robert Kuske, MD
Arizona Breast Cancer Specialists
Lori J. Pierce, MD
University of Michigan School of Medicine
SPEAKERS
Thomas B. Julian, MD
National Surgical Adjuvant Breast and Bowel Project (NSABP)
Abram Recht, MD
Harvard Medical School and Beth Israel Deaconess Medical Center
Jayant S. Vaidya, PhD
University College London
Julia White, MD
The Ohio State University Comprehensive Cancer Center
After this session, attendees should be able to
● Examine the outcomes of a randomized trial using intraoperative radiation therapy and determine how the results of the
trial may impact the use of this therapy in the treatment of patients with breast cancer
● Review the use of intraoperative radiation therapy as a treatment option for patients with breast cancer from the
perspective of potential benefits, such as preservation of breast tissue and shortened treatment periods
● Investigate the use of local radiation therapy in the treatment of patients with ductal carcinoma in situ, including how
this treatment option impacts disease pathology and ultimately patient outcomes

Debate on the Role of Local Radiation Therapy in Ductal
Carcinoma In Situ: Pro
Shivani Duggal, DO, and Thomas B. Julian, MD
Allegheny Cancer Center at Allegheny General Hospital and the National Surgical
Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA
T
he incidence of ductal carcinoma in situ (DCIS) has
seen a dramatic rise in the United States, particularly
over the last 3 decades. This increase parallels improvements
in imaging techniques. Since the utilization of
screening mammography in the 1980s, DCIS now accounts
for 14% to 30% of all diagnosed breast cancers; before such
screening, DCIS was a rare entity, representing 2% of reported
breast cancers. 1 Today, 1 in 1,300 mammograms will
result in the detection of DCIS. 2
As the incidence of DCIS rises, so does the need for
improved treatment strategies. In-breast tumor recurrence
(IBTR) remains the most common first failure event in the
management of DCIS. While mastectomy was once the
standard treatment for DCIS, with recurrence rates as low
as 1.4%, 3,4 breast-conserving surgery (BCS) and the use of
radiation therapy (RT) has now gained widespread acceptance
as an alternative approach. While BCS and RT has
been shown to be effective in local control, it is the adjuvant
RT treatment following BCS for DCIS that remains controversial.
Because the decision to add RT after surgical treatment
of DCIS is not straightforward, there is significant
heterogeneity in the management of DCIS. A populationbased
analysis 5 has shown that there is regional variation
in the use of adjuvant RT; approximately 50% of patients
do not receive RT for DCIS after BCS. This variation may
be due to differences in the perceived risk of recurrence.
The phase III, randomized National Surgical Adjuvant
Breast and Bowel Project (NSABP) B-17 6,7 clinical trial
along with three other prospective randomized clinical
trials 8-10 and their follow-up studies, 11,12 have demonstrated
and continue to show the benefit of RT following
segmentectomy, with a 50% reduction in local recurrence
rates for both DCIS and invasive breast cancer. In a report
by Wapnir and colleagues on long-term outcomes of the
NSABP B-17 and B-24 trials, patients who only received
lumpectomy had a local recurrence rate of 19.4% compared
with 8.9% in the lumpectomy-positive RT group at 15 years
of follow up, demonstrating a 52% reduction in the risk of
IBTR. 13
Studies have also been conducted based on the premise
that we may be overtreating patients with DCIS. The Eastern
Cooperative Oncology Group (ECOG) E5194 trial 14 prospectively
evaluated clinical features to identify a low-risk
Authors’ Disclosures of Potential Conflicts of Interest
population with DCIS in whom BCS alone was adequate. To
the disappointment of the study investigators, 20% of these
patients had local recurrence. The negative outcome of
E5194 eventually provided useful insight about the clinical
application of and benefits from RT. A follow-up study used
adjuvant whole-breast irradiation (WBI) in patients with
DCIS who met the criteria of E5194. Results showed that
WBI reduced the rate of local recurrence in this patient
population by more than 70%. 15 Similarly, Wong and colleagues
attempted to demonstrate that wide excision with
margins larger than or equal to 1 cm alone was adequate in
the treatment of small grade 1 or 2 DCIS. This prospective,
single-arm clinical trial closed early to accrual because the
number of local recurrences met the established stopping
criteria of the study. The study concluded that despite wide
margins, the local recurrence rate of DCIS after excision
alone is substantial enough to warrant adjuvant therapy
with radiation with or without antihormonal therapy. 16
With such compelling data supporting the need for RT
in the treatment of DCIS, attention may be better focused
on the various modalities of RT offered today, rather than
on whether to implement it or not. These include hyperand
hypofractionated WBI and accelerated partial-breast
irradiation (APBI), which is comprised of catheter-based
brachytherapy, three-dimensional conformal externalbeam
irradiation, or single-fraction intraoperative partialbreast
irradiation. The majority of early data on APBI is
encouraging, with local failure rates similar to those of
conventional WBI, 17 along with the added benefits of
shorter duration of therapy, reduced local and chronic toxicity,
and improved cosmesis and quality of life (QOL). The
phase III prospective randomized NSABP B-39/Radiation
Therapy Oncology Group (RTOG) 0413 trial evaluating the
effectiveness of APBI compared with WBI following BCS for
DCIS as well as early-stage invasive breast cancer will further
explore the benefits of APBI. That trial will evaluate
IBTR, overall survival, disease-free survival, distant DFS,
QOL issues, and the perceived convenience of care. 18
Until we have identified predictive factors to tailor treatment
for individual patients, all patients with DCIS are
candidates for radiation therapy because we cannot yet
clearly identify those in whom it is not beneficial.
Employment or
Leadership Consultant or Stock
Research
Author
Positions Advisory Role Ownership Honoraria Funding
Duggal, Shivani
Julian, Thomas B.*
*No relevant relationships to disclose.
Komen Foundation
Expert
Testimony
Other
Remuneration
17

EDUCATIONAL SUMMARIES
References
1. Baxter NN, Virnig BA, Durham SB, et al. Trends in the treatment
of ductal carcinoma in situ of the breast. J Natl Cancer Inst.
2004;96:443-448.
2. Ernster VL, Ballard-Barbash R, Barlow WE, et al. Detection of
ductal carcinoma in situ in women undergoing screening mammography.
J Natl Cancer Inst. 2002;94:1546-1554.
3. Boyages J, Delaney G, Taylor R. Predictors of local recurrence
after treatment of ductal carcinoma in situ: a meta-analysis.
Cancer. 1999;85:616-628.
4. Rashtian A, Iganej S, Liu IA, et al. Close or positive margins after
mastectomy for DCIS: Pattern of relapse and potential indications
for radiotherapy. Int J Radiation Oncology Biol Phys. 2008;72:
1016-1020.
5. Rakovitch E, Pignol JP, Chartier C, et al. The management of
ductal carcinoma in situ of the breast: A screened populationbased
analysis. Breast Cancer Res Treat. 2007;101:335-347.
6. Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared
with lumpectomy and radiation therapy for the treatment of
intraductal breast cancer. N Engl J Med. 1993;328:1581-1586.
7. Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation
therapy for the treatment of intraductal breast cancer: findings
from National Surgical Adjuvant Breast and Bowel Project B-17.
J Clin Oncol. 1998;16:441-452.
8. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy
Group; Bijker N, Meijnen P, et al. Breast-conserving
treatment with or without radiotherapy in ductal carcinoma-insitu:
ten-year results of European Organisation for Research and
Treatment of Cancer randomized phase III trial 10853—a study
by the EORTC Breast Cancer Cooperative Group and EORTC
Radiotherapy Group. J Clin Oncol. 2006;24:3381-3387.
9. Houghton J, George WD, Cuzick J, et al. UK Coordinating Committee
on Cancer Research; Ductal Carcinoma in situ Working
Party; DCIS trialists in the UK, Australia, and New Zealand.
Radiotherapy and tamoxifen in women with completely excised
ductal carcinoma in situ of the breast in the UK, Australia, and
18
New Zealand: Randomised controlled trial. Lancet. 2003;362:95-
102.
10. Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reductions
for local recurrence after postoperative radiotherapy after
sector resection for ductal carcinoma in situ of the breast. J Clin
Oncol. 2008;26:1247-1252.
11. Solin, LJ. The impact of adding radiation treatment after breast
conservation surgery for ductal carcinoma in situ of the breast.
J Natl Cancer Inst Monogr. 2010;41:187-192.
12. Bijker N, van Tienhoven G. Local and systemic outcomes in
DCIS based on tumor and patient characteristics: The radiation
oncologist’s perspective. J Natl Cancer Inst Monogr. 2010;2010:
178-180.
13. Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of
invasive ipsilateral breast tumor recurrences after lumpectomy
in NSABP B-17 and B-24 randomized clinical trials for DCIS.
J Natl Cancer Inst. 2011;103:478-488.
14. Hughes LL, Wang M, Page DL, et al. Local excision alone without
irradiation for ductal carcinoma in situ of the breast: A trial of
the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:
5319-5324.
15. Motwani SB, Goyal S, Moran MS, et al. Ductal carcinoma in situ
treated with breast-conserving surgery and radiotherapy: a comparison
with ECOG Study 5194. Cancer. 2011;117:1156-1162.
16. Wong JS, Kaelin CM, Troyan SL, et al. Prospective study of wide
excision alone for ductal carcinoma in situ of the breast. J Clin
Oncol. 2006;24:1031-1036.
17. Vicini F, Beitsch P, Quiet C, et al. Five-year analysis of treatment
efficacy and cosmesis by the American Society of Breast Surgeons
MammoSite Breast Brachytherapy Registry Trial in patients
treated with accelerated partial breast irradiation. Int J
Radiat Oncol Biol Phys. 2011;79:808-817.
18. Arthur DW, Kuerer HM, Haffty B, et al. A phase II study of
repeat breast preserving surgery and 3D-conformal partial
breast re-irradiation (PBRI) for local recurrence of breast carcinoma.
Radiation Therapy Oncology Group (RTOG) 1014. http://
rpc.mdanderson.org/rpc/credentialing/files/1014.pdf. Accessed
May 24, 2012.

Targeted Intraoperative Radiotherapy: Analysis of a
Randomized Trial—The TARGIT-A Trial
Jayant S. Vaidya, MBBS, MS, DNB, PhD
University College London, London, United Kingdom
On behalf of the TARGIT Trialists Group
We have previously published preclinical, 1,2 clinical, 3-5
radiobiological, and translational 6-8 studies that support
the use of targeted intraoperative radiotherapy
(TARGIT). In June 2010, we published the results of the
TARGIT-A multicenter, randomized clinical trial 9 that
compared “one-size-fits-all” radiotherapy (whole breast
radiotherapy-external beam radiotherapy [EBRT] group)
with risk-adjusted radiotherapy (single-dose TARGIT with
additional whole breast radiotherapy only if adverse prognostic
factors were found).
Trial eligibility criteria are described previously; 9 briefly,
patient were eligible if they were older than 45 and had
invasive duct carcinoma less than approximately 3.5 cm
that was suitable for breast-conserving surgery. In the trial,
82% of patients were less than age 70, and 64% of tumors
were more than 1 cm; 85% of tumors were less than 2 cm
and grades 1 or 2; 83% were node negative; and 90% were
ER positive. Within the TARGIT group, whole breast radiotherapy
was recommended if margins were positive (� 1
mm) at therapeutic excision before giving intraoperative
radiotherapy, extensive in situ component, or unexpected
invasive lobular carcinoma, or other adverse prognostic factors
(such as multiple positive nodes, lymphovascular invasion,
etc.) as predefined in each center’s treatment policy
document. In such cases, TARGIT served as a tumor-bed
boost. We concluded that the risk of local recurrence in the
TARGIT group was noninferior to that of the EBRT group
(the difference between the two arms was 0.25% at 4 years).
When the TARGIT-A trial was launched internationally,
10 we expected the background recurrence rate to be
6%. We chose to use an absolute difference in local recurrence,
2.5%, as a noninferiority margin. The sample size
needed was 2,232 patients. However, over the last decade,
the local recurrence rates of breast cancer have plummeted;
the Standardisation of Breast Radiotherapy (START) trial
reported a local recurrence rate of 2.3%, 11 and when we
analyzed the data for the TARGIT-A trial, we found that the
Kaplan-Meier estimate of local recurrence at 5 years was
1.5%. In the main paper 9 and in subsequent correspondence,
12 we have discussed the rationale for retaining the
absolute difference of 2.5% as an acceptable noninferiority
margin.
In addition, we discussed the issue of absolute versus
relative risks. It was suggested that risk ratios should be
used for our power calculations. However, when the recurrence
rates are so low, risk ratio is less informative at best
and misleading at worst. In any case, power calculations
fade into insignificance when faced with the reality of our
observations. We found that the actual difference between
the local recurrence rate of the two groups was 0.25%
(1.2% vs. 0.95%, p � 0.41), which is 10 times lower than our
original margin of noninferiority.
Furthermore, one can estimate the effect of a 2.5% absolute
difference in local recurrence at 5 years, on breast
cancer mortality at 15 years, using the 1:4 ratio derived
from the Oxford overview. Thus, a 2.5% difference at 5 years
can be expected to make a difference of 0.625% in mortality
at 15 years, arguably a value that is clinically acceptable. In
fact, we estimated 9 that the number of patients needed to
detect a 2.5% difference with a background of 1.5% was
much smaller than we had recruited for. We would have
only needed 585 patients to have adequate power to detect
the difference between the two arms of the trial. When this
number (585) of patients reach a minimum 5 years of followup,
and if the difference between the two treatment arms is
less than 2.5%, we could be confident of the robustness of a
noninferior result.
What is the absolute difference that is acceptable? Hitherto
in the TARGIT-A trial, this decision was based on an
“intelligent and experienced” guess by the team of experienced
clinicians/researchers assisted by two patients with
breast cancer who sit on the steering/data monitoring committee.
The acceptable difference now has more empirical
evidence to support it. Sophisticated work using individual
patient interviews, conducted in Australia by Tammy Corica
and colleagues 13 and in the United States by Michael
Alvarado and colleagues, 14 suggests that 2.5% may be the
value that patients are ready to accept as an increased risk
of local recurrence as a trade-off for the convenience of a
single-dose intraoperative radiotherapy as opposed to several
weeks of daily radiotherapy. They would need to factor
in not only the inconvenience of several weeks of radiotherapy,
but also the fact that the quality of life of women
Fig. 1. Targeted intraoperative radiotherapy (TARGIT).
Meticulous surgical placement that opposes the
tumour bed to the spherical applicator, while protecting
the skin and deeper structures.
19

EDUCATIONAL SUMMARIES
Fig. 2. K-M estimate of local recurrence in TARGIT-A trial. Total blinded local recurrence rate in November
2012 compared with May 2010.
receiving intraoperative radiotherapy has been found to be
significantly better. 15
We had previously responded 12 to the criticisms about the
relatively short follow-up. As oft repeated, unplanned analysis
comparing two groups in a randomized trial can carry
the risk of a false–positive result. For this reason, we remained
blinded to the further recurrences in the trial according
to allocated treatment and proposed and performed
a blinded analysis of the local recurrence rate for the whole
cohort in November 2011, 18 months after the Lancet publication.
We plotted the Kaplan-Meier plots and estimated
the 4-year recurrence rate.
Among the first 2,232 patients who were randomly assigned,
there were 13 recurrences at the time of the Lancet
publication and by November 2011 we had confirmed 10
additional recurrences. Those who have completed at least 4
years of follow-up increased from 420 to 692. As seen in Fig.
2, we found that the 4-year Kaplan Meier estimate of total
local recurrence was 1.08% (95% CI 0.59-1.96) at the time of
the Lancet publication and in November 2011 it was 1.28%
(95% CI 0.77-2.13). Thus, with a longer follow-up, the overall
4-year rates of the TARGIT-A trial have remained low
and stable.
At the 12 th St. Gallen International Breast Cancer Conference
in March 2011, a consensus panel of 52 experts in
breast cancer voted in favor of intraoperative radiotherapy
as part of the acceptable treatment program for suitable
patients. When asked whether they would use partial breast
irradiation (intraoperative) as the only radiotherapy for
unselected patients, 48.9% said “yes,” 35.6% said “no,” and
15.6% said “don’t know.” However, when applied to se-
20
lected patients (e.g., older than age 70) only 6.7% said “no”
(86.7% said “yes” and 6.7% said “don’t know”). The panel
was also in favor of using intraoperative radiotherapy as a
tumor-bed boost instead of an EBRT boost (60.9% said
“yes,” 17.4% said “no,” and 21.7% said “don’t know”).
When patients wish to receive TARGIT as their definitive
radiation treatment, we usually follow these steps: make
the appropriate patient selection, per the characteristics of
trial patients (for example, older than age 50, invasive ductal,
T1, grade 1 or 2, ER-positive, etc.). Every patient is given
the literature: the Lancet paper 9 and the subsequent correspondence
in the Lancet, lay summary of the trial results, a
patient information leaflet approved by our institutions,
and website with previous literature (www.targit.org.uk).
We stress that this is only for selected patients and that
about 20% of patients will require whole breast radiotherapy.
We emphasize that the noninferiority results are at 4
years, and recurrence may be higher with longer follow-up.
The patient is given consultations with the surgeon and
radiation oncologist as well as several days to make their
decision. The case is discussed in a multidisciplinary team
meeting. We have developed a free iPhone app called
TARGIT, which may be used by clinicians while making a
decision about using TARGIT in different clinical situations,
with the usual disclaimers.
We are planning to close recruitment in the TARGIT-A
trial after completing over 3,400 patients in June 2012. We
plan to analyze and publish an unblinded analysis in autumn
of 2012, including an updated one of the first cohort of
2,232 patients.

Author’s Disclosures of Potential Conflicts of Interest
Employment or
Leadership Consultant or Stock
Author
Positions Advisory Role Ownership Honoraria
Vaidya, Jayant S. Carl Zeiss
References
1. Vaidya JS, Vyas JJ, Chinoy RF, et al. Multicentricity of breast
cancer: whole-organ analysis and clinical implications. Br J Cancer.
1996;74:820-824.
2. Baum M, Vaidya JS, Mittra I. Multicentricity and recurrence of
breast cancer. Lancet. 1997;349:208.
3. Vaidya JS, Baum M, Tobias JS, et al. Targeted intra-operative
radiotherapy (Targit): an innovative method of treatment for
early breast cancer. Ann Oncol. 2001;12:1075-1080.
4. Vaidya JS, Baum M, Tobias JS, et al. Long-term results of
targeted intraoperative radiotherapy (Targit) boost during
breast-conserving surgery. Int J Radiat Oncol Biol Phys. 2011;
81:1091-1097.
5. Kraus-Tiefenbacher U, Bauer L, Scheda A, et al. Long-term
toxicity of an intraoperative radiotherapy boost using low energy
X-rays during breast-conserving surgery. Int J Radiat Oncol Biol
Phys. 2006;66:377-381.
6. Belletti B, Vaidya JS, D’Andrea S, et al.. Targeted intraoperative
radiotherapy impairs the stimulation of breast cancer cell proliferation
and invasion caused by surgical wounding. Clin Cancer
Res. 2008;14:1325-1332.
7. Herskind C, Griebel J, Kraus-Tiefenbacher U, et al. Sphere of
equivalence—a novel target volume concept for intraoperative
radiotherapy using low-energy X rays. Int J Radiat Oncol Biol
Phys. 2008;72:1575-1581.
8. Herskind C, Wenz F. Radiobiological comparison of hypo-
Research
Funding
EDUCATIONAL SUMMARIES
Expert
Testimony
Other
Remuneration
fractionated accelerated partial-breast irradiation (APBI) and
single-dose intraoperative radiotherapy (IORT) with 50-kV
X-rays. Strahlenther Onkol. 2010;186:444-451.
9. Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative
radiotherapy versus whole breast radiotherapy for breast cancer
(TARGIT-A trial): an international, prospective, randomised,
noninferiority phase 3 trial. Lancet. 2010;376:91-102.
10. Vaidya JS. A novel approach for local treatment of early breast
cancer. http://www.ucl.ac.uk/�rmhkjsv/papers/thesis.htm. Accessed
June 10, 2012.
11. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation
of Breast Radiotherapy (START) Trial B of radiotherapy
hypofractionation for treatment of early breast cancer: a randomised
trial. Lancet. 2008;371:1098-1107.
12. Vaidya JS. Intraoperative radiotherapy for early breast cancer—
authors’ reply. Lancet. 2010;376:1143-1144.
13. Corica T, Nowak A, Saunders C, et al. Patient preferences
for adjuvant radiotherapy in early breast cancer—an Australian
substudy of the International TARGIT Trial [Abstract
482]. Eur J Cancer. 2012;48(suppl):S187.
14. Alvarado M, Connolly J, Oboite M, et al. Patient preference for
choosing intraoperative or external-beam radiotherapy following
breast conservation. Eur J Cancer Suppl. 2010;8:126-127.
15. Welzel G, Hofmann F, Blank E, et al. Health-related quality of
life after breast-conserving surgery and intraoperative radiotherapy
for breast cancer using low-kilovoltage X-rays. Ann Surg
Oncol. 2010;3:359-367.
21

Debate on the Role of Radiation Therapy in Ductal
Carcinoma In Situ: Con
Abram Recht, MD
Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA
O
ne can never be absolutely certain that there is no
residual ductal carcinoma in situ (DCIS) left after
breast-conserving surgery (BCS). Radiotherapy (RT),
therefore, should always reduce the risk of local failure,
as demonstrated in randomized trials (Table 1). 1-4 However,
in these trials recurrence rates in patients treated with BCS
alone were high. This was likely because these studies included
relatively unselected patients who were eligible if
there was no DCIS at the inked margins. A number of
prospective and retrospective studies showed ipsilateral local
failure rates of 5% to15% in certain patient subgroups
treated with BCS without RT (Table 2). 5-11 The two most
important factors determining the local failure rate following
BCS without RT appear to be nuclear grade and margin
width. (The effects of other factors, such as lesion size,
patient age, 12 and necrosis, 13 are more controversial.)
Patients with high-grade DCIS (whose main characteristic
is high nuclear grade, although exact definitions differ
from one group to the next) appear to have a substantial risk
of local recurrence by 5 years following BCS, with little
increase after that. 14 Patients with low- or intermediategrade
DCIS have much lower rates of recurrence by 5 years.
Their risk increases appreciably between years 5 and 10,
although not to the same ultimate level as patients with
high-grade DCIS.
The minimum tumor-free margin width needed to
achieve excellent results is not clear. Margins of less than 1
mm are clearly inadequate, 14 whereas patients with margins
wider than 10 mm, or no tumor on re-excision, appear
to have low failure rates, except possibly for patients whose
DCIS contains a high-grade component. 8 Patients with
margin widths of 3 to 10 mm had very similar results to
those with margin widths of 10 mm or more in one prospective
trial. 9 A smaller retrospective study found a 6% failure
rate in patients with margins wider than 5 mm. 11
What are other potential consequences of not giving RT
initially? Approximately one-half to two-thirds of patients
having local failure after lumpectomy alone are treated with
salvage breast-conserving therapy. 15 This relatively low
rate of breast preservation seems due mainly to the psychological
trauma caused by a recurrence for both patients and
physicians, rather than the size of the recurrence or other
technical factors that would prevent BCS. However, this
reality means that giving RT initially to all patients might
slightly decrease the ultimate number undergoing mastectomy.
About one-half of local recurrences after lumpectomy
alone are invasive and could potentially metastasize. Fortunately,
this risk is small. Cure rates following salvage surgery
for patients with invasive local recurrences are about
80% to 90%. 1,15 The high rate of success for such treatment
is likely why RT did not reduce the risk of distant metastases
or breast cancer deaths in the randomized trials, despite
the substantial local failure rates in their unirradiated patients
(Table 1). The trials were too small to exclude a very
small difference in such outcome (e.g., 0.5 to 1% at 10 years
or more), but how meaningful would such differences be to
patients even if they exist?
The acute toxicities of RT are fortunately quite modest. 16
Radiation therapy can impair the cosmetic results of treatment
and increase rates of breast pain, but improved technology
can minimize though not eliminate such problems. 17
More ominously, however, radiation-related heart disease,
sarcomas, lung cancers, and leukemias could increase death
rates 10 to 20 years or more after treatment. However, this
risk will likely be smaller than 1% among patients irradiated
using current techniques.
In summary, careful selection and treatment results
in a modest risk of local failure following BCS without
RT. Radiotherapy will likely reduce the recurrence rate by
only a few percent in such individuals, with no impact on
breast cancer–specific mortality. I therefore prefer to
irradiate initially only women at high risk of local recurrence
(particularly if the recurrence may be a high-
Table 1. Randomized Trials Comparing Breast-Conserving Surgery with and without Radiotherapy
Trial No. of
Patients
Median
Follow-up
(Months)
Local Failure Distant Failure or
Breast Cancer Death
BCS BCS�RT BCS BCS�RT
20% 3% c
5%
9% 3% a
2%
15% 4% b
4%
12% 2% a
3%
NSABP 1
813 207 35% a
UK/ANZ 2
1,694 152 23% a
EORTC 3
1,010 126 26% b
Sweden 4
1,046 101 27% a
Abbreviations: BCS, breast-conserving surgery; EORTC, European Organisation for Research and Treatment of Cancer; NSABP, National Surgical Adjuvant Breast and
Bowel Program; RT, radiotherapy; UK/ANZ, United Kingdom, Australia, and New Zealand.
a Crude rates.
b 10-year rates.
c 15-year rates.
22

Table 2. Local Failure Rates in a Series of Highly Selected Patients Treated with Breast-Conserving Surgery without
Radiotherapy
Study Selection Criteria No. of
Patients
USC-Van Nuys 5
Bologna 6
Bordeaux 7
Harvard 8
ECOG 9
Nottingham 10
Linköping 11
grade invasive cancer) and treat other patients only
after relapse. I routinely recommend BCS without RT
to women older than age 40 with lesions 20 mm or
smaller by both radiologic and pathologic measures
with highest nuclear grade 1 or 2 and margins 5 mm or
wider or no DCIS on re-excision. Nonetheless, I will
irradiate patients with low-risk DCIS if they prefer, after I
have told them my views. The fear of recurrence can
Author’s Disclosures of Potential Conflicts of Interest
Employment or
Leadership Consultant or
Author
Positions Advisory Role
Recht, Abram CareCore
References
1. Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of
invasive ipsilateral breast tumor recurrences after lumpectomy
in NSABP B-17 and B-24 randomized clinical trials for DCIS.
J Natl Cancer Inst. 2011;103:478-488.
2. Cuzick J, Sestak I, Pinder SE, et al. Effect of tamoxifen and
radiotherapy in women with locally excised ductal carcinoma in
situ: long-term results from the UK/ANZ DCIS trial. Lancet
Oncol. 2011;12:21-29.
3. Bijker N, Meijnen P, Peterse JL, et al. Breast-conserving
treatment with or without radiotherapy in ductal carcinomain-situ:
ten-year results of European Organisation for Research
and Treatment of Cancer randomized phase III trial
10853—a study by the EORTC Breast Cancer Cooperative
Group and EORTC Radiotherapy Group. J Clin Oncol. 2006;
24:3381-3387.
4. Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reductions
for local recurrence after postoperative radiotherapy after
sector resection for ductal carcinoma in situ of the breast. J Clin
Oncol. 2008;26:1247-1252.
5. Silverstein MJ, Lagios MD. Choosing treatment for patients with
ductal carcinoma in situ: fine tuning the University of Southern
California/Van Nuys Prognostic Index. J Natl Cancer Inst
Monogr. 2010;2010:193-196.
6. Di Saverio S, Catena F, Santini D, et al. 259 Patients with DCIS
cause enormous anxiety. For some, this anxiety is worse
that the possibility of short- and long-term toxicities
from RT, even if such treatment will not change their
ultimate chance of developing metastases or dying of
breast cancer. In the end, only the patient can balance
the advantages and disadvantages of different treatment
options and make the decision that best meets her
needs and values.
Stock
Ownership Honoraria
Median
Follow-up
(Months)
Research
Funding
Measure Local
Failure
USC-VN score 4-6 Unknown 75 12-year 6%
USC-VN score 4-6 144 130 10-year 5%
VN score 3-4 134 71 Crude 13%
NG 1-2, no NG 3;
margins 10 mm
146 40 Crude 6%
Grade 1 to 2,
margin 3 mm
565 74 5/7-year 6%/11%
Margin 10 mm 256 86 Crude 11%
Margin 5 mm 33 60 Crude 6%
Abbreviations: ECOG, Eastern Cooperative Oncology Group; RT, radiotherapy; USC, University of Southern California; VN, Van Nuys.
EDUCATIONAL SUMMARIES
Expert
Testimony
Other
Remuneration
of the breast applying USC/Van Nuys prognostic index: a retrospective
review with long term follow up. Breast Cancer Res
Treat. 2008;109:405-416.
7. de Mascarel I, Bonichon F, MacGrogan G, et al. Application of the
Van Nuys prognostic index in a retrospective series of 367 ductal
carcinomas in situ of the breast examined by serial macroscopic
sectioning: practical considerations. Breast Cancer Res Treat.
2000;61:151-159.
8. Wong JS, Kaelin CM, Troyan SL, et al. Prospective study of wide
excision alone for ductal carcinoma in situ of the breast. J Clin
Oncol. 2006;24:1031-1036.
9. Hughes LL, Wang M, Page DL, et al. Local excision alone without
irradiation for ductal carcinoma in situ of the breast: a trial of the
Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:
5319-5324.
10. Rampaul RS, Valasiadou P, Pinder SE, et al. Wide local excision
with 10 mm clearance without radiotherapy for DCIS (abstr.).
Eur J Surg Oncol. 2001;27:788.
11. Arnesson LG, Smeds S, Fagerberg G, et al. Follow-up of two
treatment modalities for ductal carcinoma in situ of the breast.
Br J Surg. 1989;76:672-675.
12. Vicini FA, Kestin LL, Goldstein NS, et al. Impact of young age
on outcome in patients with ductal carcinoma-in-situ treated
with breast-conserving therapy. J Clin Oncol. 2000;18:296-
306.
23

EDUCATIONAL SUMMARIES
13. Fisher ER, Dignam J, Tan-Chiu E, et al. Pathologic findings
from the National Surgical Adjuvant Breast Project (NSABP)
eight-year update of Protocol B-17. Cancer. 1999;86:429-438.
14. Silverstein M, Recht A, Lagios M. Margin width as the sole
predictor of local recurrence in patients with DCIS of the breast.
In Silverstein M, Recht A, Lagios M (eds). Ductal Carcinoma in
Situ of the Breast (2nd ed). Baltimore, MD: Lippincott Williams
& Wilkins, 2002;643-650.
15. Recht A. Salvage of local-regional failure. In Silverstein M, Recht
24
A, Lagios M (eds). Ductal Carcinoma in Situ of the Breast (2nd
ed). Baltimore, MD: Lippincott Williams & Wilkins, 2002;539-544.
16. Recht A. Breast Cancer: Stages I and II. In Gunderson LL,
Tepper JE (eds). In Clinical Radiation Oncology (3rd ed). New
York, NY: Elsevier, 2011;1321-1338.
17. Donovan E, Bleakley N, Denholm E, et al. Randomised trial of
standard 2D radiotherapy (RT) versus intensity modulated radiotherapy
(IMRT) in patients prescribed breast radiotherapy.
Radiother Oncol. 2007;82:254-264.

Intraoperative Radiation Therapy for Breast Cancer
Julia White, MD
The Ohio State University Comprehensive Cancer Center
I
ntraoperative radiation therapy (IORT) refers to the
delivery of a single high dose of irradiation directly to
the postexcision tumor bed during surgery. IORT has been
used as a boost method before standard whole breast irradiation
(WBI) or as an intraoperative partial breast irradiation
(PBI) as the sole treatment method postlumpectomy.
The advantage of IORT is the accuracy of delivery of radiation
to the postexcision tumor bed and convenience to patients
who can avoid daily trips for treatment. The primary
disadvantage is that the final pathology is unknown at time
of delivery, and a proportion of patients will have adverse
pathology features rendering them unsuitable for breast
conservation despite having received IORT.
The initial experiences using IORT for breast cancer
delivered a boost to the lumpectomy cavity immediately
postresection. Typically, standard WBI is initiated postsurgery
with IORT at either 3 to 5 weeks, or later at 18 to 24
weeks postchemotherapy when indicated. The largest published
experience is from a pooled retrospective analysis of
six institutions from Europe that are part of the International
Society of Intraoperative Radiotherapy (ISIORT). 3
This analysis included 1,131 women who received linacbased
IORT with 6 to 8 MeV electrons that delivered a mean
dose of 9.7 Gy to the lumpectomy cavity. In this population,
37 % had positive axillary nodes and greater than 95% had
some type of systemic therapy. At a median follow-up of 52.3
months, there were five in-breast cancer recurrences yielding
a local tumor control rate of 99.4%. In this experience,
43 patients who had positive margins at final pathology
postresection with IORT were converted to mastectomy.
The Milan group has reported the preliminary results
of their electrons intraoperative therapy (ELIOT) method
used as a boost in a single-arm, prospective trial that enrolled
211 premenopausal women. 4 The ELIOT approach
uses 9 MeV electrons from a mobile linear accelerator to
deliver a single dose of 12 Gy to the tumor bed immediately
after excision, while shielding the chest wall with a lead
plate. The WBI began 4 weeks afterward with a hypofrationated
regimen of 37 Gy in 13 fractions of 2.85 Gy. With
very short follow-up (11 months) reported so far, low rates
(2.7%) of grade 3 or higher acute toxicity were seen, and no
in-breast recurrences had occurred.
The intrabeam method of IORT reported their results
delivering a boost in 321 women enrolled on a pilot trial. 5
Intrabeam is a miniature electron generator and accelerator.
Electrons are accelerated along a tube and strike the tip
to generate soft X-rays that are modulated by a spherical
applicator to give a uniform field of radiotherapy. The
spherical applicator is placed into the cavity following resection,
and radiation can be delivered in routine operating
rooms without specialized shielding. The IORT dose delivered
in this pilot study was 18 to 20 Gy at the applicator
surface and 5 to 7 Gy at 1 cm from the applicator. Standard
WBI was delivered afterwards typically with 2 Gy fractions
from 45 to 50 Gy. With a median follow-up of 60.5 months,
eight patients have had in-breast cancer recurrences for a
very low 5-year rate of 1.73%.
There is mounting experience supporting the use of IORT
as PBI to deliver the sole radiotherapy treatment postlumpectomy
in select cases. The TARGIT phase III trial
randomly assigned 2,232 women undergoing breastconserving
treatment to TARGIT (1,113 patients) and/or
standard external beam WBI (1,119 patients) postlumpectomy.
6 In the TARGIT arm, 86% received just the IORT,
and 14% received IORT with conventional WBI because of
the presence of adverse pathology features. The dosing was
similar to the boost pilot; patients received 20 Gy to the
surface of the applicator and 5 to 7 Gy at 1 cm depth. The
median age was 63 in this population of mostly stage I
hormone-sensitive breast cancers. With a median follow-up
of approximately 24 months, there were six in-breast recurrences
in the TARGIT arm and five in the WBI arm for a
4-year rate of 1.2% and 0.95%, respectively (p � 0.41).
The outcome from 842 women accrued to a phase III trial
by the Milan group randomizing to ELIOT 21 Gy versus
standard WBI 50 Gy in 25 fractions plus boost postlumpectomy
is awaited. However, the outcome of 1,822 patients
with breast cancer undergoing quadrantectomy who were
treated with ELIOT off of the clinical protocol has been
reported. 7 In this population the median age was 58, median
tumor size was 1.3 cm, 89% of patients were receptor positive,
and 71% of patients had node-negative disease. With a
mean follow-up of 40 months, there have been 66 ipsilateral
breast cancer events (3.6%), 42 (2.3%) were characterized
as a true local recurrence when it occurred in the treated
quadrant and 24 (1.3%) were characterized as ipsilateral
new breast cancer when it occurred in a new quadrant. A
subsequent study classified all 1,822 cases by the American
Society for Radiation Oncology Consensus Guidelines of
suitable, cautionary, and unsuitable for receipt of postlumpectomy
accelerated partial breast irradiation when not
enrolled in a clinical trial. 8 The 5-year rate of in-breast
recurrence for the suitable, cautionary, and unsuitable patients
were 1.5%, 4.4%, and 8.8%, respectively (p � 0.0003).
The authors concluded that the ASTRO recommendation
offered useful guidance to judge the appropriateness of PBI
using ELIOT.
Given the long documented history of success with standard
WBI following lumpectomy, it is important that alternatives
to this standard for breast radiotherapy such as
IORT demonstrate comparable therapeutic effectiveness.
So far, IORT appears effective as a boost method. Initial
experience with IORT for PBI appears promising; however,
longer follow up is necessary to clearly validate its efficacy
prior to more general adoption outside of a clinical trial.
25

EDUCATIONAL SUMMARIES
Author’s Disclosures of Potential Conflicts of Interest
Author
White, Julia*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
Consultant or
Advisory Role
References
1. Seldmayer F, Fastner G, Merz F, et al. IORT with electrons as
boost strategy during breast conserving therapy in limited stage
breast cancer: Results of an ISIORT pooled analysis. Strahlenther
Onkol. 2007;183:32-34.
2. Ivaldi GB, Leonardi MC. Orecchia R, et al. Preliminary results of
electron intraoperative therapy boost and hypofractionated external
beam radiotherapy after breast-conserving surgery in premenopausal
women. Int J Radiation Oncology Biol Phys. 2008;72:
485-493.
3. Vaidya JS, Baum M, Tobias, JS, et al. Long term results of
targeted intraoperative radiotherapy (TARGIT) boost during
breast conserving surgery. Int J Radiation Oncology Biol Phys.
2011;81:1091-1097.
26
Stock
Ownership Honoraria
Research
Funding
Expert
Testimony
Other
Remuneration
4. Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative
radiotherapy versus whole breast radiotherapy for breast cancer
(TARGIT – A trial): an international, prospective, randomized,
non-inferiority phase 3 trial. Lancet. 2010;376:91-102.
5. Veronesi U, Orecchia R, Luini A, et al. Intraoperative radiotherapy
during breast conserving surgery: study of 1,822 cases treated
with electrons. Breast Cancer Res Treat. 2010;124:141-151.
6. Leonardi MC, Maisonneuve P, Mastropasqua MG, et al. How do
the ASSTRO consensus statement guidelines for application of
accelerated partial breast irradiation fit intraoperative radiotherapy?
A retrospective analysis of patients treated at the European
Institute of Oncology. Int J Radiation Oncology Biol Phys. 2012;
83:806-8013.

GENERAL SESSION V:
Genomics for the Clinician
CHAIR
Mark D. Pegram, MD
Stanford University
SPEAKERS
Matthew J. Ellis, MD
Washington University
Charles E. Geyer Jr., MD
Clinical Trials Network of Texas
Ana M. Gonzalez-Angulo, MD, MSc
University of Texas M. D. Anderson Cancer Center
After this session, attendees should be able to
● Assess the future of breast cancer genomics and determine how new discoveries can be applied to the prevention,
diagnosis, and treatment of patients with breast cancer
● Examine the current use of genomics to inform the treatment of patients with metastatic disease and determine future
directions to more effectively prevent disease and treat patients by targeting known mutations in cancer susceptibility
genes
● Analyze the potential applications for the use of genomic testing in node-positive patients, including a determination of
appropriate use during diagnosis, treatment, and post-treatment

PI3K in Breast Cancer
Toby M. Ward, PhD, Rebecca Olson, MS, Mark D. Pegram, MD,
and Charles E. Geyer Jr., MD
Stanford University, Stanford, CA, and
Statewide Clinical Trials Network of Texas, Addison, TX
T
he product of the phosphoinositide 3-kinase (PI3KCA)
proto-oncogene is involved in transmitting growth
and survival signals from receptor tyrosine kinases and/or
RAS proteins to downstream effectors, including AKT and
the mTOR complexes. A role for PI3K in cancer was first
elucidated by the identification of a viral oncogene homolog
in avian sarcoma virus 16. 1 Subsequent studies of human
malignancy have revealed that the PI3K signaling pathway
is deregulated frequently in a wide variety of human cancers,
including breast, ovarian, lung, and endometrial cancers,
and several mechanisms of deregulation have been
described. 2-5 Thus, this pathway has received intense scrutiny
as a target for therapeutic intervention in the treatment
of breast cancer, as well as other malignancies.
Structure and Function of PI3KCA
Gene Product
Type I PI3K kinases, of which PI3KCA is a member, function
as heterodimers composed of regulatory and catalytic
subunits, such as p85 and p110 (Fig. 1). 6 Activation of
cell-surface receptors, such as the insulin receptor and the
epidermal growth factor receptor family of proteins, recruits
PI3K, providing a docking site for the p85 regulatory
subunit (either by direct interaction with the receptor or via
adaptor proteins). Upon activation, PI3K catalyzes the addition
of a phosphate group to the membrane lipid phosphatidylinositol
(4,5)-bisphosphate (PIP2), yielding the active
signaling lipid phosphatidylinositol (3,4,5)-trisphosphate
(PIP3). This activity is opposed by the tumor-suppressor
phosphatase and tensin homolog deleted on chromosome
10 (PTEN). PIP3 is able to recruit and interact with signaling
proteins that contain pleckstrin-homology (PH) or
other lipid-binding domains, transmitting signals that eventually
influence cell growth and survival pathways (among
others). 2-5
Fig. 1. Canonical PI3K signaling.
28
PI3KCA Alterations in Breast Cancer
Human breast cancer clinical specimens exhibit a high rate
of PI3KCA gene mutation (approximately 30% of unselected
primary tumors), which occur across the various
intrinsic subtypes, based upon gene expression array phenotypes.
7,8 According to a recent report from a The Cancer
Genome Atlas (TCGA) study, PI3KCA is the most commonly
mutated gene in luminal A and luminal B intrinsic
subtypes (49.7% and 30.1% of tumors harbored single nucleotide
variants [SNVs], respectively), and is second only
to p53 in ERBB2-amplified and basal breast cancer (where
40.4% and 9.7% of tumors harbored PI3KCA SNVs, respectively).
7,8 PI3KCA was one of only four genes with a mutation
frequency of more than 10% in human breast cancers,
underscoring its importance in the oncogenic process.
The majority of these mutations within PI3KCA are
in the helical domain (E542K, E545K) and kinase domain
(H1047R) of the protein, and both types of mutation increase
PI3K catalytic activity. 9 Moreover, amplification
of the PI3KCB gene has also been described in ERBB2positive
breast cancers, 10 and somatic mutation of other
components of the PI3K signaling axis are also detected in
breast cancer specimens, including mutations in the IRS
and PI3KR1 genes. 11
PTEN
Another mechanism of PI3K signaling pathway activation
is deletion or mutation of the PTEN tumor suppressor, a
phosphatase which catalyzes removal of a phosphate from
PIP3 to generate PIP2, thus opposing the activity of PI3K.
In breast cancer, PTEN loss of heterozygosity can occur by
deletion, mutation, or epigenetic silencing of the gene and
has been extensively reviewed. 12
PI3K Pathway Inhibitors
Due to its activation and involvement in breast and other
cancers, inhibition of the PI3K signaling pathway is currently
the subject of intense clinical research. Indeed, in a
recent review of clinical trials aimed at testing PI3K pathway
inhibitors, approximately 20 different drugs were reported
as being in preclinical or clinical development at the
present time. 13 These drugs target a suite of signaling intermediates
in the PI3K pathway, including (but not limited
to) PI3KCA, AKT, and the mTOR complexes (Table 1).
PI3K Mutation versus Pathway Activation:
Effect on Breast Cancer Therapy
Vis-à-vis therapeutic rationale, knowledge of PI3KCA somatic
mutational status may not be as informative as as-

Table 1. Current Clinical Trials of Agents Targeting PI3K Pathway
Clinical Trials Agent Company NCT
Phase I BYL719 Novartis NCT01219699
Phase I PX-866 Oncothyreon Inc NCT00726583
Phase I BKM-120 Novartis NCT01068483
Phase I SF1126 Semafore Pharmaceuticals NCT00907205
Phase I BEZ-235 Novartis NCT00620594
Phase I GSK1059615 GlaxoSmithKline NCT00695448
Phase I GSK690693 GlaxoSmithKline NCT00493818
Phase I AZD-8055 AstraZeneca NCT00973076
Phase I OSI-027 OSI Pharmaceuticals NCT00698243
Phase I INK-128 Intellikine NCT01058707
Phase I/II XL-147 Exelixis NCT01042925
Phase II CAL-101 Calistoga Pharmaceuticals, Inc. NCT00710528
Phase II GDC-0941 Genentech Inc NCT00960960
Phase II XL-765 Exelixis NCT01082068
Phase II Perifosine Keryx/AOI Pharmaceuticals NCT00847366
Phase II MK-2206 Merck NCT00963547
Phase II Sirolimus Wyeth/Pfizer NCT00411788
Phase II Temsirolimus Wyeth/Pfizer NCT01111825
Phase II Ridaforolimus ARIAD/Merck NCT01234857
Phase II/III Everolimus Novartis NCT01061788
Modified from Bartholomeusz C and Gonzalez-Angulo AM. 13
sessment of activation of the signaling pathway as a whole.
Indeed, while mutation of PI3KCA occurs most frequently
in the luminal A breast cancer subtype (approximately 45%
of tumors in TCGA study), mRNA and proteomic “signatures”
corresponding to PI3K pathway activation are arguably
more pronounced in the luminal B, ERBB2-positive,
and basal groups. 8 Paradoxically, PI3KCA mutation may
actually be associated with improved clinical outcome in
Authors’ Disclosures of Potential Conflicts of Interest
Employment or
Leadership
Positions
Consultant or
Advisory Role
Author
Ward, Toby M.*
Olson, Rebecca*
Pegram, Mark D. Dava Oncology (I) Bristol-Myers
Squibb;
Genentech;
GlaxoSmithKline;
Novartis; Pfizer/
Wyeth (U);
Sanofi
Geyer, Charles E., Jr.*
*No relevant relationships to disclose.
ER-positive breast cancers treated with tamoxifen monotherapy.
14 Hence, selection of therapy to include PI3K inhibitors
arguably should not be based solely on somatic
mutation of PI3KCA in patient tumors alone. Rather, biomarker
analysis of key constituents of the PI3K signaling
pathway may prove to be more informative predictive markers
of potential clinical benefit for therapies targeting the
PI3K pathway.
Stock
Ownership Honoraria
Genentech;
GlaxoSmithKline;
Sanofi
Research
Funding
Expert
Testimony
Sanofi Novartis
EDUCATIONAL SUMMARIES
Other
Remuneration
29

EDUCATIONAL SUMMARIES
References
1. Chang HW, Aoki M, Fruman D, et al. Transformation of chicken
cells by the gene encoding the catalytic subunit of PI 3-kinase.
Science. 1997;276:1848-1850.
2. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT
pathway in human cancer. Nat Rev Cancer. 2002;2:489-501.
3. McAuliffe PF, Meric-Bernstam F, Mills GB, et al. Deciphering
the role of PI3K/Akt/mTOR pathway in breast cancer biology and
pathogenesis. Clin Breast Cancer. 2010;10(suppl):S59-65.
4. Tokunaga E, Oki E, Egashira A, et al. Deregulation of the Akt
pathway in human cancer. Curr Cancer Drug Targets. 2008;8:27-
36.
5. Bader AG, Kang S, Zhao L, et al. Oncogenic PI3K deregulates
transcription and translation. Nat Rev Cancer. 2005;5:921-929.
6. Vadas O, Burke JE, Zhang X, et al. Structural basis for activation
and inhibition of class I phosphoinositide 3-kinases. Sci Signal.
2011;4:re2.
7. Mardis, E. The genomic mutation landscape of breast cancer: a
TCGA report. Cancer Research. 2011;71:92s.
8. Creighton C. Integrative genomic analyses of breast cancer from
30
The Cancer Genome Atlas (TCGA). Cancer Research. 2011;71:
93s.
9. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation.
Oncogene. 2008;27:5486-5496.
10. Crowder RJ, Phommaly C, Tao Y, et al. PIK3CA and PIK3CB
inhibition produce synthetic lethality when combined with estrogen
deprivation in estrogen receptor-positive breast cancer. Cancer
Res. 2009;69:3955-3962.
11. Jaiswal BS, Janakiraman V, Kljavin NM, et al. Somatic mutations
in p85alpha promote tumorigenesis through class IA PI3K
activation. Cancer Cell. 2009;16:463-474.
12. Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the
continuum of common cancers, rare syndromes and mouse models.
Nat Rev Cancer. 2011;11:289-301.
13. Bartholomeusz C, Gonzalez-Angulo AM. Targeting the PI3K
signaling pathway in cancer therapy. Expert Opin Ther Targets.
2012;16:121-130.
14. Loi S, Haibe-Kains B, Majjaj S, et al. PIK3CA mutations associated
with gene signature of low mTORC1 signaling and better
outcomes in estrogen receptor-positive breast cancer. Proc Natl
Acad Sci USA.2010;107:10208-10213.

Role of Genomic Testing in Patients with
Node-Positive Breast Cancer
Shaheenah Dawood, MRCP, MPH, and Ana M. Gonzalez-Angulo, MD, MSc
Dubai Hospital, Dubai, United Arab Emirates and
University of Texas M. D. Anderson Cancer Center, Houston, TX
O
ver the last decade a number of important advances
have been made in the realm of breast cancer. First
has been the documented decline in mortality associated
with breast cancer, attributed to a combination of screening
programs and incorporation of optimal polychemotherapy
and endocrine regimens that have reduced the annual odds
of breast cancer recurrence by approximately 50% to 60%. 1
Second has been the realization that breast cancer is not a
homogenous disease but rather a conglomeration of a
number of subtypes including luminal A, luminal B, HER2enriched,
and basal-like subtypes; each is associated with
a different prognostic outcome. 2 Third has been the development—through
high-throughput techniques—of gene
expression–profiling platforms that are able to not only
predict prognostic outcome but also, as the data indicate,
predict for responsiveness to chemotherapy and thus be
able to identify groups who may not require chemotherapy,
thereby avoiding both short- and long-term toxicities typically
associated with chemotherapy. 3 The two prototypes
that have the most clinical data reported and are being
evaluated in prospective clinical trials are MammaPrint
(Agendia, Inc., Amsterdam, the Netherlands) and Oncotype
Dx (Genomic Health, Inc., Santa Clara, CA). Analysis of the
NSABP-20 study, 3 a trial that randomly assigned women
with node-negative, estrogen receptor–positive breast
cancer to either tamoxifen alone or tamoxifen and chemotherapy,
revealed that women with a high recurrence
score (RS) (greater than or equal to 31) had a large benefit
from the addition of chemotherapy while those with low
RS (less than 18) derived minimal if any benefit from the
addition of chemotherapy. Such data led to the endorsement
for the use of Oncotype DX RS by the American
Society of Clinical Oncology and the National Comprehensive
Cancer Network as both a prediction and prognostic
tool among women with estrogen receptor–positive, nodenegative
breast cancer. However, the question remains as
to whether such tools would be useful among women with
node-positive disease.
Do All Women with Node-Positive Breast
Cancer Require Chemotherapy?
The current standard of care among women with nodepositive
disease is to receive adjuvant chemotherapy; a contention
derived from results of prospective clinical trials
that have shown a survival benefit among women with
estrogen receptor–positive and –negative disease. 1,4 However,
the question remains, do all women within this cohort
benefit from chemotherapy? In a retrospective subset analysis
of three prospective clinical trials looking at women
with node-positive disease, Berry and colleagues showed
that the addition of chemotherapy resulted in an absolute
improvement in 5-year disease-free survival of 22.8% and
7% among women with estrogen receptor–negative and estrogen
receptor–positive disease, respectively. 5 The results
clearly indicate that the largest benefit attained from the
addition of chemotherapy was achieved among women with
estrogen receptor–negative disease. The question then
arises as to whether all women with estrogen receptor–
positive, node-positive disease benefit equally from the addition
of chemotherapy to endocrine therapy?
Can Genomic Profiling Help Refine
Chemotherapy Prediction among
Node-Positive Disease?
Using an unselected cohort of women with early-stage
breast cancer, of whom 51% had N1 disease, Knauer and
colleagues 6 used the 70-gene MammaPrint signature to
determine the benefit of adding chemotherapy to endocrine
therapy. The authors showed that the 5-year breast cancer–
specific survival was similar within the 70-gene low-risk
group who did and did not receive chemotherapy (99% vs.
97%); among the 70-gene high-risk group, a significant benefit
was demonstrated with the addition of chemotherapy to
endocrine therapy (94% vs. 81%; p � 0.01). Looking specifically
at a cohort of women with one to three positive nodes
who received endocrine therapy the Trans-BIG collaborators
demonstrated that the prognostic outcome among
women categorized within the 70-gene low risk group was
similar among those who did and did not receive chemotherapy.
7 In a recent exploratory study of women enrolled in the
SWOG 8814 trial with node-positive, hormone receptor–
positive disease (where approximately 60% of patients had
one to three positive nodes), women were randomly assigned
to endocrine therapy alone or to endocrine therapy
and chemotherapy and Albain and colleagues 4 used the
Oncotype DX RS to determine the benefit of chemotherapy.
The authors demonstrated no benefit with the addition of
chemotherapy among women with a RS less than 18 while a
significant benefit was demonstrated among those with a
RS greater than or equal to 31. Taken collectively, these
data indicate that multigene assays may be able to define a
group within the node-positive, hormone receptor–positive
population that may not require chemotherapy. Furthermore
the data described above looked at a cohort of women
treated with tamoxifen. It is likely that among postmenopausal
women, the use of aromatase inhibitors will show
additional benefit in terms of prognostic outcome.
How Will RxPONDER Answer the Question?
Clearly the previously described data indicate that
women with node-positive, endocrine- responsive disease
31

EDUCATIONAL SUMMARIES
defined as high risk using multigene assays benefit the most
from the addition of chemotherapy to endocrine therapy.
The low- and intermediate-risk groups appear not to derive
as much benefit, and larger prospective clinical trials are
needed to confirm this. RxPONDER (treatment for nodepositive,
endocrine-responsive breast cancer) is a phase III
clinical trial whose primary objective is to define the benefit
of chemotherapy among women with hormone receptor–
positive breast cancer with one to three positive nodes receiving
state-of-the-art endocrine therapy. The modified
schema of the protocol is illustrated in Fig. 1. The trial will
use Oncotype DX to enroll women with a RS that is less than
or equal to 25 who will then be randomly assigned to endocrine
therapy alone or endocrine therapy plus chemotherapy.
The RS of 25 was chosen to incorporate all low-risk
groups as well as the most intermediate-risk group of
women with the hypothesis that along the RS range of 0 to
25 a point of equivalence will be identified that will function
as a cutoff point identifying patients who would and would
not benefit from the addition of chemotherapy. The investigators
of the trial hypothesize that the point of equivalence
may emerge at a RS range of 19 to 20; where patients
scoring higher would benefit from chemotherapy. Should
Fig. 1. Schema of the RxPonder trial (S1007).
32
this hypothesis be proven, it is estimated that approximately
67% of women with one to three positive nodes and
endocrine-responsive disease would avoid chemotherapy
and all the associated morbidity and cost.
Conclusion
We certainly have come a long way from the one-size-fitsall
model of breast cancer treatment to a more personalized
approach. The use of genomic profiling has certainly influenced
the practice of oncology and studies indicate that
for women with node-negative disease, RS change recommendations
for adjuvant therapy occur approximately 17%
to 26% of the time in clinical practice. 8 Women with nodepositive
disease have traditionally been considered to be
at highest risk of recurrence. However, multigene assays
may be able to identify a group of women with endocrineresponsive,
node-positive disease that may not require
chemotherapy, thus avoiding the associated toxicities. However,
prospective trials will be essential to accurately identify
the groups that will and will not benefit from
chemotherapy. Until results of such studies are available,
the current guidelines still endorse the use of adjuvant
chemotherapy among all women with node-positive disease.

Authors’ Disclosures of Potential Conflicts of Interest
Employment or
Leadership
Positions
Consultant or
Advisory Role
Stock
Ownership Honoraria
Research
Funding
Author
Dawood, Shaheenah*
Gonzalez-Angulo, Ana M. Bayer; Bristol-
Myers Squibb;
Celgene;
Genentech;
Merck; Novartis
*No relevant relationships to disclose.
References
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
Effects of chemotherapy and hormonal therapy for early breast
cancer on recurrence and 15-year survival: an overview of the
randomised trials. Lancet. 2005;365:1687-1717.
2. Sorlie T. Molecular portraits of breast cancer. Tumour subtypes
as distinct disease entities. Eur J Cancer. 2004;40:2667-2675.
3. Paik S, Tang G, Shak S et al. Gene expression and benefit of
chemotherapy in women with node negative, estrogen receptorpositive
breast cancer. J Clin Oncol. 2006;24:3726-3734.
4. Albain KS, Barlow WE, Ravdin PM, et al. Adjuvant chemotherapy
and timing of tamoxifen in postmenopausal patients with
endocrine-responsive, node-positive breast cancer: a phase 3, openlabel,
randomised controlled trial. Lancet. 2009;374:2055-2063.
EDUCATIONAL SUMMARIES
Expert
Testimony
Other
Remuneration
5. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor
status and outcomes of modern chemotherapy for patients with
node-positive breast cancer. JAMA. 2006;295:1658-1667.
6. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the
70-gene signature for adjuvant chemotherapy in early breast cancer.
Breast Cancer Res Treat. 2010;120:655-661.
7. Mook S, Schmidt MK, Viale G, et al. The 70-gene prognosissignature
predicts disease outcome in breast cancer patients with
1-3 positive lymph nodes in an independent validation study.
Breast Cancer Res Treat. 2009;116:295-302.
8. Oratz R, Paul D, Cohn AL, et al. Impact of a commercial reference
laboratory test recurrence score on decision making in early-stage
breast cancer. J Oncol Pract. 2007;3:182-186.
33

Breast Cancer Whole Genome Sequencing
Matthew J. Ellis, MB BChir, PhD
The Breast Cancer Program, Siteman Cancer Center,
Washington University, St. Louis, MO
T
he application of whole cancer genome sequencing
approaches to breast cancer has changed our thinking
about the disease. Since this technique is unbiased, all
classes of somatic mutations are revealed, and because it is
digital in nature, information on gene copy number and
minor allele frequencies reveal a degree of complexity hitherto
unsuspected. We have focused this technology on two
areas. First is an analysis of samples from clinical trials, only
in this setting can adequate prospective consent for genetic
research and data sharing, high quality samples, and detailed
clinical outcomes can be obtained. Second is a comparison
of the whole genome sequences of human breast
cancers with their counterpart xenograft sample after passage
in immunodeficient mice. The objective of these mouse
modelling studies is to document the genome-wide similarities
and differences as a prelude to the use of xenograft
panels for therapeutic modelling based on pharmacological
hypotheses generated by analysis of genomic data.
To correlate the variable clinical features of estrogen
receptor–positive breast cancer with somatic alterations, we
studied pretreatment tumor biopsies accrued from patients
in two studies of neoadjuvant aromatase inhibitor therapy.
Eighteen significantly mutated genes were identified, including
five genes (RUNX1, CBFB, MYH9, MLL3, and
SF3B1) previously linked to hematopoietic disorders. These
findings suggest that breast cancer, like leukemia, can be
viewed as a stem-cell disorder that produces indolent or
aggressive tumors that display varying phenotypes depending
on differentiation blocks generated by different mutation
repertoires. Mutant MAP3K1 was associated with
luminal A status, low grade histology, and low proliferation
rates, whereas mutant TP53 was associated with the
opposite pattern. Moreover, mutant GATA3 correlated with
suppression of proliferation upon aromatase inhibitor treatment.
Pathway analysis demonstrated that mutations in
MAP2K4, a MAP3K1 substrate, produced similar perturbations
as MAP3K1 loss. These analyses also identified transcriptional
associations to Ki67 response residing in a
connected network under the control of several key “hub”
genes including MYC, FYN, and MAP kinases, among oth-
Author’s Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Ellis, Matthew J. AstraZeneca;
GlaxoSmithKline;
Novartis; Pfizer
References
ers. Targeting these hubs in resistant tumors could produce
therapeutic advances. Aside from the common PIK3CA mutations,
druggable mutations were relatively uncommon
but were observed in HER2, KIT, PDGFA, DDR1/2, MET,
JAK1, CSFR1, LTK, BRAF, and AKT1/2. If these mutations
are activating and drug sensitive, these are findings
are significant given that breast cancer is so common that
drug-sensitizing mutations with a 1% prevalence represent
a population with a similar magnitude to chronic myeloid
leukemia and promyelocytic leukemia, diseases in which a
randomized trials are feasible. Distinct phenotypes in estrogen
receptor–positive breast cancer are associated with specific
patterns of somatic mutations that map into cellular
pathways linked to tumor biology, but most recurrent mutations
are relatively infrequent. Prospective clinical trials
based on these findings will require comprehensive genome
sequencing and large mutation-screening programs. 1
Regarding paired whole genome analysis of human breast
cancer samples and their counterpart xenografts, our Human
and Mouse Linked Evaluation of Tumors (HAMLET)
program has successfully obtained over 30 breast tumor
lines from poor prognosis subtypes (luminal B, basal-like,
claudin-low, and HER2-enriched). As others have found,
luminal A breast cancers are absent from these panels,
possibly because their growth fraction is too low. Our initial
report documented that the genome sequences of a breast
primary tumor, a brain metastasis, and a xenograft derived
from the primary tumor exhibit great similarities in their
mutational repertoires; however, mutation frequencies
were remodeled during the xenograft formation and metastatic
process when compared with the primary tumor. 2
Furthermore, new mutations were detected. Whole genome
analysis of multiple, additional xenograft pairs reveal a
similar pattern but considerable variation in the number of
genome-wide, newly detected mutations. In several cases,
the xenograft-specific mutations are likely to be functionally
significant. These data suggest that serial monitoring of the
xenograft genome will be necessary to ensure that new
mutations have not arisen, producing inconsistencies in the
therapeutic modelling data.
Stock
Ownership Honoraria
Bioclassifier;
University
Genomics
1. Ellis MJ, Ding L, Shen D, et al. Whole-genome analysis informs
breast cancer response to aromatase inhibition. Nature. 2012;486:
353-360.
34
AstraZeneca;
GlaxoSmithKline;
Novartis
Research
Funding
AstraZeneca;
Novartis
Expert
Testimony
Other
Remuneration
2. Ding L, Ellis MJ, Shunqiang L et al. Genome remodelling in a
basal-like breast cancer metastasis and xenograft. Nature. 2010;
464:999-1005.

GENERAL SESSION VI:
Health Care Delivery and Prevention
CHAIR
Bruce Haffty, MD
The Cancer Institute of New Jersey
SPEAKERS
Benjamin O. Anderson, MD
Fred Hutchinson Cancer Research Center, University of Washington
Rowan T. Chlebowski, MD, PhD
Los Angeles Biomedical Research Institute at Harbor-UCLA
Los Angeles Medical Center
After this session, attendees should be able to
● More effectively integrate currently available evidence-based strategies to reduce breast cancer risk and mortality
● Partner with advocacy and other support resources to address health care disparities in patient care

Breast Health Care Delivery in Context: The World Health
Organization’s Initiative for Noncommunicable Diseases
D
espite the common misconception that breast cancer
is primarily a problem of high-income countries,
breast cancer affects countries at all economic levels. Breast
cancer is world’s most common cancer among women and
the most likely reason that a woman will die of cancer
around the globe, with over 50% of the 425,000 breast
cancer deaths in 2010 occurred in developing, rather than
developed, countries. The number of young lives lost to
breast cancer is even more disproportionately distributed.
In 2010, breast cancer killed 68,000 women age 15 to 49 in
developing countries compared with 26,000 in developed
countries. If cancer will seriously be addressed as a global
health issue, then breast cancer in low- and middle-income
countries (LMCs) cannot be ignored. 1
The World Health Organization (WHO) reported that in
2008, an estimated 36 million of the 57 million global deaths
were due to noncommunicable diseases (NCDs), principally
cardiovascular diseases, cancers, chronic respiratory diseases,
and diabetes, including 9 million deaths before the
age of 60, nearly 80% of which occurred in developing countries.
In response, the United Nations (UN) held an historic
high-level meeting from September 19 to 20, 2011, to consider
the prevention and control of NCDs. According to
WHO, the aim was to adopt “a concise, action-oriented
outcome document that will shape the global agendas for
generations to come.” 2 While the NCD political declaration
mentions cancer generally, it provides no specific reference
to breast cancer as a leading problem or to cancer treatment
priorities in practice. The document promotes “increased
access to cost-effective cancer screening programs, as determined
by national situations” but otherwise gives no guidance
about how diagnosed cancers should be managed. 3
This UN “action-oriented outcome document” on NCDs
is surprisingly silent on breast cancer. The UN and WHO
have embraced tobacco control, arguably the lowest hanging
fruit of cancer prevention, and discussed the prevention
of infection-associated cancers like cervical and liver cancer
through increased access to cost-effective hepatitis B (HBV)
and human papillomavirus (HPV) vaccinations; however,
they limited the discussion of common cancers that lack an
infectious origin, like breast and colon cancers, to the modification
of risk factors (unhealthy diet, obesity, and physical
inactivity), interventions which are unlikely to make major
shifts in breast cancer outcome. Prior to the UN summit,
WHO released an executive summary, “Global Status Report
on Noncommunicable Diseases 2010,” which outlines
the core obstacles in addressing NCDs in LMCs. 4 This analysis
notes that biennial mammographic screening (age 50 to
70) to downstage disease combined with breast cancer treatment
at all stages are among “the best buys” for health care
interventions to tackle NCDs. The report asserts that these
breast cancer interventions could avert 19% of the cancer
36
Benjamin O. Anderson, MD
Fred Hutchinson Cancer Research Center,
University of Washington, Seattle, WA
burden, and, as such, is cost-effective. However, the document’s
editor and principal author, Ala Alwan, MD, who
then served as WHO Assistant Director-General of NCDs
and Mental Health, concluded that breast cancer interventions
are nonetheless impractical for poorer countries, both
because of implementation costs and limited feasibility of
treatment in the primary care setting in LMCs. Is this
pessimistic perspective the end of the road for breast cancer
in developing countries, or are there sequential steps that
can be taken to address the most common cancer among
women?
Breast Cancer Early Detection Strategies:
Screening versus Clinical Downstaging
Breast cancer screening has been a source of heated debate
among health care policy makers. The discussion about
mammographic screening’s strengths, limitations, frequency,
and target age group, which has relevance to high
income countries with established health care infrastructures,
has overshadowed more practical questions for addressing
breast cancer outcomes in LMCs. Throughout the
world, women in developing countries are most often first
diagnosed with locally advanced (stage III) or metastatic
(stage IV) cancer. These large, palpable, visible, or ulcerated
cancers are easily detected on inspection and clinical examination,
obviating the value of screen detection. Advanced
cancers are more expensive to treat, less likely to respond
to therapy, and most often prove incurable in any health
care setting. The critical questions, then, must not revolve
around mammographic availability in LMCs, but instead
should focus on interventions whereby cancers can be diagnosed
at less advanced stages, so-called “clinical downstaging,”
followed by adequate locoregional and systemic
treatments. 5
It is critically important that WHO provide direct technical
guidance to member states about breast cancer as a
relevant NCD in LMCs. Education about early detection,
breast lumps, and self-examination is not a costly intervention
and may help a woman seek curative treatment while
it is still realistic, rather than waiting until the tumor is
advanced and likely untreatable except through palliative
care. For countries to make informed decisions, they need
meaningful data, including median tumor size at diagnosis,
as a key, first step in assessing the real burden and
options for solutions in addressing the most common lifethreatening
female cancer on earth.
As simple as it might sound, knowledge of median invasive
tumor size provides a powerful indicator regarding the
state of breast cancer detection and sheds light for early
detection strategies in LMCs. Regions where median tumor
size exceeds 3 to 4 cm are dominated by clinically detectible
disease and therefore need to improve public knowledge

about breast cancer and access to health care facilities
where cancer diagnoses can be made in an accurate and
timely fashion. Practical interventions include outreach
and public education about the signs and symptoms of
breast cancer, the importance of early detection when it is
still a small palpable mass or thickening, the promotion of
breast self-examination (BSE), and the establishment of
diagnostic tissue sampling and analysis to permit the accu-
Author’s Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Anderson, Benjamin O. GE Healthcare;
Navidea
Biopharmaceuticals
References
1. Forouzanfar MH, Foreman KJ, Delossantos AM, et al. Breast and
cervical cancer in 187 countries between 1980 and 2010: a systematic
analysis. Lancet. 2011;378:1461-1484.
2. United Nations high-level meeting on noncommunicable disease
prevention and control. http://www.who.int/nmh/events/un_ncd_
summit2011/en/. Accessed June 26, 2012.
3. Political Declaration of the High-level Meeting of the General
rate and timely diagnosis of clinically detectible disease.
Image detection of clinically occult cancers only becomes
relevant when the median tumor size is less than 2 to 3 cm,
and even then, the best methods for detection remain an
important area of investigation. The decision of how to
intervene in breast cancer will be made at the individual
country level and must be adapted to existing resources.
One size does not fit all.
Stock
Ownership Honoraria
Research
Funding
GE Healthcare;
Sanofi-Aventis
EDUCATIONAL SUMMARIES
Expert
Testimony
Other
Remuneration
Assembly on the Prevention and Control of Noncommunicable
Diseases (Resolution A/RES/66/2). http://www.un.org/en/ga/66/
resolutions.shtml. Accessed June 26, 2012.
4. Alwan A, et al. Global status report on noncommunicable diseases
2010. Geneva: WHO Press; 2012.
5. Anderson BO, Yip CH, Smith RA, et al. Guideline implementation
for breast healthcare in low-income and middle-income countries:
overview of the Breast Health Global Initiative Global Summit
2007. Cancer. 2008;113:2221-2243.
37

Reducing Breast Cancer Risk: Progress toward Resolution
Rowan T. Chlebowski, MD, PhD
Los Angeles Biomedical Research Institute at Harbor-UCLA
Los Angeles Medical Center, Torrance, CA
A
series of randomized, full-scale clinical trials have recently
addressed lifestyle changes in adjuvant breast
cancer, changed concepts regarding menopausal hormone
therapy and breast cancer, and identified new approaches to
breast cancer risk reduction.
The Women’s Intervention Nutrition Study (WINS) is a
multicenter clinical trial for postmenopausal patients with
early-stage resected breast cancer. Two thousand four hundred
and thirty seven women were randomly assigned to
standard therapy with or without a lifestyle intervention
targeting fat intake. Intervention participants reduced dietary
fat intake, lost weight, and experienced a significant
increase in disease-free survival (hazard ratio [HR]: 0.76;
95% CI [0.60-0.98]; p � 0.03). 1 Long-term follow-up is
underway and other ongoing studies are evaluating the
emerging hypothesis that weight loss along with increased
physical activity will improve breast cancer outcome.
The Women’s Health Initiative (WHI) hormone therapy
program included two separate randomized, placebocontrolled
trials. In one, 16,608 postmenopausal women
with no prior hysterectomy were randomly assigned to estrogen
plus progestin or placebo. In the second, 10,739
postmenopausal women with prior hysterectomy were randomly
assigned to estrogen alone or placebo. The use of
estrogen plus progestin significantly increased breast cancer
incidence, delayed breast cancer diagnosis, and increased
breast cancer mortality (HR: 1.96; 95% CI [1.00-
4.05]; p � 0.048). 2, 3 Surprisingly, the use of estrogen alone
had an opposite effect, significantly reducing breast cancer
incidence and reducing breast cancer mortality (HR: 0.37;
95% CI [0.13-0.91]; p � 0.03). 4 The initial report of the
adverse effects of estrogen plus progestin seen in the WHI
trial led to a worldwide reduction in hormone-therapy use
with substantial reduction in breast cancer incidence seen
in many countries. The hypothesis was raised that the
decrease in breast cancer was related to the decrease in
hormone therapy. Analyses in the WHI of breast cancer
incidence and mammography use after the estrogen plus
progestin trial were stopped, identifying a rapid reduction
in breast cancer incidence while mammography frequency
was comparable between study groups and in the interval
before and after the study intervention ended. 5 Preclinical
Author’s Disclosures of Potential Conflicts of Interest
38
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Chlebowski, Rowan T. AstraZeneca;
Novartis; Pfizer
studies have suggested a hypothesis to explain the influence
of estrogen alone in reducing breast cancer risk. Typically,
estrogen stimulates breast cellular proliferation and inhibits
apoptosis. However, after a period of estrogen deprivation,
mammary tumor gene expression profile will change
and estrogen then induces apoptosis. This finding suggests
that many breast cancers in postmenopausal women can
survive only a limited range of estrogen exposure. 4 While
tamoxifen and raloxifene are both approved for breast cancer
risk reduction, their use is uncommon due, in part, to
toxicity concerns. As aromatase inhibitors have been found
to have more breast cancer activity with more favorable
toxicity profiles than tamoxifen, the MAP.3 trial evaluated
exemestane versus placebo influence on breast cancer incidence
in a primary prevention setting. After about 3 years
of follow-up, breast cancer incidence was significantly lower
in the exemestane versus placebo group (HR: 0.35; 95% CI
[0.18-0.70]; p � 0.002). 6 The toxicity profile was quite favorable,
and no life threatening side effect differences emerged
when comparing study groups. Finally, several cohort analyses
in the large WHI population have provided support for
additional agents with a potential for breast cancer chemoprevention.
In cohort analyses in 154,768 WHI study participants,
breast cancer incidence was significantly lower in
bisphosphonate users compared with nonusers in analyses
adjusted for potential bone mineral density differences (HR:
0.68; 95% CI [0.52-0.88]; p � 0.01). Most recently, in cohort
analyses of 68,119 WHI clinical trial participants, women
with diabetes using metformin had lower breast cancer
incidence compared with women with diabetes treated with
other agents (HR: 0.75; 95% CI [0.57-0.99]; p � 0.04).
In a series of randomized clinical trials and emerging
cohort studies, our understanding of estrogen plus progestin
as compared with the influence of estrogen alone on
breast cancer incidence in postmenopausal women has been
altered. In addition, these studies have identified a range of
interventions including aromatase inhibitor use, lifestyle
change, and bisphosphonate and metformin—which can be
used alone or in combination—to address breast cancer risk
reduction. Their favorable side effect profiles suggest that
even women at modest breast cancer risk could be considered
for future intervention trials.
Stock
Ownership Honoraria
AstraZeneca;
Novartis
Research
Funding
Amgen
Expert
Testimony
Other
Remuneration

References
1. Chlebowski RT, Blackburn G, Thomson CA, et al. Dietary fat
reduction and breast cancer outcome: interim efficacy results
from the Women’s Intervention Nutrition Study (WINS). J Natl
Cancer Inst. 2006;98:1767-1776.
2. Chlebowski RT, Hendrix SL, Langer RD, et al. Estrogen plus
progestin influence on breast cancer and mammography in
healthy postmenopausal women: the Women’s Health Initiative
randomized trial. JAMA. 2003;289:3243-3253.
3. Chlebowski RT, Anderson GL, Gass M, et al. Influence of estrogen
plus progestin on breast cancer incidence and mortality. JAMA.
2010;304:1684-1692.
EDUCATIONAL SUMMARIES
4. Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated
equine oestrogen and breast cancer incidence and mortality in
postmenopausal women with hysterectomy: extended follow-up
of the Women’s Health Initiative randomised placebo-controlled
trial. Lancet Oncol. 2012;13:476-486.
5. Chlebowski RT, Kuller L, Prentice RL, et al. Breast cancer after
estrogen plus progestin use in postmenopausal women. N Engl
J Med. 2009;360:573-587.
6. Goss PE, Ingle JN, Ales-Martinez J, et al. Exemestane for breastcancer
prevention in postmenopausal women. N Engl J Med.
2011;364:2381-2391.
39

GENERAL SESSION VII:
Survivorship
CO-CHAIRS
Kathy S. Albain, MD
Loyola University Medical Center
Sandra M. Swain, MD
Washington Cancer Institute, Washington Hospital Center
SPEAKERS
Patrick G. Morris, MD, MSc
Memorial Sloan-Kettering Cancer Center
Patrick Neven, MD
University Hospitals Leuven
Denise J. O’Neill, BS
Survivors Offering Support
Ann H. Partridge, MD, MPH
Dana-Farber Cancer Institute
After this session, attendees should be able to
● Outline a plan of care to advise patients how to transition into normal life after active treatment, including the
importance of maintaining a healthy lifestyle and engaging in survivorship programs that connect similar individuals
and provide ongoing support
● Describe why survivors struggling with obesity have a greater risk for recurrence and recommend strategies to lengthen
survival and improve quality of life, such as regular physical activity and healthy eating habits
● Review recent advances in hormonal menopausal management and assist patients in selecting appropriate therapies
that address menopausal symptoms while preserving the efficacy of cancer treatments already in place
● Use quality measures to ensure that current clinical practices model best practices to support survivorship needs, such
as coordination of care, physician-provider communication, support programs and services, as well as management of the
long-term effects of treatment

Inflammation in the Pathogenesis and
Progression of Breast Cancer
Patrick G. Morris, MD, MSc, Kotha Subbaramaiah, PhD,
Andrew J. Dannenberg, MD, and Clifford A. Hudis, MD
Memorial Sloan-Kettering Cancer Center and
Weill Cornell Medical College, New York, NY
O
besity, with increasing worldwide incidence, is a risk
factor for the development of several epithelial malignancies,
including estrogen receptor (ER)– and progesterone
receptor (PR)–positive breast cancer in postmenopausal
women. 1,2 Following menopause, the conversion of androgen
precursors in peripheral adipose tissue is the main
source of estrogen synthesis. The rate-limiting step in this
process is catalyzed by the enzyme aromatase, which is
encoded by the CYP19 gene. 3 Circulating estrogens, such
as estradiol and its derivatives, are known to have stimulatory,
proliferative, and (possibly) genotoxic effects on breast
epithelial cells. Therefore, the increased risk of ER/PRpositive
breast cancer in obese, postmenopausal women
has been partially attributed to higher circulating levels
of estradiol, reflecting both increased adipose tissue and
elevated aromatase expression within those tissues. 1,4,5
However, the mechanisms underlying this obesity–breast
cancer link have been incompletely understood.
Obesity causes subclinical inflammation in adipose
tissue. 2,6-8 In both mouse models of obesity and in obese
humans, macrophages infiltrate visceral and subcutaneous
adipose tissue around necrotic adipocytes to form characteristic
crown-like structures (CLS). 7-10 These macrophages
produce a variety of proinflammatory mediators, which are
commonly found in the circulation of obese women and have
been linked to breast cancer progression and mortality. 11-13
Recently, our group demonstrated that in dietary and genetic
mouse models of obesity, CLS occur in both the adipose
tissue of the mouse mammary gland and the visceral
fat. 14 Importantly, in these mouse models, the number of
CLS lesions increases as a function of body weight, resulting
in parallel increases in several proinflammatory mediators,
which, in turn leads to increased aromatase expression.
Collectively, this results in a complex system of paracrine
interactions between macrophages, adipocytes, and other
cells. In this proposed model (Fig. 1), obesity leads to increased
lipolysis with resultant release of saturated fatty
acids, which stimulates the transcription factor, nuclear
factor kappa-B (NF-�B), to induce a series of proinflammatory
mediators in macrophages, including tumor necrosis
factor alpha (TNF-alpha), interleukin-1-beta (IL-1-beta),
and cyclooxygenase-2 (COX-2). Critically, in the mammary
gland and visceral fat of obese, oophorectomized mice, inflammatory
mediators including COX-2-derived prostaglandin
E2 (PGE2) activate the transcription of the CYP19
gene thereby encoding aromatase in neighboring cells, leading
to elevated expression and activity of aromatase. Consequently,
estrogen biosynthesis should be enhanced, leading
to upregulation of ER-target genes, including PR.
In translational clinical studies, we and others recently
described these same crown-like structures in the human
breast (CLS-B). 15,16 Although these lesions can be seen with
standard hematoxylin and eosin (H�E) staining in the
white adipose tissue of the breast, the use of immunohistochemistry
for CD68, a macrophage marker, increases detection
(Fig. 2). 15 This observation may explain why the
presence and biological significance of CLS-B has only recently
been appreciated. Importantly, the presence and
extent of breast inflammation, as evidenced by CLS-B, correlates
with increasing body mass index (BMI). In a pilot
study of 30 patients undergoing mastectomy, CLS-B were
seen in one out of 12 (approximately 8%) women with
normal BMI, seven out of 10 (70%) overweight women (BMI
25-29.9), and six out of eight (75%) obese women (BMI �
30). 15 Mirroring preclinical models, the presence of CLS-B
was associated with higher NF-kappa-B-binding activity
and increased levels of proinflammatory mediators (TNFalpha,
IL-1-beta, COX-2, and PGE 2), CYP19 gene expression,
and aromatase activity. 15,17 Although aromatase
activity correlates with both BMI and the extent of CLS-B,
the correlation appears to be stronger with extent of CLS-B,
suggesting that obesity-associated inflammation rather
than obesity alone is the critical driver of aromatase activation
in breast tissue. Overall, these results establish the
existence of an obesity-inflammation-aromatase axis occur-
Fig. 1. Paracrine interactions between macrophages
and other cell types in breast tissue of obese
women and mice. 14 Reprinted with permission from
the American Association for Cancer Research.
41

EDUCATIONAL SUMMARIES
Fig. 2. Immunohistochemical stain with CD68, a
macrophage marker, showing a prototypic crownlike
structure of the breast (CLS-B), consisting of a
necrotic adipocyte surrounded by macrophages
(200x). 15 Reprinted with permission from the American
Association for Cancer Research.
ring locally in breast tissue that is likely to contribute to the
increased risk of hormone receptor–positive breast cancer
and its progression in postmenopausal women. 14,15,17
Given the link between chronic inflammation and carci-
Authors’ Disclosures of Potential Conflicts of Interest
Author
Morris, Patrick G.*
Subbaramaiah, Kotha*
Dannenberg, Andrew J.*
Hudis, Clifford A.*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
References
Consultant or
Advisory Role
1. Cleary MP, Grossmann ME. Minireview: obesity and breast
cancer: the estrogen connection. Endocrinology. 2009;150:2537-
2542.
2. van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and
cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol
Biomarkers Prev. 2009;18:2569-2578.
3. Lorincz AM, Sukumar S. Molecular links between obesity and
breast cancer. Endocr Relat Cancer. 2006;13:279-292.
4. Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum
sex hormones, and breast cancer risk in postmenopausal women.
J Natl Cancer Inst. 2003;95:1218-1226.
5. Wake DJ, Strand M, Rask E, et al. Intra-adipose sex steroid
metabolism and body fat distribution in idiopathic human obesity.
Clin Endocrinol (Oxf). 2007;66:440-446.
6. Cancello R, Henegar C, Viguerie N, et al. Reduction of macrophage
infiltration and chemoattractant gene expression changes
in white adipose tissue of morbidly obese subjects after surgeryinduced
weight loss. Diabetes. 2005;54:2277-2286.
7. Cinti S, Mitchell G, Barbatelli G, et al. Adipocyte death defines
42
nogenesis in other tissues, 18 it is possible that obesityrelated
breast inflammation, as indicated by the extent of
CLS-B, contributes to the risk for other subtypes of breast
cancer. For example, there are some data linking obesity
with an increased risk of triple-negative breast cancer. 19 It
is possible that chronic breast inflammation (CLS-B) contributes
to this process by mechanisms other than induction
of aromatase or that estrogen production facilitates transformation
and invasion by nonhormonally dependent tumors.
Possibly, obesity-induced inflammation manifested
as CLS may also contribute to other types of malignancy.
The discovery of the obesity-inflammation-aromatase
connection provides a basis for the development of risk
reduction and novel therapeutic strategies. For example,
the effects of dietary modification and lifestyle interventions,
such as exercise, on this inflammatory process are
of considerable interest. Furthermore, the observation that
breast inflammation leading to induction of COX-2 and
PGE 2 occurs in most, but not all, overweight/obese women
might explain inconsistent results seen in epidemiological
studies in terms of the benefit of aspirin as a chemopreventive
agent. It is possible that aspirin and other nonsteroidal
anti-inflammatory drugs orprototypic inhibitors of COX
enzymes, might only be of benefit to women with increased
CLS-B–associated COX-2/PGE 2 signaling. Hence, these
and other agents with anti-inflammatory properties might
be of interest for future intervention studies that more
specifically target the at-risk subset of subjects or patients
with CLS-B.
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Ownership Honoraria
Research
Funding
Expert
Testimony
Other
Remuneration
macrophage localization and function in adipose tissue of obese
mice and humans. J Lipid Res. 2005;46:2347-2355.
8. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin
resistance. Annu Rev Physiol. 2010;72:219-246.
9. Murano I, Barbatelli G, Parisani V, et al. Dead adipocytes, detected
as crown-like structures, are prevalent in visceral fat
depots of genetically obese mice. J Lipid Res. 2008;49:1562-1568.
10. Weisberg SP, McCann D, Desai M, et al. Obesity is associated
with macrophage accumulation in adipose tissue. J Clin Invest.
2003;112:1796-1808.
11. Bachelot T, Ray-Coquard I, Menetrier-Caux C, et al. Prognostic
value of serum levels of interleukin 6 and of serum and plasma
levels of vascular endothelial growth factor in hormonerefractory
metastatic breast cancer patients. Br J Cancer. 2003;
88:1721-1726.
12. Dandona P, Weinstock R, Thusu K, et al. Tumor necrosis factoralpha
in sera of obese patients: fall with weight loss. J Clin
Endocrinol Metab. 1998;83:2907-2910.
13. Vozarova B, Weyer C, Hanson K, et al. Circulating interleukin-6
in relation to adiposity, insulin action, and insulin secretion.
Obes Res. 2001;9:414-417.

14. Subbaramaiah K, Howe LR, Bhardwaj P, et al. Obesity is associated
with inflammation and elevated aromatase expression in
the mouse mammary gland. Cancer Prev Res (Phila). 2011;4:329-
346.
15. Morris PG, Hudis CA, Giri D, et al. Inflammation and increased
aromatase expression occur in the breast tissue of obese women
with breast cancer. Cancer Prev Res (Phila). 2011;4:1021-1029.
16. Sun X, Casbas-Hernandez P, Bigelow C, et al. Normal breast
tissue of obese women is enriched for macrophage markers and
macrophage-associated gene expression. Breast Cancer Res
Treat. 2012;131:1003-1012.
EDUCATIONAL SUMMARIES
17. Subbaramaiah K, Morris PG, Zhou XK, et al. Increased levels of
COX-2 and prostaglandin E2 contribute to elevated aromatase
expression in inflamed breast tissue of obese women. Cancer
Discov. 2012;2:356-565.
18. Karin M, Greten FR. NF-kappaB: linking inflammation and
immunity to cancer development and progression. Nat Rev Immunol.
2005;5:749-759.
19. Phipps AI, Chlebowski RT, Prentice R, et al. Body size, physical
activity, and risk of triple-negative and estrogen receptorpositive
breast cancer. Cancer Epidemiol Biomarkers Prev. 2011;
20:454-463.
43

Managing Menopausal Symptoms in Patients
with Breast Cancer
Patrick Neven, MD, and Anneleen Lintermans, MD
University Hospitals Leuven, Leuven, Belgium
I
n the Western world, improved adjuvant treatments
and earlier diagnosis increase the number of breast
cancer survivors. Although many patients report positive
aspects of the survivorship experiences, most want better
symptom control of menopausal complaints. 1,2 In premenopausal
women, certain breast cancer treatments (e.g.,
chemotherapy, ovarian suppression) result in early and
sudden onset of premature menopause. For postmenopausal
women on hormone replacement therapy (HRT), a
breast cancer diagnosis requires one to end treatment and
thus symptoms return. Endocrine agents like tamoxifen
and aromatase inhibitors (AIs) lower relapse from estrogen
receptor–positive breast cancer but worsen acute menopausal
symptoms.
Menopausal symptoms during cancer treatment vary, but
hot flashes, night sweats, arthralgia, and sexual dysfunction
are most frequently reported after chemotherapy, ovarian
suppression, tamoxifen, and oral AIs. These menopausal
symptoms are also more severe in patients with breast
cancer than they would be in healthy women experiencing
natural menopause and often affect professional activities
and quality of life to the point that patients will stop or
consider stopping treatment if they do not receive help in
relieving these symptoms. 3,4 The most effective treatment
for menopausal symptoms is HRT, but cannot be used
for patients with breast cancer. Most patients do not want
to use drugs to treat side effects induced by drugs and,
although nonhormonal medical treatments can reduce
symptoms, side effects have to be anticipated. Nonpharmacological
interventions have variable results but are often
not better than placebo; however, there is some progress
according to results from recent research. 5
Recent literature from the last year shows that the medical
community has invested a lot in the pathophysiology
and management of menopausal symptoms to improve
quality of life, which will hopefully improve treatment compliance.
In focusing on that literature, we are able to discuss
the management of acute menopausal symptoms.
Vasomotor Symptoms
Most patients with breast cancer experience hot flashes,
night sweats, or both and report their symptoms as ranging
from slightly disturbing to unbearable. Endocrine agents
exacerbate symptoms, which compromise treatment adherence
and impact treatment efficacy. 3,4 Management options
remain symptomatic and large, randomized placebocontrolled
trials to evaluate the numerous suggested
remedies are scarce. Significant reductions in hot flash frequency
and intensity are seen with the use of placebo. Even
more reductions in hot flash management have been reported
with selective serotonin reuptake inhibitors (SSRIs),
serotonin-norepinephrine reuptake inhibitors (SNRIs), clonidine,
and gabapentine when compared with placebo; how-
44
ever, side effects cause many patients outside of clinical
trials to discontinue this supportive therapy prior to the
next appointment. 6 Nonmedical treatments like adapting
life style, exercise, dressing in layers, avoiding triggers
(stress situations), carrying cold drinks, and moderating
spicy food, tobacco, and caffeine may also offer some relief.
Placebo-controlled clinical trials have failed to demonstrate
a significant benefit when comparing complementary
and alternative medicine with placebo. 7,8 For example, acupuncture
and yoga has been suggested as a remedy for
menopausal symptoms. 9 When vasomotor symptoms persist,
promising results for short-term stellate ganglion block
have been reported, although further evaluation in a randomized,
placebo-controlled trial is necessary. 10 A recently
published randomized study concluded that group cognitive
behavior therapy (e.g., relaxation, paced respiration, and
sleep advice) is a safe and effective treatment option for
women to better tolerate their hot flashes and night sweats
and provides additional benefits to mood, sleep, and quality
of life. 11 Hormonal therapy, typically contraindicated in
patients with breast cancer, may be used when other treatment
modalities fail but only after careful consideration
and informed consent, as this treatment might affect relapse
rates.
Vaginal Dryness and Sexual Dysfunction
Vaginal dryness is mainly seen with AI use but tamoxifen
can also induce vulvovaginal irritation due to excessive
discharge. This may lead to dyspareunia and can enhance
loss of libido, already affected by a recent breast cancer
diagnosis and breast surgery. In the management of dyspareunia,
nonhormonal therapy (e.g., lubricants, vaginal
moisturizers) can be used to symptomatically treat vaginal
dryness and prevent postcoital irritation. 6 Cold cream, an
emulsion of water and certain fats, helps soften the vulval
skin. Topical vaginal hormones are helpful but available
data in AI users show increased circulating estradiol levels
after vaginal application of estradiol. 12 In our department,
our group uses off-label, low-dose vaginal estriol pessaries
twice weekly for 4 weeks followed by weekly applications in
patients who have failed nonhormonal therapy. 6 We participate
in an international prospective clinical study of pharmacokinetics
that looks at the efficacy and safety of vaginal
application of lyophilised lactobacilli and 0.03 mg estriol
(Gynoflor) on atrophic vaginitis in postmenopausal patients
with breast cancer treated with nonsteroidal AIs. 13 Other
modalities that require clinical trials in AI-treated patients
with breast cancer include dehydroepiandrosterone vaginal
ovules, intravaginal tamoxifen, ospemifene tablets, and intravaginal
testosterone gel. Sexual dysfunction, in particular,
decreased libido, as well as the inability to become
aroused and achieve orgasm is a field that needs further

investigation. After 2 to 3 years of follow-up, sexual dysfunction
is seen more in patients switching to an AI compared
with patients who remain on tamoxifen; some consider this
problem as more important than arthralgia. 14 Interventions
at the psychosocial level, like education, lifestyle
changes, and couples counseling can be helpful but efficacy
data are lacking. 15,16
Arthralgia and Bone Health
Musculoskeletal symptoms, the most frequently reported
complaint by AI users, now referred to as the AI-induced
musculoskeletal syndrome (AIMSS), affects daily functioning
and treatment adherence. 4,6,17 Pre-existing musculoskeletal
symptoms should be assessed and promptly treated
as they are likely to increase. There is fluid accumulation in
peripheral joints and tendon sheaths thicken; patients report
early morning stiffness and start pain, and hand-grip
strength weakens. They suddenly feel like they are 100
years old. 18 Patients and family should be educated concerning
possible AI-induced joint problems. 19 Patients should
be encouraged to adapt their lifestyle (weight control, exercise,
physiotherapy, massage, etc.) when necessary. Randomized,
controlled trials of exercise suggest beneficial
changes in inflammation; however, the evidence is still
preliminary. 20 Nonsteroidal anti-inflammatory drugs
(NSAID), acetaminophen, and cyclooxygenase-2 inhibitors
can be used if these adaptations fail to relieve the symptoms;
however, adverse effects should be closely monitored. When
Authors’ Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Neven, Patrick AstraZeneca;
Lilly; Novartis;
Pfizer; Roche
Lintermans, Anneleen*
*No relevant relationships to disclose.
References
1. Documet PI, Trauth JM, Key M, et al. Breast cancer survivors’
perception of survivorship. Oncol Nurs Forum. 2012;39:309-315.
2. DL Stan, S Pruthi, Jenkins S, et al. Needs and preferences of
breast cancer survivors: a cross-sectional survey. ASCO Breast
Cancer Symposium 2011.
3. Banning M. Adherence to adjuvant therapy in post-menopausal
breast cancer patients: a review. Eur J Cancer Care (Engl). 2012;
21:10-19.
4. Henry NL, Azzouz F, Desta Z, et al. Predictors of aromatase
inhibitor discontinuation as a result of treatment-emergent
symptoms in early-stage breast cancer. J Clin Oncol. 2012;30:
936-942.
5. Mann E, Smith MJ, Hellier J, et al. Cognitive behavioral treatment
for women who have menopausal symptoms after breast
cancer treatment (MENOS 1): a randomized controlled trial.
Lancet Oncol. 2012;13:309-318.
6. Loibl S, Lintermans A, Dieudonné AS, et al. Management of
menopausal symptoms in breast cancer patients. Maturitas.
2011;68:148-154.
7. Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III doubleblind
randomized, placebo-controlled crossover trial of black
not contraindicated, maximum start dosage of NSAID with
stomach protection should be prescribed, and efficacy of
reduced doses can be evaluated.
A drug holiday or switching to another AI may offer pain
relief in some patients. 21,22 When symptoms persist, switching
to tamoxifen can be another option. Patients suffering
from carpal tunnel syndrome (nine times more likely in AI
than tamoxifen users) or those with arthritis should be
referred to a specialist for proper diagnosis and therapy. 23
New therapeutic strategies under investigation include
glucosamine, diuretics, duloxetine, probiotics, vitamin D,
capsaicin, acupuncture, and yoga. However, randomized,
placebo-controlled studies are warranted to establish the
safety and efficacy of these interventions. Notably, recent
data from the VITAL trial in 147 letrozole users shows
promising results for adding high doses of vitamin D. 24
In summary, a subset of patients with breast cancer
experience severe, acute menopausal symptoms mainly related
to endocrine agents that need to be taken for at least 5
years. Patients, already bothered by the diagnosis and previous
treatments, are confronted with the emergence of
such symptoms and the severity of these symptoms can
threaten treatment compliance. 25 Further research in the
pathophysiology of symptoms like AIMSS is required 26 and,
in the mean time, management strategies to tackle menopausal
symptoms are important to get a maximal benefit
from adjuvant therapy.
Stock
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Research
Funding
EDUCATIONAL SUMMARIES
Expert
Testimony
Other
Remuneration
cohosh in the management of hot flashes: NCCTG Trial N01CC1.
J Clin Oncol. 2006;24:2836-2841.
8. Penotti M, Fabio E, Modena AB, et al. Effect of soy-derived
isoflavones on hot flushes, endometrial thickening, and the pulsatility
index of the uterine and cerebral arteries. Fertil Steril.
2003;79:1112-1117.
9. Hervik J, Mjaland O. Quality of life of breast cancer patients
mediated with anti-estrogens, 2 years after acupuncture treatment:
a qualitative study. Eur J Cancer. 2012;48:5148.
10. Haest K, Kumar A, Van Calster B, et al. Stellate ganglion block
for the management of hot flashes and sleep disturbances in
breast cancer survivors: an uncontrolled experimental study
with 24 weeks of follow-up. Ann Oncol. 2012;23:1449-1454.
11. Mann E, Smith MJ, Hellier J, et al. Cognitive behavioural treatment
for women who have menopausal symptoms after breast
cancer treatment (MENOS 1): a randomised controlled trial.
Lancet Oncol. 2012;13:309-318.
12. Moegele M, Buchholz S, Seitz S, et al. Vaginal estrogen therapy
in postmenopausal breast cancer patients treated with aromatase
inhibitors. Arch Gynecol Obstet. 2012;285:1397-1402.
13. A clinical study of pharmacokinetics, efficacy and safety of vaginal
application of lyophilised lactobacilli and 0.03 mg estriol
45

EDUCATIONAL SUMMARIES
(Gynoflor®) on atrophic vaginitis in postmenopausal breast cancer
patients treated with aromatase inhibitors. 2011. NCT01370551.
14. Van Calster B, Van Ginderachter J, Vlasselaer J, et al. Uterine
and quality of life changes in postmenopausal women with an
asymptomatic tamoxifen-thickened endometrium randomized
to continuation of tamoxifen or switching to anastrozole. Menopause.
2011;18:224-229.
15. Krychman ML, Katz A. Breast cancer and sexuality: multi-modal
treatment options. J Sex Med. 2012;9:5-15.
16. Bulletins-Gynecology CoP. ACOG Practice Bulletin No. 126:
Management of gynecologic issues in women with breast cancer.
Obstet Gynecol. 2012;119:666-682.
17. Mieog JS, Morden JP, Bliss JM, et al. Carpal tunnel syndrome
and musculoskeletal symptoms in postmenopausal women with
early breast cancer treated with exemestane or tamoxifen after
2-3 years of tamoxifen: a retrospective analysis of the Intergroup
Exemestane Study. Lancet Oncol. 2012;13:420-432.
18. Winters L, Habin K, Flanagan J, et al. “I feel like I am 100 years
old!” managing arthralgias from aromatase inhibitors. Clin J
Oncol Nurs. 2010;14:379-382.
19. Tanna N, Buijs H, Pitkin J. Exploring the breast cancer patient
journey: do breast cancer survivors need menopause management
support? Menopause Int. 2011;17:126-131.
20. Ballard-Barbash R, Friedenreich CM, Courneya KS, et al. Phys-
46
ical activity, biomarkers, and disease outcomes in cancer survivors:
a systematic review. J Natl Cancer Inst. 2012.
21. Briot K, Tubiana-Hulin M, Bastit L, et al. Effect of a switch of
aromatase inhibitors on musculoskeletal symptoms in postmenopausal
women with hormone-receptor-positive breast cancer:
the ATOLL (articular tolerance of letrozole) study. Breast
Cancer Res Treat. 2010;120:127-134.
22. Henry NL, Azzouz F, Desta Z, et al. Predictors of aromatase inhibitor
discontinuation as a result of treatment-emergent symptoms in
early-stage breast cancer. J Clin Oncol. 2012;30:936-942.
23. Din OS, Dodwell D, Winter MC, et al. Current opinion of aromatase
inhibitor-induced arthralgia in breast cancer in the UK. Clin
Oncol (R Coll Radiol.) 2011;23:674-680.
24. Khan Q, Kimler B, Reddy P. Randomized trial of vitamin D3 to
prevent worsening of musculoskeletal symptoms and fatigue
in women with breast cancer starting adjuvant letrozole: the
VITAL trial. J Clin Oncol. 2012;30(suppl; abstr 9000).
25. Wagner LI, Zhao F, Chapman JW, et al. Patient-reported predictors
of early treatment discontinuation: NCIC JMA.27/E1Z03
quality of life study of postmenopausal women with primary
breast cancer randomized to exemestane or anastrozole. San
Antonio Breast Cancer Symposium. Cancer Res. 2011;71(24
suppl; abstrS6–2).
26. Lintermans A, Neven P. Pharmacology of arthralgia with estrogen
deprivation. Steroids. 2011;76:781-785.

The Transition from Active Treatment to
Normal Life as a Survivor
Survivors Offering Support (SOS) functions within 12
hospitals in Maryland and Washington, DC, and is
funded by each respective hospital and a grant from the
Susan G. Komen for the Cure Maryland affiliate. SOS contracts
with hospitals to establish peer-to-peer breast cancer
support services that are integrated into the standard of
care within each hospital. Since 2004, SOS has assisted over
3,800 women diagnosed with breast cancer. While peer
mentoring serves as the cornerstone of the SOS program,
the quest for each patient to process her own personal
cancer experience and develop a strategy to successfully
transition into life after treatment has led to the development
of a workshop called Transition to Wellness (Transitions).
This “jump start into survivorship” workshop has
bridged the gap for patients moving from active treatment
to life as a breast cancer survivor. With 2.6 million breast
cancer survivors living in the United States today, 1 survivorship
care programs that provide information, practical
knowledge, and role modeling to assist patients in developing
healthy, new-normal skills for life after cancer are imperative.
Transitions is targeted at patients completing treatment
and moving into the extended survivorship phase. 2 Attendance
is highest at hospitals where medical staff integrate
the workshop with survivorship care plans and strongly
encourage patients to attend in order to prepare for life as a
cancer survivor. Breast cancer survivors share similar concerns
with survivors of other cancers. SOS surveys mirror
findings of the 2010 LIVESTRONG Report 3 with: fear of
recurrence; sadness and depression; and lowered energy
and concentration as concerns shared by over 50% of survivors.
SOS surveys of 210 patients over the past 2 years
indicate a need for information in critical areas like nutrition,
self-advocacy, long-term follow-up care, exercise, and
sexual intimacy. Transitions participants indicate a desire
to make positive changes in their lives and to improve their
future health and well-being by using the information presented
at workshops by peer mentors. Over a third of participants
indicate a desire to improve both diet and exercise.
Reducing anxiety and stress levels were noted as being
important to 25% of survey respondents.
Survivorship Care Models
As survivorship care models evolve, programs may vary
from higher-cost, vertical hospital-based programs typically
run in large university hospital settings to lower-cost, horizontal
programs where managed survivorship-care plans
are augmented by partnerships with independent not-forprofit
organizations. Partner organizations like SOS offer
specialized programs for survivors in the areas of peer support
and role modeling, exercise, nutrition, integrative medicine,
and psychosocial counseling. Economic constraints
Denise J. O’Neill, BS
Survivors Offering Support
enhance the viability of the horizontal-partnering model of
survivorship care and leverage nonmedical-based program
cost efficiencies.
SOS Transitions Overview
The SOS Transitions workshops utilize trained peer mentors
to share information vetted by medical staff and act as
behavioral models for patients. The 3-hour workshop is
designed as a starting point for transitional survivors and
offers insights and practical knowledge for the challenges
that patients may face as they enter life after cancer treatment.
The workshop has three sections. First, a survivor
panel with similar surgery and treatment experiences as the
survivor audience shares their own fears and difficulties of
early survivorship while imparting coping strategies and
success stories. Topics like the fear of recurrence, low energy,
sadness, and life-style changes are discussed with a
trained moderator highlighting key information for participants.
The panel is followed by the moderator sharing 10
healthy lifestyle ideas for breast cancer survivors. The
Healthy Lifestyle Checklist includes topics like limiting alcohol,
smoking avoidance, and the importance of exercise,
nutrition, and sleep. The lifestyle overview provides information
that encourages survivors to begin to take control of
their lives after treatment.
The trained peer moderator then shares information
about the survivor’s role as an advocate of their own care
plan. Key topic areas include maintaining a medical appointment
calendar and the importance of adhering to
follow-up care appointments and tests. Discussion about
selecting a lead physician, communicating side effects with
medical staff, and complying with daily hormonal therapy
medications are also included.
The workshop ends with a brief presentation and demonstration
from a wellness practitioner who shares how their
particular practice can improve a patient’s overall health
and well-being. A one-page survey is completed by the par-
Sidebar. Survey Comments from Survivors
Offering Support
“Transitions was educational and made me think differently
about moving forward.”
“It consolidated so many issues, strategies, and challenges
that I need to consider...very hands on.”
“It helped me organize from treatment plan to life
beyond.”
“Transitions left me less anxious with a more positive
and hopeful outlook.”
47

EDUCATIONAL SUMMARIES
ticipants listing what has been learned, and what changes, if
any, may be incorporated into a personal survivorship action
plan. The surveys are mailed back to participants 6
months later with a letter that encourages each survivor to
review their progress on their action plans.
Surveys indicate that over 90% of attendees benefited
from the peer-led workshop and that the timing of the
workshop was critical. Peer survivors are uniquely qualified
Author’s Disclosures of Potential Conflicts of Interest
Author
O’Neill, Denise J.*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
References
Consultant or
Advisory Role
1. National Cancer Institute. U.S. cancer survivors grows to nearly
12 million. http://www.cancer.gov/newscenter/pressreleases/2011/
survivorshipMMWR2011. Accessed May18, 2012.
2. Dana-Farber Cancer Institute. 2010 Spring/Summer Paths of
48
to share wisdom and information that can decrease patient
anxiety, provide direction, and reinforce compliance of medically
supervised care plans.
In summary, trained peer survivors can successfully assist
patients to navigate from active treatment into life as a
breast cancer survivor. Peer survivor-led workshops may be
a cost-effective way for hospitals to enhance future survivorship
care.
Stock
Ownership Honoraria
Research
Funding
Expert
Testimony
Other
Remuneration
Progress. Kenneth Miller, MD. http://www.dana-farber.org/News
room/Publications/Cancer-s-Seasons-of-Survivorship-.aspx. Accessed
May 18, 2012.
3. LIVESTRONG. How Cancer Has Affected Post-Treatment Survivors:
A LIVESTRONG Report. June, 2010. http://www.livestrong.
org/pdfs/3-0/LSSurvivorSurveyReport. Accessed April 30, 2012.

GENERAL SESSION VIII:
The Future of Health Policy
CHAIR
Richard L. White Jr., MD
Carolinas Medical Center
SPEAKERS
Claudia R. Baquet, MD, MPH
University of Maryland School of Medicine
Gary H. Lyman, MD, MPH
Duke University and the Duke Cancer Institute
Sandra M. Swain, MD
Washington Cancer Institute, Washington Hospital Center
After this session, attendees should be able to
● Evaluate current practice and suggest strategies that could be implemented to reduce the potential for health care
disparities for patients at risk
● Compare and contrast the processes used in changing practice standards to include a new drug versus a new technology
● Describe how Rapid Learning Systems can be used to improve the speed of clinical research and adoption of evidencebased
medicine in the oncology field and evaluate the potential of these systems to impact patient care and patient
outcomes

What Are the Differences between Approving and
Using New Drugs and New Devices
in the United States?
Gary H. Lyman, MD, MPH
Duke University and the Duke Cancer Institute, Durham, NC
W
hy does new drug development in oncology take so
long and cost so much whereas a new technology,
such as a device, test, diagnostic, or prognostic tool, undergoes
much less scrutiny and may get approved with no
demonstrated clinical validity or utility with an investment
of fewer resources? To better understand these differences,
it is important to review the process by which the United
States makes decisions on therapeutic/diagnostic modalities
and how these differences influence the utilization of these
interventions. Regulation of drugs and devices at the federal
level in the United States is handled by different agencies.
Drugs and biologics are governed by the Centers for Drug
Evaluation and Research (CDER) and Center for Biologics
Evaluation and Research (CBER), respectively, and devices
are handled by the Center for Devices and Radiological
Health (CDRH). A medical device is defined by the U.S.
Food and Drug Administration (FDA) as any health care
product that does not work through chemical action or by
metabolism and can include diagnostic aids such as in vitro
tests.
History of Drug and Device Approval in the
United States
Prior to 1900, there were essentially no laws or regulations
governing the sale or use of drugs or devices in the United
States. In 1906, the Federal Food and Drug Act was passed
preventing interstate transport of drugs that did not meet
certain standards. 1 However, it was not until the Federal
Food, Drug, and Cosmetic Act of 1938 that a formal process
for obtaining approval by the FDA was established based on
the demonstration of safety. 2 Following the thalidomide
disaster in 1962, applicants for new drug approvals were
required to demonstrate efficacy as well as some information
on safety. 2,3 Finally, it was not until 1976 that sponsors
were required to register new devices with the FDA. Although
subsequent legislation has further strengthened
and modernized these regulations, the oversight of medical
devices has always lagged behind drug regulation.
Current Regulation of Drugs and Devices in
the United States
Today, to conduct research on new drugs or biologics in
humans, sponsors must submit an investigational new drug
(IND) application. Clinical studies can then be initiated
unless the FDA places a hold on the application within
30 days of submission. For regulatory approval, sponsors
of new drugs must submit a new drug application (NDA).
An abbreviated new drug application (ANDA) can be submitted
for generic drugs not requiring clinical trials but
only demonstration of bioequivalence to the innovator
agent. Following often extensive preclinical work, a new
50
drug must demonstrate substantial evidence of effectiveness
and safety in at least one controlled clinical trial. Since
1992, drugs or biologics for treating serious diseases can be
granted accelerated approval based on surrogate endpoints
that are reasonably likely to predict clinical benefit. Such
approval is conditional on subsequent clinical studies confirming
the magnitude of benefit and safety seen with
the early studies. Accelerated approval has been granted to
35 oncology products over the past 20 years. The entire
drug development and approval process takes an average
of 8 to 10 years and sometimes longer. 2,4 Still to be determined
are the detailed processes for seeking approval of a
biosimilar or bioequivalent to approved innovator biologic
agents. 5,6
Following registry with the FDA, the risk of medical
devices is then classified as Class I (lowest risk) through
Class III (highest risk). 3 The risk determined by the CDRH
will determine the appropriate pathway the device sponsor
must follow in seeking approval. By law, most Class I and
some Class II devices are considered exempt from formal
review. The majority of Class II devices go through a standard
Premarket Notification as a 501[k] submission, which
requires demonstration of equivalence to a previous device
performing in a similar fashion with equal or better efficacy
and safety. Because demonstration of equivalence rarely
involves an actual clinical trial, once complete, the device is
said to be FDA-cleared but not approved. A new device not
demonstrated to be substantially equivalent to a prior device
will be placed in Class III. Most Class III devices go
through a more thorough Premarket Application (PMA),
which may require preclinical and interventional clinical
trials demonstrating reasonable assurance of effectiveness
and safety. This is often based on a single study with valid
scientific evidence demonstrating that the likely benefits
outweigh risks.
Similarities and Differences between Drug
and Devices Regulation and Marketing
Review and approval of drugs and devices are similar in a
number of ways. All medical devices must be registered with
the FDA and are reviewed for adulteration or misbranding. 3
There is a process for both drugs and devices to be studied in
humans either through an IND or an investigational device
exemption (IDE). Review of both drugs and devices by the
FDA is required. Cleared or approved drugs and devices
must adhere to approved regulations for production, labeling,
advertising, and postapproval surveillance, and they
can be marketed only for their intended purpose. 3 Whereas
all drugs and many devices must demonstrate both safety
and efficacy, neither is currently required to demonstrate

enefit over existing approaches, and neither needs to show
cost-effectiveness for their intended use.
However, FDA review and approval of drugs and devices
differ in a number of other ways. This explains, in part, the
considerable differences in the time and resources required
to bring these products to market. Although all medical
devices must register with the FDA and adhere to good
manufacturing practices and proper labeling, most are marketed
in the United States through a much less demanding
regulatory process than that imposed on drugs. Intervention
trials are generally not required for diagnostic devices.
Therefore, FDA allowance of low- or intermediate-risk medical
devices does not imply that clinical trials have been
conducted or that efficacy and safety have been established
based on a clinical study prior to market approval similar to
that required of drugs. Only 2% of medical devices are
approved through the PMA process, and only rarely have
randomized controlled trials been required prior to approval
of high risk devices under a PMA. 3 Finally, it should
also be noted that manufacturers of drugs are required to go
through FDA inspections while the same is not true for
manufacturers of medical devices.
Author’s Disclosures of Potential Conflicts of Interest
Conclusions
Employment or
Leadership Consultant or Stock
Research
Author
Positions Advisory Role Ownership Honoraria Funding
Lyman, Gary H. Amgen
References
1. Hyman PM, Carvajal R. Drugs and other product choices. Dermatol
Ther. 2009;22:216-224.
2. Moore SW. An overview of drug development in the United States
and current challenges. South Med J. 2003;96:1244-1255.
3. Sweet BV, Schwemm AK, Parsons DM. Review of the processes for
FDA oversight of drugs, medical devices, and combination products.
J Manag Care Pharm. 2011;17:40-50.
4. Lipsky MS, Sharp LK. From idea to market: the drug approval
process. J Am Board Fam Pract. 2001;14:362-367.
5. Hirsch BR, Lyman GH. Biosimilars: are they ready for prime-
EDUCATIONAL SUMMARIES
The reasons for the major differences in the review and
monitoring of drugs and devices in the United States are
multiple and include legislative restrictions, study design
challenges, and ethical considerations. Likewise, the great
diversity of devices developed suggests that not all require
the same level of scrutiny. Finally, review and monitoring of
the enormous volume of device submissions challenge current
FDA resources. 7,8 Although the market for drugs in the
United States far exceeds that for devices, nearly five times
as many new device submissions are received each year as
new drug applications. At the same time, nearly six-fold
more reports of adverse events from drugs are reported to
the FDA annually than from devices. Clearly, the review
and approval processes and appropriate postmarketing
monitoring of drugs and biologics as well as medical devices
in the United States needs to be reevaluated and appropriately
resourced. Doing so will provide efficient and safe
oversight of an ever-expanding portfolio of diagnostic and
therapeutic interventions available for the management of
patients with cancer.
Expert
Testimony
Other
Remuneration
time in the United States? J Natl Compr Canc Netw. 2011;9:934-
942.
6. Zelenetz AD, Ahmed I, Braud EL, et al. NCCN Biosimilars White
Paper: regulatory, scientific, and patient safety perspectives.
J Natl Compr Canc Netw. 2011;9 (Suppl 4):S1–22.
7. Feldman MD, Petersen AJ, Karliner LS, et al. Who is responsible
for evaluating the safety and effectiveness of medical devices?
The role of independent technology assessment. J Gen Intern
Med. 2008;23 (Suppl 1):57-63.
8. Ramsey SD, Luce BR, Deyo R, et al. The limited state of technology
assessment for medical devices: facing the issues. Am J Manag
Care. 1998;4:SP188–199.
51

GENERAL SESSION IX:
New Directions in Systemic Therapy for Advanced Disease
CHAIR
Heather McArthur, MD
Memorial Sloan-Kettering Cancer Center
SPEAKERS
Lisa A. Carey, MD
Lineberger Comprehensive Cancer Center
Francisco J. Esteva, MD, PhD
University of Texas M. D. Anderson Cancer Center
Mark D. Pegram, MD
Stanford University
After this session, attendees should be able to
● Assess current advances in HER2-positive breast cancer research, focusing on the implications that new data may have
on the standard of care for patients presenting with this genetic variant
● Review the prevailing systemic therapies available for the treatment of hormone-responsive breast cancer and recommend
appropriate treatment options to patients based on currently available evidence
● Describe the unique considerations for patients presenting with triple-negative breast cancer and recommend the most
appropriate treatment strategies based on current evidence

Hormone-Responsive Disease
Francisco J. Esteva, MD, PhD
University of Texas M. D. Anderson Cancer Center, Houston, TX
E
ndocrine therapy is the safest and most effective therapeutic
option for patients with estrogen receptor
(ER)- and/or progesterone receptor (PR)-positive metastatic
breast cancer. Traditionally, for a breast cancer to be considered
ER-positive or PR-positive, these receptors had to be
expressed in at least 10% of invasive cancer cells. In 2010,
the American Society of Clinical Oncology recommended
that tumors should be considered ER- and/or PR-positive
if at least 1% of breast cancer cells stained positive using
immunohistochemistry. 1 This guideline was based on limited
retrospective data 2 and it remains controversial. 3 In
premenopausal women, tamoxifen with or without luteinizing
hormone-releasing hormone agonists remains the
standard of care. In postmenopausal women, aromatase
inhibitors are the most effective front-line therapy. For
patients treated with anastrozole or letrozole in the adjuvant
setting, exemestane or fulvestrant exhibit similar efficacy
in the front-line metastatic setting. 4
Until recently, combination endocrine therapy was not
superior to single agents, and the latter was the preferred
approach. Several trials reported in the last 12 months have
challenged this concept, including the FACT, SWOG-S0226,
TAMRAD, and BOLERO-2 trials.
Bergh and collaborators compared the efficacy of anastrozole
versus a combination of fulvestrant and anastrozole in
women in the first relapse of endocrine-responsive breast
cancer (FACT trial). 5 In this study, postmenopausal
women, or premenopausal women receiving a gonadotropinreleasing
hormone agonist, with ER- and/or PR-positive
breast cancer at first relapse after primary treatment of
localized disease were randomly assigned treatment with
fulvestrant (loading dose followed by 250 mg monthly)
plus 1 mg of anastrozole daily compared with only 1 mg
of anastrozole daily. Overall survival was similar in both
groups. It should be noted, however, that a higher dose of
fulvestrant (500 mg monthly) is more effective than the
dose used in this trial. 6
Mehta and colleagues reported preliminary results of the
SWOG-S0226 trial at the 2011 Cancer Therapy and Research
Center (CTRC)-American Association of Cancer Research
(AACR) San Antonio Breast Cancer Symposium. 7 In
this study, postmenopausal women with ER- and/or PRpositive
metastatic breast cancer were randomly assigned to
receive single agent anastrozole or anastrozole plus fulvestrant.
The progression-free and overall survival among the
694 patients studied were 1.5 and 6.4 months longer, respectively,
for those randomly assigned to anastrozole plus
fulvestrant compared with those given anastrozole alone.
Unplanned subgroup analyses suggested that these benefits
were largely restricted to women who had not received
adjuvant tamoxifen.
The study populations on the FACT and SWOG-S0226
trials were quite different. Most patients who participated
in SWOG-S0226 had not received prior endocrine therapy
and were therefore more likely to respond to the combination
therapy than patients who had previously received
hormone therapy (e.g., FACT). Furthermore, crossover occurred
more frequently on the FACT trial because the
SWOG-S0226 protocol did not allow crossing over to combination
therapy. Taken together, these data support the
testing of anastrozole plus fulvestrant in the adjuvant setting
in patients with ER- and PR-positive breast cancer.
The mTOR pathway plays an important role in the development
of resistance to endocrine therapy. 8 Everolimus is
an oral mTOR inhibitor that has been shown to be effective
in patients with renal cell carcinoma, human epidermal
growth factor receptor 2 (HER2)–overexpressing breast
cancer, and neuroendocrine tumors. 9-11 In the TAMRAD
trial, 12 postmenopausal women with hormone receptor–
positive, HER2-negative, aromatase inhibitor–resistant
metastatic breast cancer were randomized to receive tamoxifen
with everolimus or tamoxifen alone. In this randomized
phase II trial, the combination of tamoxifen plus everolimus
improved the 6-month clinical benefit rate (61% vs. 42%)
and the time to progression (4.5 months vs. 8.6 months).
The main toxicities associated with tamoxifen with everolimus
compared with tamoxifen alone were fatigue (72%
vs. 53%, respectively), stomatitis (56% vs. 7%, respectively),
rash (44% vs. 7%, respectively), anorexia (43% vs. 18%,
respectively), and diarrhea (39% vs. 11%, respectively).
BOLERO-2 was a phase III randomized trial of exemestane
plus everolimus versus exemestane plus placebo in
women with ER- and/or PR-positive metastatic breast
cancer who had progressed on prior nonsteroidal aromatase
inhibitor therapy. 13 This study showed a median progression-free
survival of 6.9 months with everolimus plus exemestane
and 2.8 months with placebo plus exemestane
(p � 0.001).
Taken together, data from the TAMRAD and BOLERO-2
trials provide strong evidence for the ability of everolimus to
overcome resistance to endocrine therapy. Combination of
everolimus and endocrine therapy is currently under investigation
in the adjuvant setting. Our group is also exploring
a combination of exemestane, everolimus, and metformin in
obese postmenopausal women with ER- and/or PR-positive
metastatic breast cancer.
In summary, patients with hormone-responsive breast
cancer have several treatment options. Combination of
anastrozole and fulvestrant is an attractive option for patients
with stage IV ER- and/or PR-positive breast cancer.
For patients who develop metastatic disease while receiving
adjuvant endocrine therapy or whose metastatic breast
cancer progresses after single agent, front-line endocrine
therapy, the combination of exemestane and everolimus is
an attractive option. Novel combinations will build on this
approach in the front-line metastatic setting and ultimately
in the adjuvant setting.
53

EDUCATIONAL SUMMARIES
Author’s Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Esteva, Francisco J. Genentech;
Novartis
References
1. Hammond ME, Hayes DF, Dowsett M, et al. American Society of
Clinical Oncology/College Of American Pathologists guideline
recommendations for immunohistochemical testing of estrogen
and progesterone receptors in breast cancer. J Clin Oncol. 2010;
28:2784-2795.
2. Harvey JM, Clark GM, Osborne CK, et al. Estrogen receptor
status by immunohistochemistry is superior to the ligandbinding
assay for predicting response to adjuvant endocrine
therapy in breast cancer. J Clin Oncol. 1999;17:1474-1481.
3. Iwamoto T, Booser D, Valero V, et al. Estrogen receptor (ER)
mRNA and ER-related gene expression in breast cancers that are
1% to 10% ER-positive by immunohistochemistry. J Clin Oncol.
2012;30:729-734.
4. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized
placebo controlled trial of fulvestrant compared with exemestane
after prior nonsteroidal aromatase inhibitor therapy in postmenopausal
women with hormone receptor-positive, advanced
breast cancer: results from EFECT. J Clin Oncol. 2008;26:1664-
1670.
5. Bergh J, Jonsson PE, Lidbrink EK, et al. FACT: An Open-Label
Randomized Phase III Study of Fulvestrant and Anastrozole in
Combination Compared With Anastrozole Alone as First-Line
Therapy for Patients With Receptor-Positive Postmenopausal
Breast Cancer. J Clin Oncol. 2012;30:1919-1925.
6. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the
CONFIRM phase III trial comparing fulvestrant 250 mg with
fulvestrant 500 mg in postmenopausal women with estrogen
54
Stock
Ownership Honoraria
Research
Funding
GlaxoSmithKline
Expert
Testimony
Other
Remuneration
receptor-positive advanced breast cancer. J Clin Oncol. 2010;28:
4594-4600.
7. Mehta RS, Barlow WE, Albain KS, et al. A phase III randomized
trial of anastrozole versus anastrozole and fulvestrant as firstline
therapy for postmenopausal women with metastatic breast
cancer: SWOG S0226. Abstract S1–1. Presented at: 2011 CTRC-
AACR San Antonio Breast Cancer Symposium; December 2011;
San Antonio, TX.
8. deGraffenried LA, Friedrichs WE, Russell DH, et al. Inhibition of
mTOR activity restores tamoxifen response in breast cancer cells
with aberrant Akt Activity. Clin Cancer Res. 2004;10:8059-8067.
9. Morrow PK, Wulf GM, Ensor J, et al. Phase I/II study of trastuzumab
in combination with everolimus (RAD001) in patients
with HER2-overexpressing metastatic breast cancer who progressed
on trastuzumab-based therapy. J Clin Oncol. 2011;29:
3126-3132.
10. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic
neuroendocrine tumors. N Engl J Med. 2011;364:514-523.
11. Escudier B, Szczylik C, Porta C, et al. Treatment selection in
metastatic renal cell carcinoma: expert consensus. Nat Rev Clin
Oncol. 2012;9:327-337.
12. Bachelot T, Bourgier C, Cropet C, et al. Randomized Phase II
Trial of Everolimus in Combination With Tamoxifen in Patients
With Hormone Receptor-Positive, Human Epidermal Growth
Factor Receptor 2-Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study. J Clin
Oncol. 2012. Epub 2012 May 7.
13. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal
hormone-receptor-positive advanced breast cancer.
N Engl J Med. 2012;366:520-529.

Therapeutic Strategies Targeting ERBB2:
An Update on ERBB2-Positive Breast Cancer
T
he discovery of ERBB2 gene amplification in approximately
20% of human breast cancers (BC) and its
association with an adverse clinical prognosis, indicating
that it may be playing a critical role in disease pathogenesis,
has revolutionized the diagnosis and treatment of BC. 1-4
Trastuzumab, when added to standard adjuvant chemotherapy,
reduces relapse risk by approximately half and
reduces mortality by about one third in ERBB2-altered
early-stage BC, and to date, has withstood the test of time. 5-7
Trastuzumab, and more recently lapatinib, have established
benchmarks for treatment of ERBB2-positive disease.
8,9 These agents have set a high efficacy bar to
overcome for newer emerging ERBB2-targeted therapeutic
approaches. However, within the past year, we have witnessed
whole new paradigms that will challenge the chemotherapy
plus trastuzumab, and lapatinib plus capecitabine,
the current gold standards, as treatment for ERBB2positive
disease. These new approaches include the addition
of a second generation anti-ERBB2 antibody (pertuzumab)
in combination with trastuzumab plus chemotherapy, and
the development of an antibody-drug conjugate (ADC)
based upon trastuzumab. 10-13 Both of these new approaches
could prove to be practice changing, once again raising the
bar for clinical efficacy (and therapeutic index) in ERBB2positive
BC. Given this rapid pace of discovery research and
clinical validation, the year 2012 will likely be remembered
as a golden age of ERBB2-targeted therapy clinical research
for BC.
Second Generation Anti-ERBB2 Antibody
Pertuzumab with Binding Epitope Distinct
from Trastuzumab
According to Dennis J. Slamon, MD, PhD (oral communication,
September 1991), in an early screen of a panel of
murine monoclonal anti-ERBB2 antibodies, two antibodies
stood apart from several others in terms of demonstration of
preclinical efficacy in cell proliferation assays in vitro, and in
primary human tumor xenotransplants grown in the subrenal
capsule of athymic mice in vivo (personal communication).
Two promising murine antibodies to emerge from
these screens were 4D5, which when humanized became
trastuzumab, and 2C4, which following humanization is
now called pertuzumab. Experimentally, it became evident
that these two anti-ERBB2 antibodies were distinct, both
functionally as well as structurally. 14,15 In contrast to trastuzumab,
which binds to a juxtamembrane epitope in domain
IV of the ERBB2 extracellular domain (ECD),
pertuzumab binds to the dimerization interface contained
in domain II of the ERBB2 ECD (Fig. 1). This distinction is
biologically relevant in that pertuzumab disrupts the ability
of ERBB2 to dimerize with any other ERBB receptor family
member, thus attenuating signaling events triggered by
Mark D. Pegram, MD
Stanford University, Stanford, CA
ERBB receptor family ligands. 16 For a time it was hoped
that this could set the stage for pertuzumab treatment of
ERBB2 nonamplified tumor types, if their pathogenesis
proved to be driven by ligand-activated heterodimeric complexes
containing ERBB2 as a coreceptor. 17 Unfortunately,
with the possible exception of platinum-refractory ovarian
cancer, 18 this hypothesis was not supported by early clinical
trial data of single agent pertuzumab in ERBB2-negative
malignancies, thus focus returned to development of pertuzumab
in ERBB2-positive disease states, particularly
BC. 19-21 In preclinical models, trastuzumab plus pertuzumab
combination synergistically inhibited the survival of
ERBB2-amplified breast cancer cells. 22 Combination drug
treatment reduced levels of total and phosphorylated
ERBB2 protein and blocked receptor signaling through
Akt, resulting in induction of apoptosis, but did not affect
mitogen-activated protein kinase. 22 These results suggested
the possibility that combining ERBB2-targeting treatment
agents may be a more effective therapeutic strategy than
with a single ERBB2-directed antibody. Consequently, following
phase II proof of concept clinical studies, pivotal
randomized trials designed to explore the paradigm of dual
antibody therapy for ERBB2-positive breast cancer ensued.
19,23 In a clinical evaluation of pertuzumab and trastuzumab
(CLEOPATRA) combination in first-line metastatic
disease, 808 ERBB2-positive patients were randomly assigned
to receive docetaxel plus trastuzumab and placebo
versus docetaxel and trastuzumab plus pertuzumab. In an
independently-assessed analysis of clinical efficacy, the median
progression-free survival (PFS) in the control arm was
12.4 months, compared with 18.5 months in the pertuzumab
arm (hazard ratio [HR] � 0.62; p � 0.001). 24 An
interim analysis of overall survival (OS) also showed a
strong trend in favor of pertuzumab plus trastuzumab plus
docetaxel. However, although the p value was 0.005, it did
not cross the prespecified O’Brien-Fleming value of p �
0.001, thus the OS result must be considered preliminary
pending the protocol-planned final analysis when sufficient
numbers of events have ultimately been recorded. Notably,
the safety profile was generally similar in the two treatment
groups, and there was no increase in left ventricular systolic
dysfunction; although the rates of grade 3 or higher febrile
neutropenia and diarrhea were larger in the pertuzumabtreated
group. 24 These data suggested that further exploration
of this approach in the early disease setting was
warranted. Accordingly, a randomized phase II trial of
pertuzumab/trastuzumab combination in the neoadjuvant
setting has been conducted (NeoSphere). 10 In this multicenter,
open-label, phase II study, treatment-naive women
with ERBB2-positive BC were randomly assigned to receive
four neoadjuvant cycles of either trastuzumab plus docetaxel;
pertuzumab and trastuzumab plus docetaxel; pertuzumab
and trastuzumab; or pertuzumab plus docetaxel.
55

EDUCATIONAL SUMMARIES
Fig. 1. Pertuzumab and trastuzumab bind to distinct epitopes on the ERBB2 extracellular domain. In contrast
to trastuzumab, which binds to a juxtamembrane epitope in domain IV of the ERBB2 extracellular domain
(ECD), pertuzumab binds to the dimerization interface contained in domain II of the ERBB2 ECD. Pertuzumab
disrupts the ability of ERBB2 to dimerize with any other ERBB receptor family member, thus attenuating
signaling events triggered by ERBB receptor family ligands. Reprinted from Cancer Cell with permission from
Elsevier. 32
Patients given pertuzumab and trastuzumab plus docetaxel
had a significantly improved pathological complete response
(pCR) rate (45.8%) as compared with those given
trastuzumab plus docetaxel (29%; p � 0.0141), without
substantial differences in tolerability. 10 It should be noted
however, that the time to relapse event data have not yet
been reported in this study, therefore it is not yet known
whether improved pCR rates for the combination arm
will translate into improved relapse-free or overall survival.
Therefore, in contrast to the CLEOPATRA study in
advanced disease, the NeoSphere data cannot yet be
considered to be practice changing. Taken together, the
findings from CLEOPATRA and NeoSphere suggest that
targeting ERBB2-positive tumors with two anti-ERBB2
monoclonal antibodies that have complementary mechanisms
of action results in a more comprehensive blockade of
ERBB2 and highlights the clinical importance of preventing
the ligand-dependent formation of ERBB2-containing
dimers (particularly ligand-activated heterodimers) in order
to best silence ERBB2-driven downstream signaling
events. 25 A study of pertuzumab plus trastuzumab adjuvant
therapy in patients with newly diagnosed ERBB2-positive
early breast cancer has been initiated, and is currently
underway (APHINITY; NCT01358877). Pertuzumab was
recently FDA-approved (June 2012) for combination therapy
with trastuzumab and docetaxel in the metastatic
setting.
56
Antibody–Drug Conjugates (ADCs) based on
Trastuzumab
ADCs can be constructed by direct covalent linkage of a
therapeutic drug (often a cytotoxic/chemotherapeutic species)
directly to a monoclonal antibody backbone. By design,
the antibody component of the ADC is merely being used as
a delivery vehicle in order to transport a cytotoxic payload
selectively to tumor cells. In ADC constructs the linker
chemistry is critical to the success of the approach, since if
the chemistry is too labile, the molecule will be unstable in
the circulation and could lead to excessive toxicity if the
cytotoxic species is liberated in normal tissue compartments.
On the other hand, at least in theory, if the linker
chemistry is “too stable” then the cytotoxic species may not
be appropriately liberated in situ in the tumor microenvironment,
thus limiting potential for antitumor efficacy. Accordingly,
fine-tuning of linker chemistry is required for
optimization of ADC efficacy and may be unique to each
target, and to each cytotoxic moiety. We previously reported
preclinical efficacy of an ADC based upon trastuzumab. 26
For these experiments, a bifunctional linker was used to
create a targeted prodrug that links trastuzumab to the
chemotherapeutic agent paclitaxel, via an energy-reversible
ester bond. This study demonstrated in vivo efficacy of a
single-treatment of trastuzumab-paclitaxel ADC in decreasing
tumor volume and tumor cell density of human ERBB2-

Fig. 2. Anti-ERBB2 antibody drug-conjugate trastuzumab-DM1
(T-DM1). T-DM1 retains ERBB2targeting
properties of trastuzumab, along with
targeted delivery of the potent anti-microtubule
derivative, DM1. Following binding to ERBB2 at the
cell surface, T-DM1 undergoes receptor-mediated
endocytosis, ultimately resulting in intracellular release
of DM1 species (see text), and selective cytotoxicity
to ERBB2-overexpressing tumor cells.
positive BT-474 mammary tumor cells implanted in SCID
mice. Moreover, the ADC was more effective in killing tumor
cells than equivalent concentrations of coadministered
free trastuzumab and free paclitaxel. 26 Thus the therapeutic
index (efficacy divided by toxicity) could be increased
markedly by an ADC approach.
Another more potent trastuzumab-based ADC is
trastuzumab-DM1 (T-DM1; trastuzumab emtansine),
which is composed of a maytansinoid derivative, linked with
a nonreducible thioether linker termed MCC (Fig. 2). Derivatization
of trastuzumab in this manner occurs predominantly
on the epsilon amino groups of lysines, which are
abundant (n � 91) and distributed throughout the antibody’s
sequence. 27 Interestingly, the binding affinity, specificity,
signal perturbation capability, and effector functions
of trastuzumab remain intact despite DM1 conjugation. 28
Maytansinoids are natural products that are potent antimitotic
agents, which like the vinca alkaloids, prevent
microtubule assembly. 27 It is postulated that following
receptor-mediated endocytosis, T-DM1 undergoes intralysosomal
proteolytic degradation resulting in the release of
Lys-MCC-DM1 and subsequent antitubulin-associated cell
death. 27 In the phase I dose escalation study of T-DM1,
thrombocytopenia was found to be a dose-limiting toxicity.
29 In two phase II studies in patients with heavily
pretreated ERBB2-positive advanced cancers who had progressed
on trastuzumab and chemotherapy, or both
trastuzumab- and lapatinib-based regimens in the metastatic
setting, T-DM1 produced response rates between
33.8% and 41%. 13,30 In one study, higher response rates and
longer response durations were seen in patients with centrally
confirmed ERBB2-amplified disease, once again reinforcing
the importance of accurate ERBB2 testing in
patients receiving ERBB2-targeted therapies. In a random-
EDUCATIONAL SUMMARIES
ized study in previously untreated patients with ERBB2positive
breast cancer, T-DM1 also produced higher
response rates and had a favorable toxicity profile compared
with free trastuzumab when given in combination with free
docetaxel. 31 Importantly, in terms of therapeutic index, the
incidence of grade 3 or higher adverse events in the T-DM1
arm was just half that observed in the trastuzumab plus
docetaxel arm (37% vs. 75%). No grade 3 neutropenia was
observed with T-DM1 and, remarkably, only 1.5% of patients
experienced alopecia. Fortunately, in this study
trastuzumab-DM1 was not associated with an increased risk
of cardiotoxicity compared with trastuzumab plus docetaxel.
EMILIA (NCT00829166) is a phase III, multinational,
multicenter, open-label study evaluating the efficacy and
safety of T-DM1 compared with capecitabine plus lapatinib
(XL), an approved combination for trastuzumab-refractory
ERBB2-positive metastatic BC. Pts were randomized to
receive T-DM1 (3.6 mg/kg IV q3w) or X (1,000 mg/m 2 bid,
days 1–14 q3w) � L (1,250 mg PO qd, days 1-21) until
disease progression. Key eligibility criteria included central
confirmation of ERBB2 status (IHC 3� or FISH-positive)
and prior treatment with trastuzumab and a taxane. 32 Primary
endpoints were PFS by independent review, OS, and
safety. Baseline demographics, prior therapy, and disease
characteristics were balanced between the T-DM1 arm (495
patients) and XL arm (496 patients). Median durations of
follow-up were 12.9 months (T-DM1) and 12.4 months (XL).
Patients in the T-DM1 arm had significantly longer median
PFS than those in the XL arm (9.6 vs. 6.4 mos; HR � 0.650
[95% CI, 0.549-0.771]; p � 0.0001). Median OS was not
reached in the T-DM1 arm compared with 23.3 mos in the
XL arm (HR � 0.621 [95% CI, 0.475-0.813]; p � 0.0005);
however the interim efficacy O’Brien-Fleming statistical
boundary for OS was not crossed. In a planned analysis,
1-year survival rates (85% [95% CI, 81%-89%] compared
with 77% [72%-82%]) and 2-year survival rates (65% [59%-
72%] compared with 48% [39%-56%]) were higher with
T-DM1. There were fewer grade 3 or higher adverse events
with T-DM1 (41% vs. 57%) and fewer dose reductions (16%
with T-DM1 vs. 53% with X and 23% with L). 32 This impressive
result from an ADC therapeutic approach offers a new
paradigm for treatment of ERBB2-positive advanced BC,
and suggests that further exploration of this ADC is warranted
in (1) earlier lines of treatment for advanced disease
and (2) early-stage, ERBB2-postive breast cancer. The
MARIANNE study (BO22589/TDM4788g) is an ongoing
randomized, phase III, placebo-controlled study in first line
ERBB2-positive metastatic BC (1,092 patients) that randomly
assigns patients to receive trastuzumab plus a taxane,
T-DM1 plus placebo, or T-DM1 plus pertuzumab. 33
Primary endpoints are PFS assessed by independent review
and safety, while secondary endpoints include OS, patientreported
outcomes, and an exploratory biomarker analysis.
It is hoped that the result of this trial will help to inform
potential regimens to be considered for future adjuvant
T-DM1 campaigns.
57

EDUCATIONAL SUMMARIES
Author’s Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Pegram, Mark D. Dava Oncology (I) Bristol-Myers
Squibb;
Genentech;
GlaxoSmithKline;
Novartis; Pfizer/
Wyeth (U);
Sanofi
References
1. Slamon DJ, Clark GM, Wong SG, et al. Science. 1987;235:177-
182.
2. Slamon DJ, Godolphin W, Jones LA, et al. Science. 1989;244:707-
712.
3. Pegram M, Slamon D. Semin Oncol. 2000;27:13-19.
4. Slamon DJ, Leyland-Jones B, Shak S, et al. N Engl J Med.
2001;344:783-792.
5. Romond EH, Perez EA, Bryant J, et al. N Engl J Med. 2005;353:
1673-1684.
6. Perez EA, Romond EH, Suman VJ, et al. J Clin Oncol. 2011;29:
3366-3373.
7. Slamon D, Eiermann W, Robert N, et al. N Engl J Med. 2011;
365:1273-1283.
8. Geyer CE, Forster J, Lindquist D, et al., N Engl J Med. 2006;355:
2733-2743.
9. Cameron D, Casey M, Oliva C, et al. Oncologist. 2010;15:924-934.
10. Gianni L, Pienkowski T, Im YH, et al. Lancet Oncol. 2012;13:25-
32.
11. Baselga J, Bradbury I, Eidtmann H, et al. Lancet. 2012;379:633-
640.
12. Baselga J, Cortés J, Kim SB, et al. N Engl J Med. 2012;366:109-
119.
13. Burris HA III, Rugo HS, Vukelja SJ, et al. J Clin Oncol. 2011;29:
398-405.
14. Fendly BM, Winget M, Hudziak RM, et al. Cancer Res. 1990;50:
1550-1558.
15. Franklin MC, Carey KD, Vajdos FF, et al. Cancer Cell. 2004;5:
317-328.
16. Adams CW, Allison DE, Flagella K, et al. Cancer Immunol Immunother.
2006;55:717-727.
17. Agus DB, Akita RW, Fox WD, et al. Cancer Cell. 2002;2:127-137.
18. Makhija S, Amler LC, Glenn D, et al. J Clin Oncol. 2010;28:1215-
1223.
58
Stock
Ownership Honoraria
Genentech;
GlaxoSmithKline;
Sanofi
Research
Funding
Expert
Testimony
Sanofi Novartis
Other
Remuneration
19. Walshe JM, Denduluri N, Berman AW, et al. Clin Breast Cancer.
2006;6:535-539.
20. Agus DB, Sweeney CJ, Morris MJ, et al. J Clin Oncol. 2007;25:
675-681.
21. Herbst RS, Davies AM, Natale RB, et al. Clin Cancer Res. 2007;
13:6175-6181.
22. Nahta R, Hung MC, Esteva FJ. Cancer Res. 2004;64:2343-2346.
23. Baselga J, Gelmon KA, Verma S, et al. J Clin Oncol. 2010;28:
1138-1144.
24. Arteaga CL, Sliwkowski MX, Osborne CK, et al. Nat Rev Clin
Oncol. 2011;9:16-32.
25. Gilbert CW, McGowan EB, Seery GB, et al. Breast Cancer Res
Treat. 2011;128:347-356.
26. Lewis Phillips GD, Li G, Dugger DL, et al. Cancer Res. 2008;68:
9280-9290.
27. Krop IE, Beeram M, Modi S, et al. J Clin Oncol. 2010;28:2698-
2704.
28. Krop I, LoRusso P, Miller KD, et al. [abstract 277O]. Presented
at: European Society for Medical Oncology Congress; Milan,
Italy, October 8-12, 2010.
29. Perez EA, Dirix L, Kocsis J, et al. [abstract LBA3]. Presented at:
European Society of Medical Oncology; Milan, Italy, October
8-12, 2010.
30. Blackwell K, Miles D, Gianni L, et al. Primary results from
EMILIA, a phase III study of trastuzumab emtansine (T-DM1)
versus capecitabine (X) and lapatinib (L) in HER2-positive locally
advanced or metastatic breast cancer (MBC) previously
treated with trastuzumab (T) and a taxane. J Clin Oncol. 2012;
30 (suppl; abstr LBA1).
31. LoRusso PM, Weiss D, Guardino E, et al. Clin Cancer Res.
2011;17:6437-6447.
32. Hubbard SR. EGF receptor inhibition: attacks on multiple
fronts. Cancer Cell. 2005;7:287-288.

GENERAL SESSION XI:
Debates on Current Controversies in Systemic Therapy
CO-CHAIRS
Gabriel N. Hortobagyi, MD
University of Texas M. D. Anderson Cancer Center
Minetta C. Liu, MD
Georgetown University
SPEAKERS
Julie Gralow, MD
Fred Hutchinson Cancer Research Center
Clifford Hudis, MD
Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College
Stephen Jones, MD
US Oncology Research
Catherine Van Poznak, MD
University of Michigan
After this session, attendees should be able to
● Evaluate the benefits and risks of using anthracyclines in patients with HER2-positive and HER2-negative disease and
compare this therapeutic option with other forms of treatment to maximize efficacy and quality of life
● Assess the use of bisphosphonates to halt bone metastasis and determine whether the use of these agents can effectively
prevent disease progression in patients with early-stage breast cancer

Bone Health and the Role of Biphosphonates in Early-Stage
Breast Cancer: A Debate
Julie Gralow, MD, and Catherine Van Poznak, MD
Fred Hutchinson Cancer Research Center, Seattle, WA, and
University of Michigan, Ann Arbor, MI
A
djuvant systemic therapy is administered in an attempt
to eradicate occult tumor cells and decrease the
risk of cancer recurrence. Although the vast majority of
women diagnosed with operable breast cancer will not experience
recurrent disease, the risk of developing metastases
remains, even after optimal standard local and systemic
therapies. When breast cancer metastasizes, bone is the
most commonly affected site. 1 Osteoclast inhibition has
been studied as a means to interrupt the vicious cycle of cell
signaling between breast cancer cells and the bone microenvironment
to affect the metastatic process.
Preclinical studies suggest that bisphosphonates may inhibit
critical steps in the development of bone metastases in
addition to inhibiting resorption. Bisphosphonates inhibit
the adhesion of breast cancer cells to extracellular bone
matrix, inhibit tumor cell invasion, 2-4 and induce apoptosis.
5 Pretreatment of nude mice with risedronate before
inoculation of tumor cells reduced the development of osteolytic
lesions. 6 Clinically, there is epidemiologic evidence that
bisphosphonates used in the management of postmenopausal
osteoporosis may have anticancer effects. 7,8 It is
important to note that use of osteoclast-inhibiting therapy
to prevent osteoporotic fractures is a separate, but related,
concern in managing patients with breast cancer.
Adjuvant Osteoclast-Targeted Therapy in
Early-Stage Breast Cancer: Clinical Evidence
Studies investigating whether bisphosphonates could prevent
bone metastases and improve survival in women with
early-stage breast cancer have produced conflicting results.
Four randomized trials of oral clodronate and one trial of
oral ibandronate have been reported. Two of the four clodronate
trials showed benefit for the clodronate arm. 9-11
The primary endpoint of these two studies was the occurrence
of bone metastases and both studies met this
endpoint. 9-11 In contrast, a third study demonstrated that
bone metastases were detected similarly in the clodronate
and the control group. 12,13 A meta-analysis using the 5-year
data from these three adjuvant clodronate trials did not
show a statistically significant difference in overall survival
(OS) or bone metastasis-free survival, though heterogeneity
among the trials was noted. 14
Two additional trials of oral bisphosphonates were reported
in December 2011. The National Surgical Adjuvant
Breast and Bowel Project (NSABP) B-34 trial compared 3
years of daily 1,600 mg oral clodronate with placebo. The
primary end point, disease-free survival (DFS), was not
statistically significant between clodronate and placebo
arms. 15 Subgroup analysis suggested benefits among patients
age 50 or older at diagnosis. Oral ibandronate was
evaluated in the German Intergroup Node-Positive (GAIN)
60
study in which patients receiving one of two dose-dense
chemotherapy regimens were further randomly assigned to
ibandronate 50 mg orally daily versus placebo. 16 In the first
interim efficacy analysis, there was no difference in 3-year
DFS or overall survival (OS).
Studies with the more potent intravenous aminobisphosphonate,
zoledronic acid, have also shown conflicting results.
In the ABCSG-12 trial, premenopausal women with
estrogen receptor (ER)-positive breast cancer received ovarian
suppression for 3 years with goserelin. 17 Patients were
randomly assigned in a two-by-two design to receive tamoxifen
versus anastrozole, and zoledronic acid (4 mg, every 6
months) or not. After a median follow-up of 84 months,
patients receiving zoledronic acid had a statistically significant
28% reduced risk of recurrence, the primary study
endpoint (hazard ratio [HR]: 0.72; p � 0.014), and a 36%
reduction in risk of death. 18 The recently presented post
hoc, intent to treat analysis of the Zometa-Femara Adjuvant
Synergy Trials (ZO-FAST), which randomly assigned postmenopausal
women receiving adjuvant letrozole to either
upfront or delayed zoledronic acid, showed a 34% improvement
in DFS in favor of the upfront use arm (p � 0.037). 19
In contrast, the Adjuvant Zoledronic Acid to Reduce Recurrence
(AZURE) trial, which randomly assigned patients to
standard adjuvant systemic therapy with or without an
intensified regimen of zoledronic acid for 5 years, showed no
benefit for adjuvant zoledronic acid. 20 At a median follow-up
of 59 months, there was no significant difference in DFS or
OS. In a prespecified subgroup analysis of patients who
were more than 5 years from menopause prior to randomization,
the 5-year OS rate was 84.6% in the zoledronic acid
group and 78.7% in the control group (adjusted HR: 0.74;
95% CI [0.55-0.98]; p � 0.04). There are several important
differences between the study populations of these adjuvant
zoledronic acid trials including hormone receptor status,
menopausal status, and systemic therapies administered. A
number of hypotheses to account for the different study
outcomes can be generated by assessing the differences in
study populations.
Additional recently closed and ongoing trials will provide
further data on the utility of bisphosphonates in the adjuvant
breast cancer setting. The Southwest Oncology Group
(SWOG) S0307 trial randomly assigned 6,000 women with
stage I-III breast cancer receiving standard adjuvant therapy
to oral clodronate versus oral ibandronate versus zoledronic
acid, all for 3 years duration.
Additional strategies for osteoclast inhibition are also in
evaluation. The Denosumab as Adjuvant Treatment for
Women with High Risk Early Breast Cancer Receiving Neoadjuvant
or Adjuvant Therapy (D-CARE) trial is ongoing
and looks at the adjuvant effects of RANK ligand-targeted
therapy. ABCSG-18 will evaluate the effect of denosumab

on fracture risk in patients with breast cancer who receive
AI therapy, with DFS and OS as secondary endpoints. The
S0307 and D-CARE trials include a broad and high-risk
patient population of both pre- and postmenopausal women
and all tumor subsets, including ER-positive and -negative
tumors. The results of these trials will be critical in better
defining the efficacy of bone-modifying agents for preventing
recurrence and may provide additional data regarding
which patients and tumors are most likely to benefit from
treatment.
Authors’ Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Conclusion
The results of the studies to date have not provided sufficient
evidence to universally incorporate osteoclast inhibition
into adjuvant care, although there may be subsets of
patients for whom a bisphosphonate offers a potential anticancer
affect. The ongoing adjuvant phase III studies investigating
bisphosphonates and denosumab are likely to
provide important information, and it is anticipated that
correlative studies will aid in defining those most likely to
gain benefit from adjuvant osteoclast inhibition.
Stock
Ownership Honoraria
Research
Funding
Gralow, Julie Amgen;
Genentech;
Novartis; Roche;
Sanofi
Van Poznak, Catherine Amgen, Novartis
References
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6. Sasaki A, Boyce BF, Story B, et al. Bisphosphonate risedronate
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9. Powles T, Paterson A, McCloskey E, et al. Reduction in bone
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12. Saarto T, Blomqvist C, Virkkunen P, et al. Adjuvant clodronate
EDUCATIONAL SUMMARIES
Expert
Testimony
Other
Remuneration
treatment does not reduce the frequency of skeletal metastases
in node-positive breast cancer patients: 5-year results of a randomized
controlled trial. J Clin Oncol. 2001;19:10-17.
13. Saarto T, Vehmanen L, Virkkunen P, et al. Ten-year follow-up of
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656.
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15. Paterson AHG, Anderson SJ, Lembersky BC, et al. NSABP
Protocol B-34: A Clinical Trial Comparing Adjuvant Clodronate
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Systemic Chemotherapy and/or Tamoxifen or No Therapy–Final
Analysis. Paper presented at: San Antonio Breast Cancer Symposium;
December 2011; San Antonio, TX.
16. Möbus V DI, Elling D, Harbeck N, et al. GAIN study: a phase III
trial to compare ETC vs. EC-TX and ibandronate vs observation
in patients with node positive primary breast cancer-1st interim
efficacy analysis. Paper presented at: San Antonio Breast Cancer
Symposium; December 2011; San Antonio, TX.
17. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy
plus zoledronic acid in premenopausal breast cancer. N Engl
J Med. 2009;360:679-691.
18. Gnant M, Luschin-Ebengreuth G, Stoeger H, et al. Long-term
follow-up in ABCSG-12: significantly improved overall survival
with adjuvant zoledronic acid in premenopausal patients with
endocrine-receptor–positive early breast cancer. Paper presented
at: San Antonio Breast Cancer Symposium; December
2011; San Antonio, TX.
19. de Boer RH, Eidtmann H, Neven P, et al. Long-term survival
outcomes among postmenopausal women with hormone
receptor-positive early breast cancer receiving adjuvant letrozole
and zoledronic acid: 5-year follow-up of ZO-FAST. Paper presented
at: San Antonio Breast Cancer Symposium; December
2011; San Antonio, TX.
20. Coleman R, Cameron D, Dodwell D, et al. Breast-cancer adjuvant
therapy with Zoledronic Acid. N Engl J Med. 2011;365:1396-
1405.
61

In Favor of the Use of Anthracyclines in Patients with
HER2-Positive and HER2-Negative Breast Cancer
Clifford Hudis, MD
Memorial Sloan-Kettering Cancer Center and
Weill Cornell Medical College, New York, NY
A
nthracycline antibiotics are among the most effective
cytotoxic drugs for a wide range of malignancies. In
the 1950s, the Italian-based Farmitalia Research Laboratories
explored soil-based microbes and found the redpigmented
Streptomyces peucetius producing a cytotoxic
antibiotic called daunorubicin at a similar time as a French
group. 1 The Italians generated a mutated bacterium producing
a red antibiotic named Adriamycin (doxorubicin or
more precisely, hydroxydaunorubicin) for the Adriatic Sea.
These agents (daunorubicin and doxorubicin) served as prototypes
and there are now thousands of analogs, including
idarubicin, epirubicin, as well as novel intravenous delivery
systems such as liposomes. 2,3
The anthracyclines interact with DNA by intercalation
and inhibit the biosynthesis of macromolecules and specifically
the relaxation of DNA supercoils by topoisomerase II,
a step needed for effective transcription. By stabilizing
topoisomerase II following interruption of the DNA, these
agents prevent replication. 4
In the last decades of the 20th century, investigators built
on the demonstrations of activity in breast cancer using
cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)
by adding doxorubicin and later epirubicin as components
of palliative and curative systemic treatment. The key challenges
with these drugs include their risks of congestive
heart failure, secondary leukemia, and a host of short-term
and generally reversible toxicities such as neutropenia,
mucositis, nausea, and vomiting. Importantly, the worldwide
overview (meta-analysis) of adjuvant chemotherapy
Author’s Disclosures of Potential Conflicts of Interest
Author
Hudis, Clifford*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
References
Consultant or
Advisory Role
1. Arcamone F, Cassinelli G, Fantini G, et al. Adriamycin, 14hydroxydaunomycin,
a new antitumor antibiotic from S. peucetius
var. caesius. Biotechnol Bioeng. 1969;11:1101-1110.
2. Bonfante V, Bonadonna G, Villani, F, et al. Preliminary clinical
experience with 4-epidoxorubicin in advanced human neoplasia.
Recent Results in Cancer Research. 1980;74:192–199.
3. Symon Z, Peyser A, Tzemach D, et al. Selective delivery of
doxorubicin to patients with breast carcinoma metastases by
Stealth liposomes. Cancer. 1999;86:72-78.
4. Fornari FA, Randolph JK, Yalowich JC, et al. Interference by
doxorubicin with DNA unwinding in MCF-7 breast tumor cells.
Mol Pharmacol. 1994;45:649-656.
5. Early Breast Cancer Trialists’ Collaborative Group. Comparisons
between different polychemotherapy regimens for early
62
regimens performed approximately every 5 years in Oxford,
England, provides evidence of superiority for anthracyclinecontaining
adjuvant regimens in 18,000 randomly assigned
patients (with node-negative, and node-positive disease, all
hormone receptor profiles, and of all ages and menopausal
status). 5 Here, there was no evidence that four doses of
standard doxorubicin (60 mg/m 2 ) and cyclophosphamide
(600 mg/m 2 ) (AC) were superior to CMF regimens. However,
regimens with greater cumulative doses, such as
cyclophosphamide, doxorubicin, and 5-fluorouracil or cyclophosphamide,
epirubicin, and 5-fluorouracil, showed reductions
in breast cancer and all-cause mortality of 22% and
36%, respectively. Not explored fully in the study were
optimal regimens, such as dose-dense AC-paclitaxel and
their comparative toxicities. 6,7 Despite this, there are biological
factors (e.g., topoisomerase II expression), clinical
factors (age, use of additional targeted therapies, prior
treatments), and specific phase III trials (such as docetaxel/
cyclophamide or TC compared to AC) that have raised questions
about the ongoing role of the anthracyclines. 8-13
The challenge for medical oncologists in 2012 is to identify
situations where the anthracyclines remain critical and
those where they might be avoided with no compromise in
overall outcomes. Continued discussion and research is
needed to better identify the most appropriate and optimal
role for these highly effective agents but the superior overall
outcomes in nearly all randomized studies testing these
agents makes it clear that they cannot simply be abandoned.
Stock
Ownership Honoraria
Research
Funding
Expert
Testimony
Other
Remuneration
breast cancer: meta-analysis of long-term outcome among
100,000 women in 123 randomised trials. Lancet. 2012;379:432–
444.
6. Citron ML, Berry DA, Cirincione C, et al. Randomized trial of
dose-dense versus conventionally scheduled and sequential versus
concurrent combination chemotherapy as postoperative adjuvant
treatment of node-positive primary breast cancer: first
report of Intergroup Trial C9741/Cancer and Leukemia Group B
Trial 9741. J Clin Oncol. 2003;21:431-439.
7. Morris P, Dickler M, McArthur H, et al. Dose-dense adjuvant
doxorubicin and cyclophosphamide is not associated with frequent
short-term changes in left ventricular ejection fraction.
J Clin Oncol. 2009;27:6117-6123.
8. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of
trastuzumab plus adjuvant chemotherapy for operable human
epidermal growth factor receptor 2-positive breast cancer: joint

analysis of data from NCCTG N9831 and NSABP B-31. J Clin
Oncol. 2011;29:3366-3373.
9. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant
chemotherapy for operable HER2-positive breast cancer.
N Engl J Med. 2005;353:1673-1684.
10. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab
in HER2-positive breast cancer. N Engl J Med. 2011;365:1273-
1283.
11. Press M, Sauter G, Boyce M, et al. Alteration of topoisomerase
II-alpha gene in human breast cancer: association with respon-
EDUCATIONAL SUMMARIES
siveness to anthracycline-based chemotherapy. J Clin Oncol.
2011;29:859-867.
12. Jones SE, Holmes FA, O’Shaughnessy JA, et al. Docetaxel with
cyclophosphamide is associated with an overall survival benefit
compared to doxorubicin and cyclophosphamide: 7-year follow-up
of US Oncology Research Trial 9735. J Clin Oncol. 2009;27:1177-
1183.
13. Gianni L, Norton L, Wolmark N, et al. Role of anthracyclines in
the treatment of early breast cancer. J Clin Oncol. 2009;27:4798-
4808.
63

Marker-Driven Personalized Therapy for Breast Cancer
Gabriel N. Hortobagyi, MD
University of Texas M. D. Anderson Cancer Center, Houston, TX
Optimal treatment for primary breast cancer is multidisciplinary
and adapted to the clinical and molecular
characteristics of the tumor. 1 Wide surgical excision
remains a cornerstone of curative treatment and postoperative
radiotherapy is known to improve survival. 2 Increasingly,
the molecular subtype of breast cancer is known to
influence local-regional control, and because of this there is
a large interest in determining optimal local-regional therapeutic
interventions. Systemic treatments reduce annual
odds of recurrence by 50% to 65% and annual odds of death
by 40% to 50%. 3
Breast cancer includes several molecularly defined subgroups,
defined by gene expression or protein profiling. 4,5 At
the clinical level, determination of hormone-receptor (HR)
expression, human epidermal growth factor receptor 2
(HER2), grade, and proliferation markers is considered a
practical method to identify clinically relevant subsets of
patients for whom distinct therapeutic decisions are made. 1
Patients with HR-positive, HER2-negative tumors with low
proliferation rate (or low grade) benefit from adjuvant endocrine
therapy; chemotherapy provides limited or no benefit
for this group but does result in incremental benefit for
patients with high-grade or highly proliferative tumors.
Patients with HER2-positive tumors benefit from trastuzumab
combined with chemotherapy, although the magnitude
of this benefit is modulated by hormone-receptor
expression. Patients with triple-negative breast cancer (absent
HR and normal HER2 expression) benefit from chemotherapy
and probably from antivascular endothelial growth
factor therapy such as bevacizumab. However, no specifically
targeted therapeutics exist for this subtype. 6
Adjuvant! Online is widely utilized to estimate risk of
recurrence and death and Oncotype DX and Mammaprint
are increasingly used to define the early breast cancer populations
that benefit from adjuvant systemic therapy. 1
These assays have been validated retrospectively in multiple
datasets, some of them from prospective clinical trials.
From these early validations, only the OncotypeDX seems
to have the ability to predict benefit from specific treatment
Author’s Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Hortobagyi, Gabriel N. Allergan;
Genentech;
Novartis (U);
Sanofi
References
1. Hortobagyi GN. Towards individualized breast cancer therapy:
translating biological concepts to the bedside. Oncologist. 2012;
17:577-584.
2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG),
Darby S, McGale P, et al. Effect of radiotherapy after breast-
64
modalities. Both the OncotypeDx and the Mammaprint are
undergoing definitive evaluation in large, multicenter clinical
trials (TAILORx, RxPONDER, and MINDACT). 7,8
In general, these first-generation genomic assays work
very well for groups of patients but less precisely for individuals.
With technological advances, these approaches are
being overtaken by full sequencing strategies in an attempt
to individualize treatment strategies by finding specific
drivers within tumors. Several companies have developed
commercial products that are currently being assessed in
clinical trials (e.g., Foundation Medicine). Genomic assays
are being studied to determine whether specific therapeutic
interventions would be effective in reducing risk of tumor
cell dissemination and death. Preliminary evidence suggests
that some assays might predict benefit from chemotherapy
whereas others might predict benefit from
endocrine therapy within estrogen receptor–positive subtypes.
9
Widely used biomarkers (HR and HER2) have limited
utility in selecting optimal therapy. The absence of HR and
HER2 is a sensitive indicator of resistance to endocrine and
HER2-directed therapies, respectively, but these assays
have limited ability to predict response to those same treatments.
There is interest in understanding mechanisms of
resistance to commonly used drugs; thus, coactivation of
membrane-based growth factor receptor systems (EGFR,
HER2, insulin-like growth factor receptor, etc.) has been
linked to resistance to endocrine agents, and dysregulation
of the PI3K/AKT/mTOR-signaling pathways is associated
with resistance to endocrine and trastuzumab therapy.
Combinations of targeted agents are currently under assessment.
10,11 There is ample evidence that dual inhibition
of commonly dysregulated cell-signaling pathways is more
successful than the use of monotherapy in the metastatic
setting, and this concept is currently under evaluation in
the adjuvant setting. As our understanding of driving molecular
anomalies expands, we will get closer to individualized
cancer therapy.
Stock
Ownership Honoraria
Research
Funding
Novartis
Expert
Testimony
Other
Remuneration
conserving surgery on 10-year recurrence and 15-year breast
cancer death: meta-analysis of individual patient data on 10,801
women in 17 randomised trials. Lancet. 2011;378:1707-1716.
3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
Effects of chemotherapy and hormonal therapy for early breast
cancer on recurrence and 15-year survival: an overview of the
randomised trials. Lancet. 2005;365:1687-1717.

4. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns
of breast carcinomas distinguish tumor subclasses with clinical
implications. Proc Natl Acad Sci USA.2001;98:10869-10874.
5. Gonzalez-Angulo AM, Hennessy BT, Meric-Bernstam F, et al.
Functional proteomics can define prognosis and predict pathologic
complete response in patients with breast cancer. Clin
Proteomics. 2011;8:11.
6. Gelmon K, Dent R, Mackey JR, et al. Targeting triple-negative
breast cancer: optimising therapeutic outcomes. Ann Oncol.
Epub 2012 Apr 19.
7. Sparano JA. TAILORx: trial assigning individualized options for
treatment (Rx). Clin Breast Cancer. 2006;7:347-350.
8. Cardoso F, Van’t Veer L, Rutgers E, et al. Clinical application of
EDUCATIONAL SUMMARIES
the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008;26:
729-735.
9. Tang G, Shak S, Paik S, et al. Comparison of the prognostic and
predictive utilities of the 21-gene recurrence score assay and
Adjuvant! for women with node-negative, ER-positive breast
cancer: results from NSABP B-14 and NSABP B-20. Breast
Cancer Res Treat. 2011;127:133-142.
10. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal
hormone-receptor-positive advanced breast cancer.
N Engl J Med. 2012;366:520-529.
11. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab
plus docetaxel for metastatic breast cancer. N Engl J Med.
2012;366:109-119.
65

“Just Say No” to Anthracyclines for Early Breast Cancer
T
he use of anthracyclines for adjuvant therapy of early
breast cancer is associated with the potential for serious
long-term consequences for some women treated with
curative intent. These include late bone-marrow effects
(e.g., leukemia or myelodysplastic syndromes) and myocardial
damage (e.g., congestive heart failure [CHF]). Anthracyclines
have been a mainstay of adjuvant regimens since
early work with the regimen in the early 1970s, 1 including
more modern regimens like anthracycline taxane, dosedense
anthracycline/paclitaxel; docetaxel, doxorubicin hydrochloride,
and cyclophosphamide (TAC); and fluorouracil,
epirubicin, and cyclophosphamide (FEC)/docetaxel. But
these commonly used regimens still have the potential to
cause late toxicities of bone-marrow and heart damage. This
is well illustrated by long-term follow-up of the BCIRG 001
study comparing TAC with doxorubicin in combination
with fluorouracil and cyclophosphamide (FAC). 2 With 10
years of follow-up, TAC remained significantly superior to
FAC in terms of disease-free survival (DFS) and overall
survival (OS). However, rates of CHF continued to increase
over the 10 years of follow-up with both of these anthracyline
regimens with rates of CHF of 3.5% with TAC and
2.3% with FAC. 2 Beyond the diagnosis of CHF, 15 to 17% of
patients exhibited decreases of cardiac ejection fractions of
over 20%. In addition, there were nine cases of hematologic
malignancies often associated with anthracycline usage.
Similar data have been observed in other trials using
anthracycline if long-term follow-up was performed (it is
not always performed). We would all accept the risks to our
patients from use of anthracycline regimens if there were
no alternative nonanthracycline treatment options. Fortunately,
that is not the case.
Pivotal Nonanthracycline Trials
There are two studies that strongly support the use of
anthracycline-free treatment for early breast cancer. The
first is the study we conducted at US Oncology Research
comparing classic anthracycline chemotherapy to a nonanthracycline
regimen of docetaxel/cyclophosphamide (TC). 3
In this study, women with early breast cancer were randomized
to four cycles of chemotherapy; at 7 years of follow-up,
we reported superior overall survival (OS) (87% TC vs. 82%
anthracycline, hazard ration [HR]: 0.69) as well as diseasefree
survival (DFS) (81% TC vs. 75% anthracycline, HR:
0.74) with fewer instances of CHF or bone marrow damage
in the TC arm. These results were seen in HER2-positive
disease as well as in HER2-negative disease, as the study
was conducted at a time when adjuvant trastuzumab was
not routinely utilized. Based on this study, one must consider
the use of TC for node-negative or node-positive early
breast cancer, particularly those with more limited nodal
involvement and HER2-negative disease. In fact, since the
publication of this study, the use of the TC regimen in the
66
Stephen Jones, MD
US Oncology Research, The Woodlands, TX
United States has increased dramatically, thereby sparing
many women the exposure to anthracyclines.
The second pivotal trial is the recently published BCIRG
006, 4 which deals with the addition of trastuzumab to either
an anthracycline-based regimen (AC-TH) or a nonanthracycline
regimen of docetaxel/carboplatin (TCH) for women
with HER2-overexpressed early breast cancer. This study
compared DFS at 5 years by regimen and found rates of 75%
for ACT and rates of 84% and 81% for AC-TH and TCH,
respectively. Both trastuzumab regimens were significantly
superior to the arm without trastuzumab (ACT) and not
different between the two trastuzumab-containing arms.
Those who favor use of anthracyclines for HER2-positive
disease cite the 84% 5-year rate of DFS with AC-TH as
“numerically different” than 81% for TCH. In fact, this
is not a valid medical or statistical conclusion and is only
an argument used by those who want to promote anthracyclines
for early breast cancer. In addition, there was significantly
more cases of acute leukemia and cardiac
dysfunction in the anthracycline arms compared with the
TCH arm. For example, there were eight cases of leukemia
with seven in the anthracycline arms and one in the TCH
arm. Based on this randomized prospective trial for women
with early HER2-positive disease, the TCH regimen has
also been widely adopted, sparing many women the added
risk of anthracyclines.
Both of these trials provide convincing arguments for
treating women with anthracycline-free regimens, but
there is additional supporting science to be reviewed.
Supporting Science
The reputed primary target for anthracyclines is topoisomerase
II alpha (TOP2A). Although this may not be the only
target, it is the predominant mechanism of action. Over the
years, there has been increasing evidence of the role of
TOP2A in predicting sensitivity to anthracyclines, but probably
the most impressive body of work was reported by
Press et al. 5 In that study, the laboratory analyzed alterations
in nearly 5,000 breast cancers from trials of chemotherapy
with or without trastuzumab using data from a
metastatic trial as the test set and data from BCIRG 005
and 006 as the validation set. In the BCIRG 005 trial (a
study of HER2-negative breast cancer where the HER2
testing was also done by Press and colleagues), there were
no cases of TOP2A amplification in 1,614 breast cancers. 6 In
the BCIRG 006 study of HER2-overexpressed breast cancer
summarized above, Press and colleagues found in 2,990
cases that overamplification of TOP2A occurred in 35%
whereas TOP2A-normal was seen in 60% of cases and
TOP2A-deletions was seen in 5% of cases. In this trial, since
there were 2 anthracycline arms (AC-T and AC-TH) as well
as a nonanthracycline arm (TCH), the investigators could
compare outcomes related to alterations in a gene copy of

TOP2A. In the AC-T arm, there was a clear-cut benefit with
anthracycline use without trastuzumab only in the group of
women where TOP2A overexpression existed. And in the
presence of trastuzumab, the use of anthracyclines did not
make a difference regardless of TOP2A gene copy or anthracycline
use. This is the largest study from a single laboratory
with excellent quality controls to examine this issue. If one
looks at all invasive breast cancer based on this data—since
almost all of anthracycline sensitivity relates to TOP2A
overexpression and such overexpression occurs almost
entirely in the HER2-positive population—less than 10% of
breast cancer will actually benefit from the use of anthracyclines.
That 10% resides almost entirely in the HER2positive
population, which is now being treated with
trastuzumab-based regimens. This strongly argues that
few, if any, women will benefit from anthracycline regimens.
Unanswered Questions
In the original AC (doxorubicin/cyclophosphamide) versus
TC trial, we used four courses of therapy. Recent data from
the BCIRG 005 trial 6 and the NSABP trial 7 (which did not
Author’s Disclosures of Potential Conflicts of Interest
Employment or
Leadership Consultant or Stock
Author
Positions Advisory Role Ownership Honoraria
Jones, Stephen Genentech Genentech
References
1. Jones SE, Durie BG, Salmon SE. Combination chemotherapy with
adriamycin and cyclophosphamide for advanced breast cancer.
Cancer. 1975;36:90-97.
2. Martin M, Mackey J, Pienkowski T, et al. Ten-year follow-up
analysis of the BCIRG 001, trial confirms superior DFS and OS
benefit of adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide)
over FAC (fluorouracil, doxorubicin, cyclophosphamide) in
women with operable node-positive breast cancer. Cancer Research.
Presented at: 33 rd Annual San Antonio Breast Cancer
Symposium, San Antonio, TX, December 2010; abstr S4–3.
3. Jones S, Holmes FA, O’Shaughnessy J, et al. Docetaxel with
cyclophosphamide is associated with an overall survival benefit
compared with doxorubicin and cyclophosphamide: 7-Year
follow-up of US Oncology Research Trial 9735. J Clin Oncol.
2009;27:1177-1183. Epub 2009 Feb 9.
study TC) suggested that four courses of therapy might not
be enough for women with node-positive disease. For this
reason, the ideal number of cycles of TC chemotherapy has
still not been determined, but in the prospective studies 6 is
being used. The other issue for those who still support the
use of anthracyclines would be data from a randomized trial
of TC versus an anthracycline regimen. In US Oncology
06-090, six cycles of TC versus six cycles of TAC were
investiaged. This trial has been modified twice to include
bevacizumab (B46 and USON 06-090) and more recently to
take out the bevacizumab arm (NSABP B49). Ultimately,
about 4,000 women will be randomly assigned to a nonanthracycline
regimen (TC) or an anthracycline-based regimen
(TAC or a version of dose-dense ACT). Because of the
data described above and the putative target of TOP2A, I
believe that the TC regimen will be equal to anthracycline
regimens for most women with HER-negative disease.
However, whether or not there is a subset of patients who
benefit from anthracyclines (e.g., triple-negative disease)
based on some mechanism of action other than TOP2A gene
expression still remains to be answered, and this trial will
provide definite answers to these questions.
Research
Funding
EDUCATIONAL SUMMARIES
Expert
Testimony
Other
Remuneration
4. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab
in HER2-positive breast cancer. N Engl J Med. 2011;365:1273-
1283.
5. Press MF, Sauter G, Buyse M, et al. Alteration of topoisomerase
II-alpha gene in human breast cancer: association with responsiveness
to anthracycline-based chemotherapy. J Clin Oncol.
2011;29:859-867. Epub 2010 Dec 28.
6. Eiermann W, Pienkowski T, Crown J, et al. Phase III study of
doxorubicin/cyclophosphamide with concomitant versus sequential
docetaxel as adjuvant treatment in patients with human
epidermal growth factor receptor 2-normal, node-positive breast
cancer: BCIRG-005 trial. J Clin Oncol. 2011;29:3877-3884. Epub
2011 Sep 12.
7. Swain SM, Jeong JH, Geyer CE Jr., et al. Longer therapy, iatrogenic
amenorrhea, and survival in early breast cancer. N Engl
J Med. 2010;362:2053-2065.
67

Reassessing Local Treatment in the Context of Increasingly
Effective Systemic Therapy
Jay R. Harris, MD
Dana-Farber Cancer Institute and Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA
T
he current status of local treatment is that (1) improved
local treatment is now clearly linked to longterm
survival, (2) radiation therapy (RT) is generally used
after breast-conserving surgery (BCS) and selectively used
after mastectomy, and (3) RT for breast cancer has become
technically advanced and safer. However, the main focus in
research is clearly on further improvements in the effectiveness
of systemic therapy. Given this, understanding the role
of local treatment in the context of systemic therapy is
important.
In 2007, we hypothesized that the benefit of local therapy
on survival would have a parabolic relationship to increasing
effectiveness of systemic therapy (Fig. 1). 1 In the absence
of effective (adjuvant) systemic therapy, local therapy
will have no effect on survival in the many patients with
micrometastatic disease. Initially, as systemic therapy becomes
able to eradicate micrometastatic disease, local therapy
will have a bigger impact on survival. Ultimately, as we
hope, systemic therapy will become so effective that local
therapy will not be required.
The latest report from the Early Breast Cancer Clinical
Trialists’ Collaborative Group (EBCTCG) (also
known as the Oxford Overview) on the impact of adding
RT to BCS was published in 2011. 2 Seven trials of
lumpectomy in low-risk patients were added, and the
prior 10 trials were updated for a total of 10,801 women
with a median woman-year at risk of 9.5. Of note, the
EBCTCG moved from assessing the effect of RT on LR
Fig. 1. Hypothetical relationship between increasing
effectiveness of systemic therapy and the benefit
of local therapy on survival.
68
to its effect on first failure (either local recurrence [LR]
or distant metastases [DM]). It turns out that actuarial
calculation of time to LR is not statistically valid. 3 RT
reduced the annual rate of any failure (DM or LR) over
the first 10 years by about 1/2 (response rate [RR] �
0.52). RT reduced the annual rate of breast cancer
death by about 1/6 (RR � 0.82). RT, of course, mostly
reduced first LR failure. Also published in Lancet in
2011 was the EBCTCG meta-analysis of the impact of
adjuvant tamoxifen taken for 5 years. 4 Tamoxifen reduced
the annual rate of any failure over the first 10
years by about 1/2 (RR � 0.53), very similar to the
impact of RT after BCS. Tamoxifen reduced the annual
rate of death from breast cancer by about 1/3 (RR �
0.68), greater than the impact of RT since tamoxifen
reduced first LR and DM failures about equally. The
updated results from the EBCTCG continue to show
that improved local treatment is still linked to improved
long-term survival. However, the new “4:1 ratio” is
between the reduction in first failure at 10 years (not
the reduction in local-regional recurrence [LRR] at 5
years) and the reduction in mortality at 15 years.
There have been two recent sets of observations of
importance. One is that adjuvant systemic therapy developed
to address the problem of micrometastatic disease
serendipitously has served to make RT much more
effective. This is seen most clearly in National Surgical
Adjuvant Breast and Bowel Project (NSABP) trials B-14
and B-13. In the NSABP B-14 trial, women with nodenegative,
estrogen-receptor (ER) positive tumors were
randomly assigned to tamoxifen or placebo; the 10-year
rate of local recurrence after BCS was reduced from
14.7% in the placebo group to 4.3% in the tamoxifen
group. 5 Similarly, in the NSABP B-13 trial, women with
node-negative, ER-negative tumors were randomly assigned
to methotrexate and 5-fluorouracil or to no treatment;
a reduction in 10-year local recurrence rate from
13.4% to 2.6% was observed. 6 This was also seen in the
updated EBCTCG results where RT reduced first failure
by 62% in patients with ER-positive cancers treated
with tamoxifen but only by 35% in patients with ERnegative
cancers (without chemotherapy or trastuzumab).
2 The second set of observations of importance
is that the molecular subtype of breast cancer, approximated
by hormone receptor, HER2, and grade (or Ki-
67), is the major determinant of the success of RT. 7
Finally, the results of MA.20 were provocative. In this
trial, node-positive or high-risk, node-negative patients
(85% had one to three positive nodes) treated with BCS
were randomly assigned to whole breast irradiation
(WBI) or WBI and regional nodal irradiation (RNI). RNI
involved irradiation of the internal mammary nodes, supra-

clavicular, and level 3 axillary nodes. Ninety-one percent
of patients were treated with adjuvant chemotherapy
and all hormone receptor–positive patients were
treated with adjuvant hormonal therapy. Nine hundred
sixteen patients were randomly assigned to each arm.
RNI, in addition to WBI, increased disease-free survival
at 5 years with reductions in both local-regional and
distant recurrence. There was a trend in improvement
in overall survival. A similar randomization was performed
in a European Organisation for Research and
Treatment of Cancer (EORTC) trial with results due
in 2014. If the MA.20 results are seen in the EORTC
trial, the results can be hypothesized to demonstrate
that with increasingly effective systemic therapy, local
therapy assumes greater benefit in survival as shown in
Fig. 2.
Author’s Disclosures of Potential Conflicts of Interest
Author
Harris, Jay R.*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
Consultant or
Advisory Role
References
1. Punglia R, Morrow M, Winer E, et al. Local therapy and survival
in breast cancer. N Engl J Med. 2007: 356:2399-2405.
2. Darby S, McGale P, Correa C, et al. Effect of radiotherapy after
breast-conserving surgery on 10-year recurrence and 15-year
breast cancer death: meta-analysis of individual patient data for
10,801 women in 17 randomised trials. Lancet. 2011;378:1707-
1716.
3. Gelman R, Gelber R, Henderson IC, et al. Improved methodology
for analyzing local and distant recurrence. J Clin Oncol. 1990:8;
548-555.
4. Early Breast Cancer Trialists’ Collaborative Group, Davies C,
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EDUCATIONAL SUMMARIES
Fig. 2. Hypothetical relationship between increasing
effectiveness of systemic therapy and the benefit
of local therapy on survival.
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