Review - Haymarket Media Group

ajho.com
November 2008 • Vol 7 • Supplement 5
INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH ®
TRENDS IN 8
BREAST CANCER
Weekly Paclitaxel Improves 10
Disease-Free and Overall
Survival in the Adjuvant
Treatment of Breast Cancer
REVIEW
The New England Journal of Medicine
Optimizing Taxane Therapy for 15
Patients With Primary Breast Cancer:
What Are the Lessons Learned?
COMMENTARY
Special Breast Cancer Issue
THE NATION’S MOST REQUESTED HEMATOLOGY/ONCOLOGY PUBLICATION
©2008 Haymarket Media Inc.
HER2 Status and 17
Inflammatory Breast
Cancer: Evidence of
Prognostic Significance
and Trastuzumab Efficacy
REVIEW
Cancer
Inflammatory Breast 20
Cancer: Still a Challenge
COMMENTARY
Risk of Local Recurrence for 23
Breast Cancer Subtypes Defined
by ER, PR, and HER2 Status
CASE STUDY
Supplement to The American Journal of Hematology/Oncology
®

TABLE OF CONTENTS
INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH ®
Trends in Breast Cancer 8
Weekly Paclitaxel Improves Disease-Free and 10
Overall Survival in the Adjuvant Treatment of
Breast Cancer
REVIEW
The New England Journal of Medicine
Rachel E. Raab, MD; Joseph A. Sparano, MD ➢ Montefiore-Einstein Cancer Center,
Bronx, New York
Optimizing Taxane Therapy for Patients 15
With Primary Breast Cancer: What Are the
Lessons Learned?
COMMENTARY
Lawrence N. Shulman, MD ➢ Dana-Farber Cancer Institute, Brigham
and Women’s Hospital, Boston, Massachusetts
HER2 Status and Inflammatory Breast Cancer: 17
Evidence of Prognostic Significance and
Trastuzumab Efficacy
REVIEW
Cancer
Shaheenah Dawood, MRCP(UK), MPH; Ana M. Gonzalez-Angulo, MD ➢ Dubai Hospital,
U.A.E.
Inflammatory Breast Cancer: Still a Challenge 20
COMMENTARY
Nancy U. Lin, MD ➢ Dana-Farber Cancer Institute, Boston, Massachusetts
Risk of Local Recurrence for Breast Cancer Subtypes 23
Defined by ER, PR, and HER2 Status
CASE STUDY
Paul L. Nguyen, MD, et al ➢ Harvard Medical School, Boston, Massachusetts
4 The American Journal of Hematology/Oncology
November 2008 • Vol 7 • Supplement 5
®
Editor in Chief, Medical Oncology
Lawrence N. Shulman, MD
Editor in Chief, Surgical Oncology
Douglas J. Schwartzentruber, MD, FACS
Associate Editor, Radiation Oncology
Marcus E. Randall, MD
Publisher
Steve Svec
201-799-4874
Steve.svec@haymarketmedia.com
Senior Editorial Director
Kristin Lee Siyahian
Kristinlee.siyahian@haymarketmedia.com
Editorial Director
Kristen Olafson
Kristen.olafson@haymarketmedia.com
Senior Copy Editor
Bjarne Hansen
Production Editor
Rick Maffei
Art Director
Robert Mancuso
Production Inquiries
Leslie Carsman
646-638-6075
Director of Sales
Chad Holloway
201-799-4878
Chad.holloway@haymarketmedia.com
Circulation Department
ajhosubs@haymarketmedia.com
For reprints contact:
Greg Rucker
212-221-9595 ext 105
Greg.rucker@parsintl.com
Haymarket Media Inc.
CEO
Lee Maniscalco
CFO
Michael Kriak
Associate Publishing Director
Jeff Forster
Group Editor
Tanya Gregory, PhD

LettertoOurReaders
Dear Colleague,
Each year, we devote an issue to breast cancer. This month, we address several recent reports on advances in the
field and in the care of patients with this disease.
We are still learning how to optimally administer cytotoxic chemotherapy; the manuscript by Sparano and colleagues
is critical in comparing the two principal taxanes available to us, as well as two different schedules of
administration. Survival and toxicity data taken together are essential for establishing optimal taxane therapy in
the adjuvant setting for both standard care and future clinical trials.
Continued exploration into differences in the biologic subtypes of breast cancer determined by hormone receptor
status and HER2 status is helping us to better understand the disease, and what optimal therapies will be, based
on these subgroups of patients. The manuscript by Dawood and colleagues exploring HER2 status in inflammatory
breast cancer and the manuscript by Nguyen and colleagues looking at biologic subtypes associated with
local and distant recurrence after breast-conserving therapy are examples of these advances.
Once a year, it is worthwhile to review the substantial progress we have made in our understanding of breast
cancer and the treatment of this disease. Survival rates have risen dramatically over the last two decades, partly
due to improved screening, but also due to better therapies for these patients.
We appreciate your continued interest in The American Journal of Hematology/Oncology and trust that you will
benefit from the information presented here.
Sincerely,
Lawrence N. Shulman, MD
Editor in Chief, Medical Oncology
November 2008 • Vol 7 • Supplement 5 7

in Breast Cancer
The following is an invited report based on abstracts presented at recent oncology meetings.
Bevacizumab With Docetaxel or Docetaxel With
Placebo as First-Line Therapy in Locally
Recurrent or Metastatic Breast Cancer: The
AVADO Study
The AVADO study, a randomized, double-blind, placebo-controlled,
phase III trial, evaluated the combination
of bevacizumab plus docetaxel as first-line therapy in
patients with locally recurrent or metastatic breast cancer.
A previous study had demonstrated superior progression-free
survival (PFS) for bevacizumab plus paclitaxel
compared with paclitaxel alone.
Patient eligibility criteria included HER2-negative,
inoperable locally recurrent or metastatic breast cancer;
no prior chemotherapy for advanced disease; ECOG PS
0-1; adequate left ventricular ejection fraction (LVEF),
and no CNS metastases. From March 2006 to April 2007,
researchers in 24 countries randomized 736 patients to
docetaxel 100 mg/m2 plus placebo or docetaxel plus
bevacizumab at either 7.5 mg/kg or 15 mg/kg.
Docetaxel was administered every 3 weeks for up to 9
cycles. Bevacizumab or placebo was administered every
3 weeks until disease progression or unacceptable toxicity.
PFS was the primary end point.
With a median follow-up of approximately 11
months, both bevacizumab-containing arms demonstrated
statistically significantly superior PFS compared
with docetaxel alone (bevacizumab 7.5 mg/kg,
P=0.0035; bevacizumab 15 mg/kg; P=0.0001). The overall
response rate (CR + PR) was 44.4% in the docetaxel
alone arm vs 55.2% (P=0.0295) and 63.1% (P=0.0001) in
the bevacizumab 7.5 mg/kg and 15 mg/kg arms, respectively.
Grade ≥3 adverse events for the docetaxel alone,
bevacizumab 7.5 mg/kg, and bevacizumab 15 mg/kg
arms were 67.0%, 74.8%, and 74.1%, respectively, and
included GI perforation 0.9%, 0.4%, and 0.4% and febrile
neutropenia 12.0%, 15.2%, and 16.6%, respectively.
Overall survival rate data were immature at the time of
the report.
Results indicate that both doses of bevacizumab in
combination with docetaxel significantly improved PFS
and response rate when compared with docetaxel alone.
Safety results were comparable in the two bevacizumab
arms, and although toxicities were slightly increased relative
to the control group, no new safety concerns
emerged.
Miles D, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract LBA1011.
By Beverly Moy, MD, MPHTrends
8 The American Journal of Hematology/Oncology
A Phase III Study of Capecitabine vs
Capecitabine Plus Trastuzumab in HER2+
Patients With Metastatic Breast Cancer That
Progressed During Trastuzumab Treatment
(GBG 26/BIG 3-05)
Agreement is lacking on whether trastuzumab treatment
should be continued beyond disease progression. The
German Breast Group (GBG) and the Breast
International Group (BIG) conducted a treatment
beyond progression (TBP) phase III study, GBG 26/BIG
3-05, of trastuzumab therapy.
Eligible patients had HER2+, locally advanced or
metastatic breast cancer that progressed during
trastuzumab treatment with or without adjuvant and/or
first-line metastatic chemotherapy. Patients were prospectively
randomized to receive either capecitabine
(2500 mg/m 2 on days 1-14, every 21 days) or capecitabine
plus continuation of trastuzumab (6 mg/kg, every 3
weeks). The primary end point was time to progression.
The slowly accruing trial was closed prematurely after
the registration of lapatinib.
Between January 2004 and May 2007, a total of 156
patients were randomized. Of these, 78 received capecitabine,
and 78 received capecitabine plus trastuzumab.
Patients were stratified according to previous treatment:
taxane/trastuzumab as first-line therapy (111 patients),
taxanes/trastuzumab as adjuvant therapy (3 patients),
trastuzumab alone or without taxanes as first-line treatment
(42 patients). Of note, 75 patients (48.1%) had
received anthracyclines.
Visceral metastasis was observed in 119 patients
(76.3%). At the time of the report, median follow-up was
11.8 months, and analysis had revealed a PFS of 5.6
months with 53 events in the capecitabine group and 8.5
months with 48 events in the capecitabine plus
trastuzumab group (HR=0.71). In patients receiving
capecitabine or capecitabine plus trastuzumab, respectively,
brain metastases were seen in 4 patients vs 7
patients; overall survival was 19.9 months with 31
events vs 20.3 months with 26 events (HR=0.79); crude
response rates were 24.6% vs 49.1%; and primary progressions
were seen in 26.3% vs 16%.
Reported grade 3/4 toxicities for capecitabine and
capecitabine plus trastuzumab, respectively, included
neutropenia, 3.3% vs 6.3%; febrile neutropenia, 0% vs
0%; vomiting, 6.0% vs 1.6%; diarrhea, 20.9% vs 14.8%;

hand-foot syndrome, 23.9% vs 31.1%; and cardiac, 2.9% vs
4.9%. There were no therapy-related deaths.
The preliminary results of this TBP study suggest similar
toxicity but higher efficacy for continuing trastuzumab
beyond progression when second-line chemotherapy with
capecitabine is initiated. The final efficacy analysis was
scheduled to be released at a later date.
Von Minckwitz G, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1025.
Anastrozole Plus Gefitinib Compared With
Anastrozole Plus Placebo in Postmenopausal
Women With Hormone Receptor–Positive
Metastatic Breast Cancer
Preclinical data indicate the presence of crosstalk between
growth factor receptor pathways and the estrogen receptor.
Thus, a technique to overcome hormonal resistance
might involve inhibition of both epidermal growth factor
receptor and estrogen receptor signaling. This phase II
multicenter, double-blind, randomized trial was designed
to evaluate the efficacy and tolerability of anastrozole
plus gefitinib vs anastrozole plus placebo in postmenopausal
women with newly diagnosed hormone
receptor–positive metastatic breast cancer.
Ninety-four patients were randomized to receive anastrozole
1 mg/day plus either gefitinib 250 mg/day or
placebo (50 women received anastrozole plus placebo; 43
received anastrozole plus gefitinib; one died prior to
treatment). PFS was the primary end point. The secondary
end points included objective response rate, clinical
benefit rate (defined as objective response or stable disease
≥24 weeks), overall survival, safety, and tolerability.
Enrollment was stopped early because of slow
recruitment, and fewer statistical analyses were performed.
However, a marked advantage in PFS was seen
for anastrozole plus gefitinib over anastrozole plus
placebo (median 14.5 vs 8.2 months). Complete response
was noted in 1 patient in each group. A numerical
advantage in clinical benefit rate was seen for anastrozole
plus gefitinib (21 patients, 49%) vs anastrozole plus
placebo (17 patients, 34%). There were no unexpected
safety or tolerability findings. Treatment-related adverse
events, mostly mild, were seen in 79% of patients in the
anastrozole plus gefitinib arm vs 38% in the anastrozole
plus placebo arm. Death occurred in 2 patients in the
anastrozole plus gefitinib arm and 1 patient in the anastrozole
plus placebo arm; none were considered related
to treatment.
The authors concluded that anastrozole plus gefitinib
was well tolerated and showed a marked advantage in
PFS when compared with anastrozole plus placebo in
postmenopausal women with newly diagnosed hormone
receptor–positive metastatic breast cancer. They also reported
that the data suggest the need for further investigation
of this combination.
Cristofanilli M, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1012.
Lapatinib Alone or in Combination With
Trastuzumab in Heavily Pretreated HER2+
Metastatic Breast Cancer That Progressed on
Trastuzumab Therapy
Preclinical data indicate possible synergy between
trastuzumab and lapatinib, an oral, small-molecule
inhibitor of EGFR and HER2 with a mechanism of action
distinct from that of trastuzumab. In this randomized
phase III study, researchers evaluated lapatinib alone and
in combination with trastuzumab in women with HER2+
metastatic breast cancer who had experienced progressive
disease while on trastuzumab therapy.
Women with these characteristics were eligible for participation
if they had also received prior anthracycline and
taxane therapy and had measurable lesions or bone-only
disease. Patients were first stratified according to hormone
receptor status and the presence of visceral or nonvisceral
disease, then randomized to receive either lapatinib (1500
mg qd) or lapatinib (1000 mg qd) plus trastuzumab (2
mg/kg weekly after a 4 mg/kg loading dose). The primary
end point was PFS (determined by investigator assessment);
secondary end points were clinical benefit rate at 24
weeks, response rate, and overall survival. Patients who
progressed while taking lapatinib were allowed to cross
over to the lapatinib plus trastuzumab arm.
Of the 296 patients who were randomized, all had
received prior trastuzumab therapy and a median of 6 prior
chemotherapy regimens. The addition of trastuzumab to
lapatinib significantly improved PFS (median 8.4 weeks for
lapatinib vs 12.0 weeks for lapatinib plus trastuzumab;
P=0.029) and clinical benefit rate (13.2% for lapatinib vs
25.2% for lapatinib plus trastuzumab; P=0.020). Response
rate and overall survival were similar in the two arms.
In general, both treatment arms were well tolerated.
Grade 1/2 diarrhea was higher in the lapatinib plus
trastuzumab arm (53% vs 41%); acneiform rash was more
common in the lapatinib alone arm and was likely caused by
the higher lapatinib dose. An asymptomatic decline in LVEF
(>20%, and below LLN) occurred in 5% of the patients in the
combination arm and in 2% of patients in the lapatinib
alone arm. One patient in the lapatinib plus trastuzumab
arm died; death was attributed to cardiac toxicity.
This is the largest study of two targeted agents in
HER2+ metastatic breast cancer and the first to demonstrate
the synergy of lapatinib plus trastuzumab in a phase
III trial. The authors concluded that the combination of
lapatinib plus trastuzumab in patients progressing on
trastuzumab-based therapy improved clinical outcome
without major changes in the side effect profile. The
authors also referred to the ongoing ALTTO (Adjuvant
Lapatinib and/or Trastuzumab Treatment Optimization)
study, in which the role of combined anti-HER2 therapy
plus chemotherapy is being studied in less heavily pretreated
patients with early-stage disease.
O’Shaughnessy J, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1015.
November 2008 • Vol 7 • Supplement 5 9

Review
Weekly Paclitaxel Improves Disease-Free and Overall
Survival in the Adjuvant Treatment of Breast Cancer
Rachel E. Raab, MD; Joseph A. Sparano, MD
Department of Medical Oncology, Montefiore-Einstein Cancer Center, Bronx, New York
The Eastern Cooperative Oncology Group
(ECOG) recently published their data comparing
the efficacy of paclitaxel and docetaxel
and a schedule of either weekly or every 3 weeks in
the adjuvant treatment of breast cancer. 1 The benefit
of adjuvant chemotherapy in reducing the risk of
recurrence and death from operable breast cancer is
well known. A meta-analysis conducted by the Early
Breast Cancer Trialists’ Collaborative Group revealed
that anthracycline-based chemotherapy
reduced the annual breast cancer death rate by
about 38% for women younger than 50 years of age
and by about 20% for women 50 to 69 years of age. 2
None of the randomized trials included in this meta-
The benefit of adjuvant
chemotherapy in reducing the risk
of recurrence and death from operable
breast cancer is well known.
analysis involved taxanes. The benefit of adjuvant
taxane therapy was established by two trials: the
NSABP B-28 and the CALGB 9344. 3,4 The NSABP
B-28 trial randomized patients to receive adjuvant
therapy with either four cycles of doxorubicin and
cyclophosphamide or four cycles of doxorubicin and
cyclophosphamide followed by four cycles of pac-
10 The American Journal of Hematology/Oncology
litaxel given every 3 weeks. Although no overall
survival benefit was demonstrated, a significant
improvement in disease-free survival was shown for
patients receiving adjuvant paclitaxel. The CALGB
9344 trial demonstrated not only a benefit in disease-free
survival for patients receiving adjuvant
paclitaxel following doxorubicin and cyclophosphamide
therapy but also a benefit in overall survival.
The results of these trials led to the approval
of paclitaxel for the adjuvant treatment of nodepositive
breast cancer. Another taxane, docetaxel, is
also approved for the adjuvant treatment of breast
cancer. A randomized phase III trial comparing docetaxel
plus doxorubicin and cyclophosphamide
(TAC) with fluorouracil plus doxorubicin and
cyclophosphamide (FAC) demonstrated improved
disease-free and overall survival in women receiving
TAC. 5 In metastatic breast cancer, phase III trials
have demonstrated that weekly paclitaxel 6 or every-
3-week docetaxel 7 is superior to paclitaxel every 3
weeks. There have been no data, however, from randomized
trials in the adjuvant setting comparing
docetaxel with paclitaxel or weekly versus every-3week
therapy.
The ECOG study compared adjuvant paclitaxel
versus docetaxel and an every-3-week schedule with
a weekly schedule in patients with axillary lymph
node–positive or high-risk, lymph node–negative
breast cancer. 7 The standard of care was considered
paclitaxel every 3 weeks, and the factorial design of
the trial allowed for comparison with three experimental
arms: paclitaxel weekly for 12 cycles, docetaxel
every 3 weeks for four cycles, or docetaxel
weekly for 12 cycles.
For a more detailed discussion, please see the following: Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant
treatment of breast cancer. N Engl J Med. 2008;358:1663-1671.

Figure
Paclitaxel 175 mg/m2
every 21 days for 4 doses
n=1253
Randomization scheme.
Trial Design
Eligible patients had operable, histologically confirmed
adenocarcinoma of the breast with histologically
involved lymph nodes (tumor stage T1, T2, or
T3 and nodal stage N1 or N2) or high-risk, axillary
lymph node–negative disease (T2 or T3, N0) without
distant metastases. Adequate organ function was
required. Exclusion criteria included history of
myocardial infarction, congestive heart failure, heart
disease, pregnancy, or history of hypersensitivity
reaction to paclitaxel or docetaxel. Full inclusion and
exclusion criteria can be found online in the supplementary
appendix of the original article.
A total of 5052 patients were enrolled, of whom
4950 (98%) were eligible. All patients received doxorubicin
(60 mg/m 2 of body surface area) and
cyclophosphamide (600 mg/m 2 of body surface area)
every 3 weeks for four cycles. Patients were then randomized
to one of four treatment arms (Figure).
Women who had breast-sparing surgery received
radiotherapy according to accepted standards of care,
and patients who had a modified radical mastectomy
received radiotherapy at the discretion of the treating
physician. All women with hormone receptor–
positive disease received tamoxifen 20 mg daily for 5
years. The protocol was modified in 2005 to allow for
a change to an aromatase inhibitor prior to completion
of 5 years of tamoxifen or to begin an aromatase
inhibitor after completing 5 years of tamoxifen.
Operable breast cancer,
lymph node positive or high-risk node negative
N=4950
Doxorubicin 60 mg/m 2 +
cyclophosphamide 600 mg/m2
every 21 days for 4 cycles
Paclitaxel 80 mg/m2
weekly for 12 doses
n=1231
Docetaxel 100 mg/m2
every 21 days for 4 doses
n=1236
Weekly paclitaxel and breast cancer
Docetaxel 35 mg/m2
every 21 days for 12 doses
n=1230
The primary end point of the study was diseasefree
survival, which was defined as the time from
randomization to disease recurrence and included
death from recurrence, death without recurrence,
and contralateral breast cancer. The study had 86%
power to detect a 17.5% reduction in the hazard
rate for failure among the docetaxel groups or with
weekly instead of every-3-week dosing. All eligi-
The primary end point
of the study was
disease-free survival.
ble patients undergoing randomization were
included in the efficacy analysis, and all treated
patients were included in the adverse events
analysis. The log-rank test was used for analysis
of disease-free and overall survival. Kaplan-Meier
analysis was used to estimate distributions of
events with respect to time. Cox proportional hazards
models were used to estimate hazard ratios
November 2008 • Vol 7 • Supplement 5 11

Review
and to test for significant differences in the times
to events. A post hoc analysis of outcomes according
to hormone receptor status and HER2 status
was performed.
Study Results
Between October 1999 and January 2002, 5052
patients were enrolled, of whom 4950 were eligible.
The benefit of weekly paclitaxel was
seen in patients with HER2-negative
disease irrespective of their
hormone receptor status.
There were no significant differences among the
patient groups. The median age was 51 years, and
the majority of patients were hormone receptor positive
(69.5%) and HER2 negative (67.5%). Most
patients (97%) received all four cycles of doxorubicin
and cyclophosphamide. The proportions of patients
who received all taxane doses were 95% (paclitaxel
Table 1
5-Year Disease-Free Survival and Overall Survival in Four Treatment Arms
12 The American Journal of Hematology/Oncology
every 3 weeks), 88% (paclitaxel weekly), 87% (docetaxel
every 3 weeks), and 75% (docetaxel weekly).
The proportions of patients who required dose modification
of the taxane were 22%, 29%, 28%, and 40%,
respectively.
At a median follow-up of 63.8 months, 1048
patients had a recurrence of breast cancer or cancer
in the contralateral breast, and 686 had died. The
estimated 5-year disease-free survival rates were
76.9% for the patients receiving every-3-week paclitaxel,
81.5% for patients receiving weekly paclitaxel,
81.2% for patients receiving every-3-week docetaxel,
and 77.6% for patients receiving weekly docetaxel
(Table 1). The study met its end point and demonstrated
a significant improvement in disease-free survival
in the group receiving weekly paclitaxel and in
the group receiving docetaxel every 3 weeks (Table
2). Weekly paclitaxel compared with standard therapy
was associated with an improved overall survival
(hazard ratio, 1.32, P=0.01) that was not seen in the
patients receiving weekly docetaxel or every-3-week
docetaxel (Table 3).
Recent data have suggested that patients with
hormone receptor–positive and HER2-negative
breast cancer may not derive a benefit from adjuvant
taxane therapy. 7 Therefore, the investigators analyzed
the effect of hormone receptor status and
HER2 expression on the efficacy of weekly paclitaxel
Treatment Arm 5-Year Disease-Free Survival 5-Year Overall Survival
Every-3-week paclitaxel 76.9% 86.5%
Weekly paclitaxel 81.5% 89.7%
Every-3-week docetaxel 81.2% 87.3%
Weekly docetaxel 77.6% 86.2%
Table 2
Hazard Ratio for Disease-Free Survival in the Experimental Treatment Arms Compared With
Standard Every-3-Week Paclitaxel
Treatment Arm Hazard Ratio 95% CI P Value
Weekly paclitaxel 1.27 1.03-1.57 0.006
Every-3-week docetaxel 1.23 1.00-1.52 0.02
Weekly docetaxel 1.09 0.89-1.34 0.29

and demonstrated that patients with HER2-negative
disease had improved disease-free and overall survival
with weekly paclitaxel irrespective of hormone
receptor status (Table 4).
Grade 3/4 toxic effects were more common in
patients receiving the every-3-week docetaxel (71%)
compared with those receiving weekly docetaxel
(45%), weekly paclitaxel (28%), or every-3-week
paclitaxel (30%). The majority of grade 3/4 adverse
events in the every-3-week docetaxel arm was related
to neutropenia (46%), infection (13%), and neuropathy
(4%). Neuropathy of grade 2, 3, and 4 was
more common in the weekly paclitaxel group compared
with paclitaxel every 3 weeks (27% vs 20%).
Other adverse effects were similar in the weekly and
every-3-week paclitaxel groups.
Discussion
In women with lymph node–positive or high-risk
lymph node–negative breast cancer, weekly paclitaxel
compared with standard taxane therapy every 3
weeks resulted in a significantly improved overall
and disease-free survival. Patients receiving docetaxel
every 3 weeks also had improved disease-free sur-
Weekly paclitaxel and breast cancer
Table 3
Hazard Ratio for Overall Survival in the Experimental Treatment Arms Compared With Standard
Every-3-Week Paclitaxel
Treatment Group Hazard Ratio 95% CI P Value
Weekly paclitaxel 1.32 1.02-1.72 0.01
Every-3-week docetaxel 1.13 0.88-1.46 0.25
Weekly docetaxel 1.02 0.80-1.32 0.80
Table 4
Disease-Free and Overall Survival in HER2-Negative Patients According to Hormone Receptor
(HR) Status
Variable Hazard Ratio 95% CI P Value
Overall survival
HR+ 1.36 0.92-2.00 0.12
HR– 1.33 0.91-1.94 0.14
Disease-free survival
HR+ 1.31 1.00-1.72 0.05
HR– 1.37 0.98-1.93 0.97
vival but not overall survival. These results are consistent
with findings in metastatic breast cancer that
demonstrate a benefit of weekly paclitaxel or every-
3-week docetaxel compared with every-3-week
paclitaxel.
Treatment with doxorubicin and cyclophosphamide
was well tolerated, with 97% of patients completing
all four cycles. The majority of patients in
all treatment arms also completed taxane therapy.
Toxic effects, mainly neutropenia, infection, and
grade 2, 3, or 4 neuropathy, were more common in
the every-3-week docetaxel group compared with
the other groups.
Of particular interest was that the benefit of weekly
paclitaxel was seen in patients with HER2negative
disease irrespective of their hormone receptor
status. This is contradictory to recent data from
Hayes and colleagues, who suggested that the benefit
of adjuvant taxane therapy was not seen in
patients with hormone receptor–positive disease or
HER2-negative disease. 8 The results from the recent
ECOG trial are consistent with those demonstrated
in a subgroup analysis of the GEICAM 9906 trial,
which compared six cycles of fluorouracil, epirubi-
November 2008 • Vol 7 • Supplement 5 13

Review
cin, and cyclophosphamide (FEC) with four cycles of
FEC followed by eight cycles of weekly paclitaxel. 9
The authors concluded that patients treated with
weekly paclitaxel had improved outcomes regardless
of hormone receptor status.
Conclusion
The randomized trial conducted by ECOG is one
of the first trials to compare standard every-3-week
paclitaxel with weekly paclitaxel and docetaxel
either weekly or every 3 weeks in the adjuvant setting.
A 32% reduction in the hazard ratio for death in
the weekly paclitaxel group compared with standard
therapy was seen. The benefit of disease-free survival
for weekly paclitaxel was seen in women with
HER2-negative disease irrespective of hormone
receptor status. ✦
References
1. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the
adjuvant treatment of breast cancer. N Engl J Med. 2008;358:
1663-1671.
2. Early Breast Cancer Trialist’ Collaborative Group (EBCTCG).
Effects of chemotherapy and hormonal therapy for early breast
cancer on recurrence and 15-year survival: an overview of the
randomized trials. Lancet. 2005;365:1687-1717.
3. Mamounas EP, Bryant J, Lembersky B, et al. Paclitaxel after
doxorubicin plus cyclophosphamide as adjuvant chemotherapy
for node-positive breast cancer: results from the NSABP B-
28. J Clin Oncol. 2005;23:3686-3696.
4. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes
from adding sequential paclitaxel but not from escalat-
14 The American Journal of Hematology/Oncology
ing doxorubicin dose in an adjuvant chemotherapy regimen
for patients with node-positive primary breast cancer. J Clin
Oncol. 2003;21:976-983.
5. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel
for node-positive breast cancer. N Engl J Med. 2005;352:
2302-2313.
6. Seidman AD, Berry D, Cirrincione C, et al. CALGB 9840: phase
III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion
versus standard (S) 3h infusion every third week in the treatment
of metastatic breast cancer (MBC), with trastuzumab (T)
for HER2 positive MBC and randomized for T in HER2 normal
MBC. J Clin Oncol. 2004;22(July 15 suppl):6s. Abstract 512.
7. Jones SE, Erban J, Overmeyer B, et al. Randomized phase III
study of docetaxel compared with paclitaxel in metastatic
breast cancer. J Clin Oncol. 2005;23:5542-5551.
8. Hayes DF, Thor AD, Dressler LG, et al. HER 2 and response to
paclitaxel in node-positive breast cancer. N Engl J Med. 2007;
357:1496-1506.
9. Rodriguez-Lescure A, Martin M, Ruiz A, et al. Subgroup analysis
of GEICAM 9906 trial comparing six cycles of FE 90 C
(FEC) to four cycles of FE 90 C followed by 8 weekly paclitaxel
administrations (FECP): relevance of HER2 and hormonal status
(HR). J Clin Oncol. 2007;25(June 20 suppl):589s. Abstract
10598.
Supported by grants from the Department of Health and Human
Services and the National Institutes of Health.
Author disclosures: Dr Sparano: speaker and consultant: Sanofi-
Aventis.
Correspondence address: Rachel E. Raab, MD, East Carolina
University Brody School of Medicine, Department of
Hematology/Oncology, 600 Moye Blvd, Brody 3E 127,
Greenville, NC 27834; phone: (252) 744-3326; fax: (252) 744-
3418; e-mail: raabr@ecu.edu.
Committed to bringing you the latest and most relevant information in cancer management.
Look in an upcoming issue for a review by Dr Henry L. Gomez
of his recent article:
INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH ®
Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced
or metastatic breast cancer. J Clin Oncol. 2008;26:2999-3005.
Commentary by Drs Heather L. McArthur and Maura N. Dickler.
®

Commentary
Optimizing Taxane Therapy for Patients With Primary
Breast Cancer: What Are the Lessons Learned?
Lawrence N. Shulman, MD
Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, Massachusetts
The article by Sparano and colleagues comparing
different taxanes and different dose schedules
represents an important step forward in
the treatment of primary breast cancer and also highlights
some important lessons for drug development
in our field. 1
Since the introduction of paclitaxel nearly 20 years
ago, physicians have struggled to determine the
ideal dosing and schedule. Through much of the
1980s and 1990s, our philosophy on chemotherapy
administration was based on delivering the maximum
dose possible, with the interval of therapy
determined by the time needed for normal organ
recovery. However, a series of dose escalation studies
with paclitaxel in metastatic breast cancer suggested
that higher doses were not necessarily associated
with better outcomes. 2 Prolonged paclitaxel infusions
were also tried based on preclinical data but
failed to show a benefit. In both of these circumstances,
toxicity was considerably worse.
Since the introduction of docetaxel, the younger
sibling of paclitaxel, there has been debate as to
whether one taxane is better than the other for
the treatment of breast cancer (as well as other
diseases). 3-5
The North American Breast Intergroup study
reported by Sparano and colleagues enrolled approximately
5000 patients with node-positive or high-risk
node-negative primary breast cancer comparing the
two taxanes and two schedules following standard
cyclophosphamide and doxorubicin therapy.
Paclitaxel or docetaxel was administered either
weekly or every 3 weeks. Differences in disease-free
and overall survival were small, with a small numerical
advantage favoring weekly paclitaxel. One could
argue that the results with weekly paclitaxel were no
different than those for every-3-week docetaxel, and
either would be acceptable therapy. An important
consideration, however, is toxicity. When cancer outcomes
are similar, toxicity and quality of life should
be of paramount importance. Docetaxel administered
every 3 weeks had a 46% incidence of grade
Since the introduction of docetaxel,
. . . there has been debate as to whether
one taxane is better than the other.
3/4 neutropenia and a 16% likelihood of febrile neutropenia,
whereas weekly paclitaxel had a 2% and
1% incidence of these toxicities, respectively. Grade
3/4 neuropathy was slightly more likely in the
patients receiving weekly paclitaxel versus every-3week
docetaxel, 8% versus 4%. Finally, grade 3/4
fatigue was more likely to occur with every-3-week
docetaxel compared with weekly paclitaxel, 9% versus
3%. Although fatigue is not a life-threatening toxicity,
for these patients it was significant, and the
combination of toxicities caused by docetaxel result-
Dr Lawrence N. Shulman was invited to provide commentary on the following article: Sparano JA, Wang M, Martino S, et al. Weekly
paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358:1663-1671.
November 2008 • Vol 7 • Supplement 5 15

Commentary
ed in a high rate of failure to complete the 12 weeks
of taxane therapy. Some have argued that if a greater
proportion of patients had completed therapy on the
docetaxel arms, the survival for those arms would
have been superior to the paclitaxel arms. I would
argue that survival for patients on the weekly paclitaxel
arm was at least as good as for patients on any
of the other treatment arms, and the toxicity was less,
making it better tolerated and therefore the preferred
treatment.
The results of this study are consistent with other
studies that suggest that weekly paclitaxel is superior
to every-3-week paclitaxel, and that every-3-week
docetaxel is superior to weekly docetaxel. Why the
optimal schedule is different for the two taxanes is
not known. This is supported by the study by
Seidman and colleagues of paclitaxel in the metastatic
setting, as well as by studies of docetaxel in breast
cancer and other diseases. 6,7
One question that remains unanswered is the
comparative efficacy of weekly paclitaxel versus
dose-dense paclitaxel (administered every 2 weeks).
Citron and colleagues demonstrated that cyclophosphamide
and doxorubicin followed by paclitaxel
was more effective if administered every 2 weeks
versus every 3 weeks. 8 Sparano and colleagues
administered the cyclophosphamide/doxorubicin
cycles every 3 weeks and compared weekly taxane
versus every-3-week taxane. Although there is no
direct comparison between weekly and dose-dense
paclitaxel, one might expect them to be roughly
similar based on the relative advantage of each of
these regimens when compared with every-3-week
therapy.
Finally, one must ask why it has taken us so long
to determine optimal dose schedules for one of the
most widely used and effective classes of therapies
16 The American Journal of Hematology/Oncology
for breast cancer – the taxanes – which has been in
our armamentarium for quite a long time. F
References
1. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the
adjuvant treatment of breast cancer. N Engl J Med. 2008;358:
1663-1671.
2. Winer E, Berry D, Woolf S, et al. Failure of higher-dose paclitaxel
to improve outcome in patients with metastatic breast
cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol.
2004;22:2061-2068.
3. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III
study of docetaxel compared with paclitaxel in metastatic
breast cancer. J Clin Oncol. 2005;23:5542-5551.
4. Valero V, Jones S, Von Hoff D, et al. A phase II study of docetaxel
in patients with paclitaxel-resistant metastatic breast cancer.
J Clin Oncol. 1998;16:3362-3368.
5. Chevallier B, Fumoleau P, Kerbrat P, et al. Docetaxel is a major
cytotoxic drug for the treatment of advanced breast cancer: a
phase II trial of the Clinical Screening Cooperative Group of
the European Organization for Research and Treatment of
Cancer. J Clin Oncol. 1995;13:314-322.
6. Seidman AD, Berry D, Cirrincione C, et al. CALGB 9840: phase
III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion
versus standard (S) 3h infusion every third week in the treatment
of metastatic breast cancer (MBC), with trastuzumab (T)
for HER2 positive MBC and randomized for T in HER2 normal
MBC. J Clin Oncol. 2004;22(July 15 suppl):6s. Abstract 512.
7. Burstein H, Manola J, Younger J, et al. Docetaxel administered
on a weekly basis for metastatic breast cancer. J Clin Oncol.
2000;18:1212-1219.
8. Citron ML, Berry DA, Cirrincione 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 [published correction appears in
J Clin Oncol. 2003;21:2226]. J Clin Oncol. 2003;21:1431-1439.
Author disclosures: consultant: EMD Serono, Serenex.
Correspondence address: Lawrence N. Shulman, MD, Dana-
Farber Cancer Institute, 44 Binney Street, Boston, MA 02115;
phone: (617) 632-2277; fax: (617) 632-2260; e-mail: Lawrence_
Shulman@dfci.harvard.edu.

HER2 Status and Inflammatory Breast Cancer:
Evidence of Prognostic Significance and
Trastuzumab Efficacy
Shaheenah Dawood, MRCP(UK), MPH 1 ; Ana M. Gonzalez-Angulo, MD 2
Review
1 Department of Medical Oncology, Dubai Hospital, U.A.E.; 2 Department of Breast Medical Oncology, The University of Texas
M.D. Anderson Cancer Center, Houston, Texas
Inflammatory breast cancer (IBC) is an aggressive
subset of locally advanced breast cancer that
accounts for approximately 1% to 6% 1 of breast
cancers in the United States. For a disease historically
known to be uniformly fatal, a multimodality
approach to management incorporating primary systemic
chemotherapy, radiation therapy, and surgery
has improved long-term outcomes of patients with
IBC. 2,3 However, prognosis still remains poor compared
with other types of breast cancer, with 5-year
survival rates ranging from 30% to 50%. 1-3 The persistently
poor prognosis associated with this disease
has been attributed to a number of factors, including
an inherently aggressive biology and a lack of insight
into specific prognostic factors associated with the
disease. Moreover, most clinical trials actively
exclude patients with IBC, and due to the rarity of
the disease, most prospective and retrospective studies
attempting to answer specific clinical questions
related to IBC have been small.
HER2 is amplified in approximately 30% of breast
tumors. 4 Its main function is to mediate growth and
survival of cells, thus promoting tumor aggressiveness
that is associated with both poor disease-free
and overall survival. 5,6 Trastuzumab, a monoclonal
antibody targeting the HER2 receptor, has been
shown in randomized clinical trials to significantly
improve survival outcomes of women with HER2positive
breast tumors in both the metastatic 7 and
adjuvant 8,9 setting, thereby altering the natural
course of the disease. Although several studies have
observed an increased incidence of HER2 amplification
and/or overexpression of its protein, with rates
ranging from 50% to 100% of IBC tumors tested, its
prognostic significance in this aggressive subtype of
breast cancer had as yet not been established. 10-12
Moreover, the efficacy of trastuzumab in women
with HER2-positive IBC was also not known. We
Most clinical trials actively
exclude patients with
inflammatory breast cancer.
thus embarked on a study 13 involving a cohort of
patients with stage III IBC to primarily study the
prognostic impact of HER2 status. In addition, we
sought to determine whether trastuzumab was an
efficacious agent in this cohort.
Study Design and Results
A cohort of 179 women with stage III IBC diagnosed
between 1989 and 2005 with known HER2 status
were identified from the prospectively maintained
M.D. Anderson breast cancer systems database. For
the purposes of this study, women were identified
as having IBC if they presented with rapidly developing
signs and symptoms, over less than 3
months, that included breast enlargement, erythe-
For a more detailed discussion, please see the following: Dawood S, Broglio K, Gong Y, et al. Prognostic significance of HER-2 status in
women with inflammatory breast cancer. Cancer. 2008;112:1905-1911.
November 2008 • Vol 7 • Supplement 5 17

Review
ma and/or peau d’orange, and biopsy-confirmed
invasive carcinoma with or without evidence of
dermal lymphatic invasion. Tumors were classified
as HER2 positive if they exhibited 3+ staining by
immunohistochemistry (IHC) and/or gene amplification
by fluorescence in situ hybridization (FISH)
technique. Tumors were classified as HER2 negative
if they exhibited 1+ or negative staining by
HER2 is amplified
in approximately
30% of breast tumors.
IHC and/or no gene amplification by FISH. All
patients received adjuvant anthracycline-based
chemotherapy regimens followed by a mastectomy,
comprehensive radiation therapy to chest wall and
axilla, and adjuvant hormonal therapy when appropriate.
Patients with HER2-positive tumors did not
receive adjuvant trastuzumab as the monoclonal
antibody had not received approval for use in the
Unadjusted estimates*
18 The American Journal of Hematology/Oncology
adjuvant setting at the time of diagnosis. Upon
recurrence, patients with HER2-positive tumors
were allowed to have received trastuzumab.
Recurrence-free survival (RFS), defined from the
date of diagnosis to the date of local or distant
recurrence or last follow-up, and overall survival
(OS), defined from the date of diagnosis to death
from any cause or last follow-up, was computed.
The Kaplan-Meier product limit method was used
to determine 5-year survival estimates, which were
compared across groups using log-rank statistics.
Cox proportional hazards models were then fitted
to determine the association of HER2 status to survival
outcomes after adjusting for patient and
tumor characteristics.
Of the 179 patients, 111 (62%) had HER2-negative
disease and 68 (38%) had HER2-positive disease.
Median age for the cohort was 51 years (range, 28-78
years), and median follow-up among all patients still
alive at last follow-up was 41 months (range, 3-198
months). At the time of the analysis a total of 104
patients had recurred; 62 of 111 (55.9%) with HER2negative
disease and 42 of 68 (61.8%) with HER2positive
disease. Of the 42 patients with HER2-positive
disease who recurred, 31 (73.8%) received
trastuzumab in the metastatic setting. The Table
summarizes the unadjusted and adjusted RFS and
OS estimates. Overall Kaplan-Meier estimates for 5year
RFS was 37.8% (95% CI, 29.9%-45.7%), and 5-
Table
Unadjusted and Adjusted 5-Year Recurrence-Free and Overall Survival Estimates
Recurrence- Overall
Free Survival P Value Survival P Value
HER2 negative 38.8% 49.8%
(28.7%-48.8%) (38.0%-60.6%)
HER2 positive 36.5% 0.750 57.8% 0.245
(24.0%-49.0%) (43.4%-69.8%)
Adjusted estimates †
HER2 0.75 0.241 0.56 0.024
(positive vs negative) (0.46-1.22) (0.34-0.93)
*These are Kaplan-Meier estimates that have been compared across groups using log-rank statistics.
† These are adjusted hazard ratios. The models were adjusted for age (continuous), estrogen receptor status (positive vs negative),
progesterone receptor status (positive vs negative), lymphovascular invasion (yes vs no), grade of tumor (3 vs 1 and 2), lymph node
status (positive vs negative), and pathological complete response (yes vs no).

year OS was 53.1% (95% CI, 44.0%-61.3%). In the univariate
analysis, no significant differences were
observed in both survival end points when stratified
by HER2 status, although a nonsignificant trend that
favored patients with HER2-positive disease compared
to those with HER2-negative disease was
noted for OS. After adjusting for age, grade, hormone
receptor status, pathological complete
response, lymph node status, and lymphovascular
invasion, HER2 status was not observed to significantly
affect RFS. In the multivariate model for OS,
patients with HER2-positive disease had a 44%
decreased risk of death that was statistically significant
(HR=0.56; 95% CI, 0.34-0.93; P=0.024) compared
with patients with HER2-negative disease.
Discussion
The study we conducted is unique for a number of
reasons. First, most studies have been hampered by
nonspecific clinical diagnostic criteria used to identify
patients with IBC, making interpretation and comparisons
difficult. Using standard institutional criteria
for IBC, which conform to the American Joint
Committee on Cancer definition of IBC, allowed us
to clearly identify patients with IBC and separate
them from women with locally advanced non-IBC
tumors. Second, our sample size was relatively large
compared with previously published studies involving
patients with IBC. Third, by using a cohort that
did not receive trastuzumab in the adjuvant setting
but was allowed to use the agent upon recurrence,
we were uniquely able to study both the prognostic
impact of HER2 status as well as the efficacy of
trastuzumab in patients with IBC.
The results of our study indicate that HER2 status
did not impact RFS, even after controlling for patient
and tumor characteristics in the multivariate model.
This is in sharp contrast to the initial observations
made by Slamon and colleagues, 4 who reported
HER2 amplification not only as being associated
with worse RFS and OS outcomes compared with
women whose tumors did not exhibit HER2 amplification
but also as being of superior prognostic significance
to other well-established factors such as hormone
receptor status and the presence of lymph
node involvement. As such, we hypothesize that
prognostic factors typically used for non-IBC tumors
may not confer the same information in IBC tumors.
Studies have shown that factors such as increased
expression of the epidermal growth factor receptor
and p53 and loss of p27 may be indicative of poor
HER2 status and inflammatory breast cancer
prognosis in the IBC cohort, although larger studies
are required to confirm this. 14,15
When assessing overall survival, results from our
multivariate model indicated that women with
HER2-positive tumors had a 44% decreased risk of
death that was statistically significant (HR=0.56; 95%
CI, 0.34-0.93; P=0.024) compared with women with
The results of our study
indicate that HER2 status did
not impact relapse-free survival.
HER2-negative tumors. The improved survival
observed is attributed to the fact that the majority of
women with HER2-positive disease who relapsed
received trastuzumab. This observation indicates
that trastuzumab is indeed efficacious when administered
to women with IBC tumors. It also provides
evidence of the fact that when trastuzumab is administered
to patients with HER2-positive IBC, they
attain superior outcomes compared to patients with
HER2-negative tumors.
Conclusion
The results of this study are important and applicable
to the clinical management of women with IBC.
Randomized clinical trials that have assessed the
efficacy of trastuzumab have been unable to determine
its efficacy in women with IBC tumors. The
results of this study provide evidence of the efficacy
of this agent in this cohort despite the lack of
prognostic difference observed between women
with HER2-positive and HER2-negative tumors in
the absence of trastuzumab administration. It is
well known that the natural history of this aggressive
subtype of breast cancer is different compared
with other types of breast cancer, making it important
for future research to focus on conducting clinical
trials specifically aimed at this cohort. Until
such initiatives are undertaken, results from studies
such as ours will be an important component in
guiding physician management of women with
IBC. F
(continued on page 22)
November 2008 • Vol 7 • Supplement 5 19

Commentary
Inflammatory Breast Cancer: Still a Challenge
Nancy U. Lin, MD
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Inflammatory breast cancer (IBC) is a relatively
rare disease, comprising less than 3% of breast
cancer cases in the United States. 1 Compared
with locally advanced, noninflammatory breast cancer,
IBC appears to be a distinct entity with a unique
mode of presentation and underlying biology.
Unfortunately, even with multimodality therapy, the
prognosis for patients with IBC remains poor. 2
Overexpression and/or amplification of HER2 is
present in 25% to 30% of primary breast carcinomas. 3
In contrast, HER2 is overexpressed in approximately
half of IBC cases. 4,5 In all patients with breast cancer,
Inflammatory breast cancer
appears to be a distinct entity with
a unique mode of presentation
and underlying biology.
overexpression of HER2 is associated with a higher
risk of relapse and worse overall survival (OS) 3 ; however,
the contribution of HER2 overexpression to the
prognosis of patients with IBC is not well defined.
Dawood and colleagues therefore set out to examine
the prognostic significance of HER2 status in
women with IBC diagnosed between 1989 and 2005
20 The American Journal of Hematology/Oncology
at the University of Texas M.D. Anderson Cancer
Center. 6 In all, 179 patients fulfilled the inclusion/
exclusion criteria for this retrospective analysis. A
strength of the study is the relatively uniform treatment
of the patients: all patients received an anthracycline,
and nearly 80% received a taxane as part of
their primary systemic chemotherapy. In addition,
the exclusion of patients who received trastuzumab
in the neoadjuvant or adjuvant setting allowed the
authors to describe the impact of HER2 upon relapsefree
survival (RFS) independent of an effective targeted
therapy. Chemotherapy was followed by mastectomy
and comprehensive radiotherapy in all patients,
and hormonal therapy was given to patients with
hormone receptor–positive disease. There was no difference
in the rate of pathologic complete response
(pCR) by HER2 status. After a median follow-up of 35
months, 56% of patients with HER2-negative disease
and 62% of patients with HER2-positive disease
developed a disease recurrence, a difference that was
not statistically significant.
What could account for the lack of prognostic significance
of HER2 for RFS described in this study
compared with the reproducible influence of HER2
status on prognosis in all-comers with breast cancer?
One possibility relates to common characteristics of
IBC present across breast cancer subtypes that lead to
a more aggressive clinical phenotype. Using expression
profiling, Bertucci and colleagues identified the
same five molecular subtypes (luminal A and B,
basal, HER2 positive, and normal breast-like) in IBC
as have been observed in non-IBC. 7 At the same time,
a single 109-gene set was able to distinguish between
IBC and non-IBC within each subtype. These genes
Dr Nancy U. Lin was invited to provide commentary on the following article: Dawood S, Broglio K, Gong Y, et al. Prognostic significance of
HER-2 status in women with inflammatory breast cancer. Cancer. 2008;112:1905-1911.

include those related to cell motility, invasion, proliferation,
and angiogenesis. Van Laere and colleagues
reported similar findings: a set of 50 discriminator
genes distinguished IBC from non-IBC even after
excluding estrogen receptor (ER)- or HER2-related
genes. 8 When IBC-related genes are activated, tumor
behavior may be more aggressive regardless of subtype,
and the influence of HER2 status may be less
relevant. Another possibility relates to the distribution
of molecular subtypes within the Dawood study.
Sixty percent of the HER2-negative tumors were also
ER negative. Although progesterone receptor status
was not reported, one can assume that the majority
of these tumors would probably fall into the “triplenegative”
subtype. Thus, triple-negative tumors
were overrepresented compared with their incidence
in non-IBC tumors, and a binary comparison of the
prognosis of HER2-positive and HER2 negative
patients would be heavily influenced by the prognosis
of patients with triple-negative IBC. In this light,
it would be of interest to explore the prognosis of the
IBC patients according to molecular subtype (ie,
luminal A, luminal B, basal-like, HER2-positive).
Third, as the authors point out, the use of anthracyclines
across all patients may have preferentially benefited
those with HER2-positive tumors. In a pooled
analysis of eight randomized trials for early breast
cancer, anthracyclines were superior to nonanthracycline-containing
regimens in patients with HER2positive
but not HER2-negative tumors. 9 Thus, any
difference in natural history between HER2-positive
versus HER2-negative IBC may have been attenuated
by treatment effect.
With respect to OS, HER2-positive status was a
favorable prognostic factor in this study, likely due to
the availability of effective targeted therapy (eg,
trastuzumab) for patients with HER2-positive IBC at
the time of recurrence. Nevertheless, it is sobering
that even in a group of women treated in a comprehensive
fashion at a highly regarded cancer center
that the 5-year overall survival rate for the entire
cohort was only 53.1%. How can we improve? First,
given the impact of trastuzumab on OS after IBC
recurrence, as demonstrated by Dawood and colleagues,
and the proven benefits of trastuzumab in
the adjuvant setting for early breast cancer, it is likely
that the current standard use of trastuzumab in the
preoperative setting for patients with IBC is already
having a favorable effect upon outcomes in patients
with HER2-positive disease. Preliminary results
from the NOAH (NeOAdjuvant Herceptin) study
The challenge of IBC
indicate that the addition of trastuzumab substantially
improves the rate of pCR in patients with IBC
compared with chemotherapy alone. 10 Given that
pCR is highly correlated with RFS and OS, these
results are highly encouraging. Next, there is also
early evidence of efficacy from a phase II study of the
oral epidermal growth factor receptor/HER2
inhibitor lapatinib in patients with recurrent or
anthracycline-refractory IBC in which 50% of
patients experienced a clinical response. 11 Ongoing
trials will further clarify whether lapatinib has a role
in patients with newly diagnosed IBC.
Looking beyond HER2, a number of other biologic
characteristics appear to be strongly associated
with both RFS and OS in patients with IBC. These
include molecules related to angiogenesis (hypoxiainducible
factor 1, vascular endothelial growth factor,
etc), cytoskeletal organization and cell motility
(eg, Rho proteins), and chemokines (CXCR4,
CCR7). 7,12 Several small studies have already been
completed evaluating the safety of angiogenic blockade
in patients with IBC, and these studies have also
demonstrated associated changes in tumor blood
flow. 13,14 In the future, pharmacologic targeting of the
angiogenesis and other pathways may improve outcomes
in both HER2-positive and HER2-negative
IBC.
In summary, while Dawood and colleagues did
not observe a relationship between HER2 status and
RFS, the observed association between HER2 positivity
and improved OS is powerful evidence that
effective targeted therapy can yield meaningful
improvements in outcomes from IBC. The elucidation
of pathways important in the development and
maintenance of the IBC phenotype and the development
of drugs to target these pathways continue to
move forward. However, because of the relative rarity
of IBC, the pace of further advances in the field
will depend not only on the pipeline of new targeted
drugs but upon a concerted effort to sustain multidisciplinary
and cross-institutional collaborations. ✦
References
1. Levine PH, Veneroso C. The epidemiology of inflammatory
breast cancer. Semin Oncol. 2008;35:11-16.
2. Gonzalez-Angulo AM, Hennessy BT, Broglio K, et al. Trends
for inflammatory breast cancer: is survival improving?
Oncologist. 2007;12:904-912.
3. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer:
correlation of relapse and survival with amplification of the
HER-2/neu oncogene. Science. 1987;235:177-182.
4. Cabioglu N, Gong Y, Islam R, et al. Expression of growth factor
November 2008 • Vol 7 • Supplement 5 21

Commentary
and chemokine receptors: new insights in the biology of
inflammatory breast cancer. Ann Oncol. 2007;18:1021-1029.
5. Parton M, Dowsett M, Ashley S, et al. High incidence of HER-
2 positivity in inflammatory breast cancer. Breast. 2004;13:97-
103.
6. Dawood S, Broglio K, Gong Y, et al. Prognostic significance of
HER-2 status in women with inflammatory breast cancer.
Cancer. 2008;112:1905-1911.
7. Bertucci F, Finetti P, Rougemont J, et al. Gene expression profiling
identifies molecular subtypes of inflammatory breast cancer.
Cancer Res. 2005;65:2170-2178.
8. Van Laere S, Van der Auwera I, Van den Eynden GG, et al.
Distinct molecular signature of inflammatory breast cancer by
cDNA microarray analysis. Breast Cancer Res Treat. 2005;93:237-
246.
9. Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy
of adjuvant anthracyclines in early breast cancer: a pooled
analysis of randomized trials. J Natl Cancer Inst. 2008;100:14-20.
10. Gianni L, Semiglazov V, Manikhas GM, et al. Neoadjuvant
trastuzumab in locally advanced breast cancer (NOAH): antitumor
and safety analysis. J Clin Oncol. 2007;25(June 20 supplement).
Abstract 532.
11. Johnston S, Trudeau M, Kaufman B, et al. Phase II study of pre-
HER2 status and inflammatory breast cancer
(continued from page 19)
References
1. Jaiyesimi IA, Buzdar AU, Hortobagyi G. Inflammatory breast
cancer: a review. J Clin Oncol. 1992;10:1014-1024.
2. Cristofanilli M, Buzdar AU, Hortobagyi GN. Update on the
management of inflammatory breast cancer. Oncologist.
2003;8:141-148.
3. Buzdar AU, Singeltary SE, Booser DJ, et al. Combined modality
treatment of stage III and inflammatory breast cancer. M.D.
Anderson Cancer Center experience. Surg Oncol Clin N Am.
1995;4:715-734.
4. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer:
correlation of relapse and survival with amplification of the
HER-2/neu oncogene. Science. 1987;235:177-182.
5. Borg A, Tandon AK, Sigurdsson H, et al. HER-2/neu amplification
predicts poor survival in node-positive breast cancer.
Cancer Res. 1990;50:4322-4327.
6. Winstanley J, Cooke T, Murray GD, et al. The long term prognostic
significance of c-erb-2 in primary breast cancer. Br J
Cancer. 1991;63:447-450.
7. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy
plus a monoclonal antibody against HER2 for metastatic
breast cancer that overexpresses HER2. N Engl J Med.
2001;344:783-792.
8. 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.
9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.
Trastuzumab after adjuvant chemotherapy in HER2-positive
breast cancer. N Engl J Med. 2005;353:1659-1672.
22 The American Journal of Hematology/Oncology
dictive biomarker profiles for response targeting human epidermal
growth factor receptor 2 (HER-2) in advanced inflammatory
breast cancer with lapatinib monotherapy. J Clin Oncol.
2008;26:1066-1072.
12. Kleer CG, van Golen KL, Merajver SD. Molecular biology of
breast cancer metastasis. Inflammatory breast cancer: clinical
syndrome and molecular determinants. Breast Cancer Res.
2000;2:423-429.
13. Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor
effects of bevacizumab in patients with inflammatory and
locally advanced breast cancer. J Clin Oncol. 2006;24:769-777.
14. Overmoyer B, Fu P, Hoppel C, et al. Inflammatory breast cancer
as a model disease to study tumor angiogenesis: results of
a phase IB trial of combination SU5416 and doxorubicin. Clin
Cancer Res. 2007;13:5862-5868.
Author disclosures: Research support: Genentech, Glaxo-
SmithKline; consultant: GlaxoSmithKline (

CaseStudy
Risk of Local Recurrence for Breast Cancer Subtypes
Defined by ER, PR, and HER2 Status
Paul L. Nguyen, MD 1,2 ; Alphonse G. Taghian, MD, PhD 2,3 ; Jay R. Harris, MD 2,4
1 Harvard Radiation Oncology Program; 2 Harvard Medical School; 3 Department of Radiation Oncology, Massachusetts
General Hospital; 4 Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital;
all Boston, Massachusetts
A60-year-old female had a routine screening
mammogram that showed a 1 cm density
with associated microcalcifications in the
upper outer quadrant of the patient’s left breast. A
core biopsy revealed an infiltrating ductal carcinoma
(IDC), grade 2, with associated ductal carcinoma in
situ (DCIS). The tumor was estrogen receptor (ER)
positive, progesterone receptor (PR) positive, and
HER2 negative. The patient elected breast-conserving
therapy and had a negative sentinel lymph node
biopsy. Pathology from the lumpectomy showed a
1.2 cm grade 2 IDC without evidence of extensive
intraductal component (EIC). There was no lymphovascular
invasion. There was a focally positive inferior
margin, but all other margins were >2 mm. The
Oncotype DX recurrence score was 11 (low risk). A
reexcision of the inferior margin was performed and
was negative except for a single 1 mm focus of DCIS
that came within 1 mm of the final inferior reexcision
margin. The issue of a second reexcision to achieve a
>2 mm inferior margin was discussed, but both the
patient and surgeon were concerned that this might
lead to a poor cosmetic result given the patient’s relatively
small breast size.
Discussion
Classic Predictors of Local Recurrence After Breast-
Conserving Therapy
For women who undergo breast-conserving therapy
for invasive breast cancer, the risk of local recurrence
has been shown in several studies to be based on factors
such as margin status, nodal status, young age,
and presence or absence of EIC (defined as an infiltrating
ductal cancer in which greater than 25% of
the tumor volume is DCIS, and DCIS extends beyond
the invasive cancer into surrounding breast
parenchyma). 1-3
While the exact relative importance of each of the
factors is not always consistent across studies, most
have agreed that margin status is one of the most
important predictors of local recurrence for women
undergoing breast-conserving therapy, and patients
are almost always advised to undergo reexcision if
the tumor involves an inked margin (ie, a positive
margin), unless that positive margin is at the skin or
is a deep margin that has already extended to the
pectoral fascia. The issue of whether a “close margin,”
as our patient has, is a risk factor for local recurrence
is less clear. Investigators have variably
. . . most have agreed that margin
status is one of the most important
predictors of local recurrence.
defined a close margin as having tumor within 1 or 2
mm of the inked surface, and while several studies
have found an association between increasing margin
width and lower local recurrence, only three published
studies have subdivided this width enough to
make finer comparisons. 2,4 One study from Tufts-
New England Medical Center showed a 12-year local
recurrence rate of 9% for margins 0.1 to 2.0 mm, 5%
for 2.1 to 5.0 mm, and 0% for >5 mm. 5 Also, the
Harvard Joint Center for Radiation Therapy found
that 8-year rates of local recurrence were 7% for margins
0.1 to 1.0 mm, 6% for 1.1 to 2.0 mm, and 4% for
November 2008 • Vol 7 • Supplement 5 23

CaseStudy
2.1 to 5 mm. 6 However, a William Beaumont study
found that 12-year local recurrence was 17% for margins
0.1 to 1.0 mm, 14% for 1.1 to 2.0 mm, and 15%
for 2.1 to 3.0 mm, making the impact of a

factors such as age and margin status were not significant,
although there may have been too few
patients with positive margins (3.3%) or age

CaseStudy
References
1. Zhou P, Recht A. Young age and outcome for women with
early-stage invasive breast carcinoma. Cancer. 2004;101:1264-
1274.
2. Recht A. Lessons of studies of breast-conserving therapy with
and without whole-breast irradiation for patient selection for
partial-breast irradiation. Semin Radiat Oncol. 2005;15:123-132.
3. Schnitt SJ, Connolly JL. Processing and evaluation of breast
excision specimens. A clinically oriented approach. Am J Clin
Pathol. 1992;98:125-137.
4. Recht A. Breast Cancer: Stages T1 and T2. In: Gunderson LL,
Tepper JE, eds. Clinical Radiation Oncology. 2nd ed.
Philadelphia, PA: Churchill Livingstone; 2007:1475-1502.
5. Neuschatz AC, DiPetrillo T, Safaii H, et al. Long-term followup
of a prospective policy of margin-directed radiation dose
escalation in breast-conserving therapy. Cancer. 2003;97:30-39.
6. Park CC, Mitsumori M, Nixon A, et al. Outcome at 8 years after
breast-conserving surgery and radiation therapy for invasive
breast cancer: influence of margin status and systemic therapy
on local recurrence. J Clin Oncol. 2000;18:1668-1675.
7. Goldstein NS, Kestin L, Vicini F. Factors associated with ipsilateral
breast failure and distant metastases in patients with
invasive breast carcinoma treated with breast-conserving therapy.
A clinicopathologic study of 607 neoplasms from 583
patients. Am J Clin Pathol. 2003;120:500-527.
8. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of
human breast tumours. Nature. 2000;406:747-752.
9. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns
of breast carcinomas distinguish tumor subclasses with
clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869-
10874.
10. Brenton JD, Carey LA, Ahmed AA, et al. Molecular classification
and molecular forecasting of breast cancer: ready for clinical
application? J Clin Oncol. 2005;23:7350-7360.
26 The American Journal of Hematology/Oncology
11. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of
breast tumor subtypes in independent gene expression data
sets. Proc Natl Acad Sci U S A. 2003;100:8418-8423.
12. Sotiriou C, Neo SY, McShane LM, et al. Breast cancer classification
and prognosis based on gene expression profiles from a
population-based study. Proc Natl Acad Sci U S A. 2003;100:
10393-10398.
13. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes,
and survival in the Carolina Breast Cancer Study. JAMA.
2006;295:2492-2502.
14. Nguyen PL, Taghian AG, Katz MS, et al. Breast cancer subtype
approximated by estrogen receptor, progesterone receptor, and
HER-2 is associated with local and distant recurrence after
breast-conserving therapy. J Clin Oncol. 2008;26:2373-2378.
15. Kyndi M, Sorensen FB, Knudsen H, et al. Estrogen receptor,
progesterone receptor, HER-2, and response to postmastectomy
radiotherapy in high-risk breast cancer: the Danish Breast
Cancer Cooperative Group. J Clin Oncol. 2008;26:1419-1426.
16. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.
Trastuzumab after adjuvant chemotherapy in HER2-positive
breast cancer. N Engl J Med. 2005;353:1659-1672.
17. 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.
Author disclosures: No relationships with industry were reported.
Correspondence address: Paul L. Nguyen, MD, Harvard
Radiation Oncology Program, 75 Francis Street, L2, Boston,
MA 02115; phone: (617) 732-6310; e-mail: pnguyen@
LROC.harvard.edu.
Committed to bringing you the latest and most relevant information in cancer management.
Look in an upcoming issue for a review by Dr Giorgio Zavagno
of his recent article:
INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH ®
Role of resection margins in patients treated with breast conservation surgery. Cancer. 2008;
112:1923-1931.
Commentary by Drs Laurie Kirstein and David August.
®