Review - Haymarket Media Group
Review - Haymarket Media Group
Review - Haymarket Media Group
You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
ajho.com<br />
November 2008 • Vol 7 • Supplement 5<br />
INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH ®<br />
TRENDS IN 8<br />
BREAST CANCER<br />
Weekly Paclitaxel Improves 10<br />
Disease-Free and Overall<br />
Survival in the Adjuvant<br />
Treatment of Breast Cancer<br />
REVIEW<br />
The New England Journal of Medicine<br />
Optimizing Taxane Therapy for 15<br />
Patients With Primary Breast Cancer:<br />
What Are the Lessons Learned?<br />
COMMENTARY<br />
Special Breast Cancer Issue<br />
THE NATION’S MOST REQUESTED HEMATOLOGY/ONCOLOGY PUBLICATION<br />
©2008 <strong>Haymarket</strong> <strong>Media</strong> Inc.<br />
HER2 Status and 17<br />
Inflammatory Breast<br />
Cancer: Evidence of<br />
Prognostic Significance<br />
and Trastuzumab Efficacy<br />
REVIEW<br />
Cancer<br />
Inflammatory Breast 20<br />
Cancer: Still a Challenge<br />
COMMENTARY<br />
Risk of Local Recurrence for 23<br />
Breast Cancer Subtypes Defined<br />
by ER, PR, and HER2 Status<br />
CASE STUDY<br />
Supplement to The American Journal of Hematology/Oncology<br />
®
TABLE OF CONTENTS<br />
INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH ®<br />
Trends in Breast Cancer 8<br />
Weekly Paclitaxel Improves Disease-Free and 10<br />
Overall Survival in the Adjuvant Treatment of<br />
Breast Cancer<br />
REVIEW<br />
The New England Journal of Medicine<br />
Rachel E. Raab, MD; Joseph A. Sparano, MD ➢ Montefiore-Einstein Cancer Center,<br />
Bronx, New York<br />
Optimizing Taxane Therapy for Patients 15<br />
With Primary Breast Cancer: What Are the<br />
Lessons Learned?<br />
COMMENTARY<br />
Lawrence N. Shulman, MD ➢ Dana-Farber Cancer Institute, Brigham<br />
and Women’s Hospital, Boston, Massachusetts<br />
HER2 Status and Inflammatory Breast Cancer: 17<br />
Evidence of Prognostic Significance and<br />
Trastuzumab Efficacy<br />
REVIEW<br />
Cancer<br />
Shaheenah Dawood, MRCP(UK), MPH; Ana M. Gonzalez-Angulo, MD ➢ Dubai Hospital,<br />
U.A.E.<br />
Inflammatory Breast Cancer: Still a Challenge 20<br />
COMMENTARY<br />
Nancy U. Lin, MD ➢ Dana-Farber Cancer Institute, Boston, Massachusetts<br />
Risk of Local Recurrence for Breast Cancer Subtypes 23<br />
Defined by ER, PR, and HER2 Status<br />
CASE STUDY<br />
Paul L. Nguyen, MD, et al ➢ Harvard Medical School, Boston, Massachusetts<br />
4 The American Journal of Hematology/Oncology<br />
November 2008 • Vol 7 • Supplement 5<br />
®<br />
Editor in Chief, Medical Oncology<br />
Lawrence N. Shulman, MD<br />
Editor in Chief, Surgical Oncology<br />
Douglas J. Schwartzentruber, MD, FACS<br />
Associate Editor, Radiation Oncology<br />
Marcus E. Randall, MD<br />
Publisher<br />
Steve Svec<br />
201-799-4874<br />
Steve.svec@haymarketmedia.com<br />
Senior Editorial Director<br />
Kristin Lee Siyahian<br />
Kristinlee.siyahian@haymarketmedia.com<br />
Editorial Director<br />
Kristen Olafson<br />
Kristen.olafson@haymarketmedia.com<br />
Senior Copy Editor<br />
Bjarne Hansen<br />
Production Editor<br />
Rick Maffei<br />
Art Director<br />
Robert Mancuso<br />
Production Inquiries<br />
Leslie Carsman<br />
646-638-6075<br />
Director of Sales<br />
Chad Holloway<br />
201-799-4878<br />
Chad.holloway@haymarketmedia.com<br />
Circulation Department<br />
ajhosubs@haymarketmedia.com<br />
For reprints contact:<br />
Greg Rucker<br />
212-221-9595 ext 105<br />
Greg.rucker@parsintl.com<br />
<strong>Haymarket</strong> <strong>Media</strong> Inc.<br />
CEO<br />
Lee Maniscalco<br />
CFO<br />
Michael Kriak<br />
Associate Publishing Director<br />
Jeff Forster<br />
<strong>Group</strong> Editor<br />
Tanya Gregory, PhD
LettertoOurReaders<br />
Dear Colleague,<br />
Each year, we devote an issue to breast cancer. This month, we address several recent reports on advances in the<br />
field and in the care of patients with this disease.<br />
We are still learning how to optimally administer cytotoxic chemotherapy; the manuscript by Sparano and colleagues<br />
is critical in comparing the two principal taxanes available to us, as well as two different schedules of<br />
administration. Survival and toxicity data taken together are essential for establishing optimal taxane therapy in<br />
the adjuvant setting for both standard care and future clinical trials.<br />
Continued exploration into differences in the biologic subtypes of breast cancer determined by hormone receptor<br />
status and HER2 status is helping us to better understand the disease, and what optimal therapies will be, based<br />
on these subgroups of patients. The manuscript by Dawood and colleagues exploring HER2 status in inflammatory<br />
breast cancer and the manuscript by Nguyen and colleagues looking at biologic subtypes associated with<br />
local and distant recurrence after breast-conserving therapy are examples of these advances.<br />
Once a year, it is worthwhile to review the substantial progress we have made in our understanding of breast<br />
cancer and the treatment of this disease. Survival rates have risen dramatically over the last two decades, partly<br />
due to improved screening, but also due to better therapies for these patients.<br />
We appreciate your continued interest in The American Journal of Hematology/Oncology and trust that you will<br />
benefit from the information presented here.<br />
Sincerely,<br />
Lawrence N. Shulman, MD<br />
Editor in Chief, Medical Oncology<br />
November 2008 • Vol 7 • Supplement 5 7
in Breast Cancer<br />
The following is an invited report based on abstracts presented at recent oncology meetings.<br />
Bevacizumab With Docetaxel or Docetaxel With<br />
Placebo as First-Line Therapy in Locally<br />
Recurrent or Metastatic Breast Cancer: The<br />
AVADO Study<br />
The AVADO study, a randomized, double-blind, placebo-controlled,<br />
phase III trial, evaluated the combination<br />
of bevacizumab plus docetaxel as first-line therapy in<br />
patients with locally recurrent or metastatic breast cancer.<br />
A previous study had demonstrated superior progression-free<br />
survival (PFS) for bevacizumab plus paclitaxel<br />
compared with paclitaxel alone.<br />
Patient eligibility criteria included HER2-negative,<br />
inoperable locally recurrent or metastatic breast cancer;<br />
no prior chemotherapy for advanced disease; ECOG PS<br />
0-1; adequate left ventricular ejection fraction (LVEF),<br />
and no CNS metastases. From March 2006 to April 2007,<br />
researchers in 24 countries randomized 736 patients to<br />
docetaxel 100 mg/m2 plus placebo or docetaxel plus<br />
bevacizumab at either 7.5 mg/kg or 15 mg/kg.<br />
Docetaxel was administered every 3 weeks for up to 9<br />
cycles. Bevacizumab or placebo was administered every<br />
3 weeks until disease progression or unacceptable toxicity.<br />
PFS was the primary end point.<br />
With a median follow-up of approximately 11<br />
months, both bevacizumab-containing arms demonstrated<br />
statistically significantly superior PFS compared<br />
with docetaxel alone (bevacizumab 7.5 mg/kg,<br />
P=0.0035; bevacizumab 15 mg/kg; P=0.0001). The overall<br />
response rate (CR + PR) was 44.4% in the docetaxel<br />
alone arm vs 55.2% (P=0.0295) and 63.1% (P=0.0001) in<br />
the bevacizumab 7.5 mg/kg and 15 mg/kg arms, respectively.<br />
Grade ≥3 adverse events for the docetaxel alone,<br />
bevacizumab 7.5 mg/kg, and bevacizumab 15 mg/kg<br />
arms were 67.0%, 74.8%, and 74.1%, respectively, and<br />
included GI perforation 0.9%, 0.4%, and 0.4% and febrile<br />
neutropenia 12.0%, 15.2%, and 16.6%, respectively.<br />
Overall survival rate data were immature at the time of<br />
the report.<br />
Results indicate that both doses of bevacizumab in<br />
combination with docetaxel significantly improved PFS<br />
and response rate when compared with docetaxel alone.<br />
Safety results were comparable in the two bevacizumab<br />
arms, and although toxicities were slightly increased relative<br />
to the control group, no new safety concerns<br />
emerged.<br />
Miles D, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract LBA1011.<br />
By Beverly Moy, MD, MPHTrends<br />
8 The American Journal of Hematology/Oncology<br />
A Phase III Study of Capecitabine vs<br />
Capecitabine Plus Trastuzumab in HER2+<br />
Patients With Metastatic Breast Cancer That<br />
Progressed During Trastuzumab Treatment<br />
(GBG 26/BIG 3-05)<br />
Agreement is lacking on whether trastuzumab treatment<br />
should be continued beyond disease progression. The<br />
German Breast <strong>Group</strong> (GBG) and the Breast<br />
International <strong>Group</strong> (BIG) conducted a treatment<br />
beyond progression (TBP) phase III study, GBG 26/BIG<br />
3-05, of trastuzumab therapy.<br />
Eligible patients had HER2+, locally advanced or<br />
metastatic breast cancer that progressed during<br />
trastuzumab treatment with or without adjuvant and/or<br />
first-line metastatic chemotherapy. Patients were prospectively<br />
randomized to receive either capecitabine<br />
(2500 mg/m 2 on days 1-14, every 21 days) or capecitabine<br />
plus continuation of trastuzumab (6 mg/kg, every 3<br />
weeks). The primary end point was time to progression.<br />
The slowly accruing trial was closed prematurely after<br />
the registration of lapatinib.<br />
Between January 2004 and May 2007, a total of 156<br />
patients were randomized. Of these, 78 received capecitabine,<br />
and 78 received capecitabine plus trastuzumab.<br />
Patients were stratified according to previous treatment:<br />
taxane/trastuzumab as first-line therapy (111 patients),<br />
taxanes/trastuzumab as adjuvant therapy (3 patients),<br />
trastuzumab alone or without taxanes as first-line treatment<br />
(42 patients). Of note, 75 patients (48.1%) had<br />
received anthracyclines.<br />
Visceral metastasis was observed in 119 patients<br />
(76.3%). At the time of the report, median follow-up was<br />
11.8 months, and analysis had revealed a PFS of 5.6<br />
months with 53 events in the capecitabine group and 8.5<br />
months with 48 events in the capecitabine plus<br />
trastuzumab group (HR=0.71). In patients receiving<br />
capecitabine or capecitabine plus trastuzumab, respectively,<br />
brain metastases were seen in 4 patients vs 7<br />
patients; overall survival was 19.9 months with 31<br />
events vs 20.3 months with 26 events (HR=0.79); crude<br />
response rates were 24.6% vs 49.1%; and primary progressions<br />
were seen in 26.3% vs 16%.<br />
Reported grade 3/4 toxicities for capecitabine and<br />
capecitabine plus trastuzumab, respectively, included<br />
neutropenia, 3.3% vs 6.3%; febrile neutropenia, 0% vs<br />
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<br />
4.9%. There were no therapy-related deaths.<br />
The preliminary results of this TBP study suggest similar<br />
toxicity but higher efficacy for continuing trastuzumab<br />
beyond progression when second-line chemotherapy with<br />
capecitabine is initiated. The final efficacy analysis was<br />
scheduled to be released at a later date.<br />
Von Minckwitz G, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1025.<br />
Anastrozole Plus Gefitinib Compared With<br />
Anastrozole Plus Placebo in Postmenopausal<br />
Women With Hormone Receptor–Positive<br />
Metastatic Breast Cancer<br />
Preclinical data indicate the presence of crosstalk between<br />
growth factor receptor pathways and the estrogen receptor.<br />
Thus, a technique to overcome hormonal resistance<br />
might involve inhibition of both epidermal growth factor<br />
receptor and estrogen receptor signaling. This phase II<br />
multicenter, double-blind, randomized trial was designed<br />
to evaluate the efficacy and tolerability of anastrozole<br />
plus gefitinib vs anastrozole plus placebo in postmenopausal<br />
women with newly diagnosed hormone<br />
receptor–positive metastatic breast cancer.<br />
Ninety-four patients were randomized to receive anastrozole<br />
1 mg/day plus either gefitinib 250 mg/day or<br />
placebo (50 women received anastrozole plus placebo; 43<br />
received anastrozole plus gefitinib; one died prior to<br />
treatment). PFS was the primary end point. The secondary<br />
end points included objective response rate, clinical<br />
benefit rate (defined as objective response or stable disease<br />
≥24 weeks), overall survival, safety, and tolerability.<br />
Enrollment was stopped early because of slow<br />
recruitment, and fewer statistical analyses were performed.<br />
However, a marked advantage in PFS was seen<br />
for anastrozole plus gefitinib over anastrozole plus<br />
placebo (median 14.5 vs 8.2 months). Complete response<br />
was noted in 1 patient in each group. A numerical<br />
advantage in clinical benefit rate was seen for anastrozole<br />
plus gefitinib (21 patients, 49%) vs anastrozole plus<br />
placebo (17 patients, 34%). There were no unexpected<br />
safety or tolerability findings. Treatment-related adverse<br />
events, mostly mild, were seen in 79% of patients in the<br />
anastrozole plus gefitinib arm vs 38% in the anastrozole<br />
plus placebo arm. Death occurred in 2 patients in the<br />
anastrozole plus gefitinib arm and 1 patient in the anastrozole<br />
plus placebo arm; none were considered related<br />
to treatment.<br />
The authors concluded that anastrozole plus gefitinib<br />
was well tolerated and showed a marked advantage in<br />
PFS when compared with anastrozole plus placebo in<br />
postmenopausal women with newly diagnosed hormone<br />
receptor–positive metastatic breast cancer. They also reported<br />
that the data suggest the need for further investigation<br />
of this combination.<br />
Cristofanilli M, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1012.<br />
Lapatinib Alone or in Combination With<br />
Trastuzumab in Heavily Pretreated HER2+<br />
Metastatic Breast Cancer That Progressed on<br />
Trastuzumab Therapy<br />
Preclinical data indicate possible synergy between<br />
trastuzumab and lapatinib, an oral, small-molecule<br />
inhibitor of EGFR and HER2 with a mechanism of action<br />
distinct from that of trastuzumab. In this randomized<br />
phase III study, researchers evaluated lapatinib alone and<br />
in combination with trastuzumab in women with HER2+<br />
metastatic breast cancer who had experienced progressive<br />
disease while on trastuzumab therapy.<br />
Women with these characteristics were eligible for participation<br />
if they had also received prior anthracycline and<br />
taxane therapy and had measurable lesions or bone-only<br />
disease. Patients were first stratified according to hormone<br />
receptor status and the presence of visceral or nonvisceral<br />
disease, then randomized to receive either lapatinib (1500<br />
mg qd) or lapatinib (1000 mg qd) plus trastuzumab (2<br />
mg/kg weekly after a 4 mg/kg loading dose). The primary<br />
end point was PFS (determined by investigator assessment);<br />
secondary end points were clinical benefit rate at 24<br />
weeks, response rate, and overall survival. Patients who<br />
progressed while taking lapatinib were allowed to cross<br />
over to the lapatinib plus trastuzumab arm.<br />
Of the 296 patients who were randomized, all had<br />
received prior trastuzumab therapy and a median of 6 prior<br />
chemotherapy regimens. The addition of trastuzumab to<br />
lapatinib significantly improved PFS (median 8.4 weeks for<br />
lapatinib vs 12.0 weeks for lapatinib plus trastuzumab;<br />
P=0.029) and clinical benefit rate (13.2% for lapatinib vs<br />
25.2% for lapatinib plus trastuzumab; P=0.020). Response<br />
rate and overall survival were similar in the two arms.<br />
In general, both treatment arms were well tolerated.<br />
Grade 1/2 diarrhea was higher in the lapatinib plus<br />
trastuzumab arm (53% vs 41%); acneiform rash was more<br />
common in the lapatinib alone arm and was likely caused by<br />
the higher lapatinib dose. An asymptomatic decline in LVEF<br />
(>20%, and below LLN) occurred in 5% of the patients in the<br />
combination arm and in 2% of patients in the lapatinib<br />
alone arm. One patient in the lapatinib plus trastuzumab<br />
arm died; death was attributed to cardiac toxicity.<br />
This is the largest study of two targeted agents in<br />
HER2+ metastatic breast cancer and the first to demonstrate<br />
the synergy of lapatinib plus trastuzumab in a phase<br />
III trial. The authors concluded that the combination of<br />
lapatinib plus trastuzumab in patients progressing on<br />
trastuzumab-based therapy improved clinical outcome<br />
without major changes in the side effect profile. The<br />
authors also referred to the ongoing ALTTO (Adjuvant<br />
Lapatinib and/or Trastuzumab Treatment Optimization)<br />
study, in which the role of combined anti-HER2 therapy<br />
plus chemotherapy is being studied in less heavily pretreated<br />
patients with early-stage disease.<br />
O’Shaughnessy J, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1015.<br />
November 2008 • Vol 7 • Supplement 5 9
<strong>Review</strong><br />
Weekly Paclitaxel Improves Disease-Free and Overall<br />
Survival in the Adjuvant Treatment of Breast Cancer<br />
Rachel E. Raab, MD; Joseph A. Sparano, MD<br />
Department of Medical Oncology, Montefiore-Einstein Cancer Center, Bronx, New York<br />
The Eastern Cooperative Oncology <strong>Group</strong><br />
(ECOG) recently published their data comparing<br />
the efficacy of paclitaxel and docetaxel<br />
and a schedule of either weekly or every 3 weeks in<br />
the adjuvant treatment of breast cancer. 1 The benefit<br />
of adjuvant chemotherapy in reducing the risk of<br />
recurrence and death from operable breast cancer is<br />
well known. A meta-analysis conducted by the Early<br />
Breast Cancer Trialists’ Collaborative <strong>Group</strong> revealed<br />
that anthracycline-based chemotherapy<br />
reduced the annual breast cancer death rate by<br />
about 38% for women younger than 50 years of age<br />
and by about 20% for women 50 to 69 years of age. 2<br />
None of the randomized trials included in this meta-<br />
The benefit of adjuvant<br />
chemotherapy in reducing the risk<br />
of recurrence and death from operable<br />
breast cancer is well known.<br />
analysis involved taxanes. The benefit of adjuvant<br />
taxane therapy was established by two trials: the<br />
NSABP B-28 and the CALGB 9344. 3,4 The NSABP<br />
B-28 trial randomized patients to receive adjuvant<br />
therapy with either four cycles of doxorubicin and<br />
cyclophosphamide or four cycles of doxorubicin and<br />
cyclophosphamide followed by four cycles of pac-<br />
10 The American Journal of Hematology/Oncology<br />
litaxel given every 3 weeks. Although no overall<br />
survival benefit was demonstrated, a significant<br />
improvement in disease-free survival was shown for<br />
patients receiving adjuvant paclitaxel. The CALGB<br />
9344 trial demonstrated not only a benefit in disease-free<br />
survival for patients receiving adjuvant<br />
paclitaxel following doxorubicin and cyclophosphamide<br />
therapy but also a benefit in overall survival.<br />
The results of these trials led to the approval<br />
of paclitaxel for the adjuvant treatment of nodepositive<br />
breast cancer. Another taxane, docetaxel, is<br />
also approved for the adjuvant treatment of breast<br />
cancer. A randomized phase III trial comparing docetaxel<br />
plus doxorubicin and cyclophosphamide<br />
(TAC) with fluorouracil plus doxorubicin and<br />
cyclophosphamide (FAC) demonstrated improved<br />
disease-free and overall survival in women receiving<br />
TAC. 5 In metastatic breast cancer, phase III trials<br />
have demonstrated that weekly paclitaxel 6 or every-<br />
3-week docetaxel 7 is superior to paclitaxel every 3<br />
weeks. There have been no data, however, from randomized<br />
trials in the adjuvant setting comparing<br />
docetaxel with paclitaxel or weekly versus every-3week<br />
therapy.<br />
The ECOG study compared adjuvant paclitaxel<br />
versus docetaxel and an every-3-week schedule with<br />
a weekly schedule in patients with axillary lymph<br />
node–positive or high-risk, lymph node–negative<br />
breast cancer. 7 The standard of care was considered<br />
paclitaxel every 3 weeks, and the factorial design of<br />
the trial allowed for comparison with three experimental<br />
arms: paclitaxel weekly for 12 cycles, docetaxel<br />
every 3 weeks for four cycles, or docetaxel<br />
weekly for 12 cycles.<br />
For a more detailed discussion, please see the following: Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant<br />
treatment of breast cancer. N Engl J Med. 2008;358:1663-1671.
Figure<br />
Paclitaxel 175 mg/m2<br />
every 21 days for 4 doses<br />
n=1253<br />
Randomization scheme.<br />
Trial Design<br />
Eligible patients had operable, histologically confirmed<br />
adenocarcinoma of the breast with histologically<br />
involved lymph nodes (tumor stage T1, T2, or<br />
T3 and nodal stage N1 or N2) or high-risk, axillary<br />
lymph node–negative disease (T2 or T3, N0) without<br />
distant metastases. Adequate organ function was<br />
required. Exclusion criteria included history of<br />
myocardial infarction, congestive heart failure, heart<br />
disease, pregnancy, or history of hypersensitivity<br />
reaction to paclitaxel or docetaxel. Full inclusion and<br />
exclusion criteria can be found online in the supplementary<br />
appendix of the original article.<br />
A total of 5052 patients were enrolled, of whom<br />
4950 (98%) were eligible. All patients received doxorubicin<br />
(60 mg/m 2 of body surface area) and<br />
cyclophosphamide (600 mg/m 2 of body surface area)<br />
every 3 weeks for four cycles. Patients were then randomized<br />
to one of four treatment arms (Figure).<br />
Women who had breast-sparing surgery received<br />
radiotherapy according to accepted standards of care,<br />
and patients who had a modified radical mastectomy<br />
received radiotherapy at the discretion of the treating<br />
physician. All women with hormone receptor–<br />
positive disease received tamoxifen 20 mg daily for 5<br />
years. The protocol was modified in 2005 to allow for<br />
a change to an aromatase inhibitor prior to completion<br />
of 5 years of tamoxifen or to begin an aromatase<br />
inhibitor after completing 5 years of tamoxifen.<br />
Operable breast cancer,<br />
lymph node positive or high-risk node negative<br />
N=4950<br />
Doxorubicin 60 mg/m 2 +<br />
cyclophosphamide 600 mg/m2<br />
every 21 days for 4 cycles<br />
Paclitaxel 80 mg/m2<br />
weekly for 12 doses<br />
n=1231<br />
Docetaxel 100 mg/m2<br />
every 21 days for 4 doses<br />
n=1236<br />
Weekly paclitaxel and breast cancer<br />
Docetaxel 35 mg/m2<br />
every 21 days for 12 doses<br />
n=1230<br />
The primary end point of the study was diseasefree<br />
survival, which was defined as the time from<br />
randomization to disease recurrence and included<br />
death from recurrence, death without recurrence,<br />
and contralateral breast cancer. The study had 86%<br />
power to detect a 17.5% reduction in the hazard<br />
rate for failure among the docetaxel groups or with<br />
weekly instead of every-3-week dosing. All eligi-<br />
The primary end point<br />
of the study was<br />
disease-free survival.<br />
ble patients undergoing randomization were<br />
included in the efficacy analysis, and all treated<br />
patients were included in the adverse events<br />
analysis. The log-rank test was used for analysis<br />
of disease-free and overall survival. Kaplan-Meier<br />
analysis was used to estimate distributions of<br />
events with respect to time. Cox proportional hazards<br />
models were used to estimate hazard ratios<br />
November 2008 • Vol 7 • Supplement 5 11
<strong>Review</strong><br />
and to test for significant differences in the times<br />
to events. A post hoc analysis of outcomes according<br />
to hormone receptor status and HER2 status<br />
was performed.<br />
Study Results<br />
Between October 1999 and January 2002, 5052<br />
patients were enrolled, of whom 4950 were eligible.<br />
The benefit of weekly paclitaxel was<br />
seen in patients with HER2-negative<br />
disease irrespective of their<br />
hormone receptor status.<br />
There were no significant differences among the<br />
patient groups. The median age was 51 years, and<br />
the majority of patients were hormone receptor positive<br />
(69.5%) and HER2 negative (67.5%). Most<br />
patients (97%) received all four cycles of doxorubicin<br />
and cyclophosphamide. The proportions of patients<br />
who received all taxane doses were 95% (paclitaxel<br />
Table 1<br />
5-Year Disease-Free Survival and Overall Survival in Four Treatment Arms<br />
12 The American Journal of Hematology/Oncology<br />
every 3 weeks), 88% (paclitaxel weekly), 87% (docetaxel<br />
every 3 weeks), and 75% (docetaxel weekly).<br />
The proportions of patients who required dose modification<br />
of the taxane were 22%, 29%, 28%, and 40%,<br />
respectively.<br />
At a median follow-up of 63.8 months, 1048<br />
patients had a recurrence of breast cancer or cancer<br />
in the contralateral breast, and 686 had died. The<br />
estimated 5-year disease-free survival rates were<br />
76.9% for the patients receiving every-3-week paclitaxel,<br />
81.5% for patients receiving weekly paclitaxel,<br />
81.2% for patients receiving every-3-week docetaxel,<br />
and 77.6% for patients receiving weekly docetaxel<br />
(Table 1). The study met its end point and demonstrated<br />
a significant improvement in disease-free survival<br />
in the group receiving weekly paclitaxel and in<br />
the group receiving docetaxel every 3 weeks (Table<br />
2). Weekly paclitaxel compared with standard therapy<br />
was associated with an improved overall survival<br />
(hazard ratio, 1.32, P=0.01) that was not seen in the<br />
patients receiving weekly docetaxel or every-3-week<br />
docetaxel (Table 3).<br />
Recent data have suggested that patients with<br />
hormone receptor–positive and HER2-negative<br />
breast cancer may not derive a benefit from adjuvant<br />
taxane therapy. 7 Therefore, the investigators analyzed<br />
the effect of hormone receptor status and<br />
HER2 expression on the efficacy of weekly paclitaxel<br />
Treatment Arm 5-Year Disease-Free Survival 5-Year Overall Survival<br />
Every-3-week paclitaxel 76.9% 86.5%<br />
Weekly paclitaxel 81.5% 89.7%<br />
Every-3-week docetaxel 81.2% 87.3%<br />
Weekly docetaxel 77.6% 86.2%<br />
Table 2<br />
Hazard Ratio for Disease-Free Survival in the Experimental Treatment Arms Compared With<br />
Standard Every-3-Week Paclitaxel<br />
Treatment Arm Hazard Ratio 95% CI P Value<br />
Weekly paclitaxel 1.27 1.03-1.57 0.006<br />
Every-3-week docetaxel 1.23 1.00-1.52 0.02<br />
Weekly docetaxel 1.09 0.89-1.34 0.29
and demonstrated that patients with HER2-negative<br />
disease had improved disease-free and overall survival<br />
with weekly paclitaxel irrespective of hormone<br />
receptor status (Table 4).<br />
Grade 3/4 toxic effects were more common in<br />
patients receiving the every-3-week docetaxel (71%)<br />
compared with those receiving weekly docetaxel<br />
(45%), weekly paclitaxel (28%), or every-3-week<br />
paclitaxel (30%). The majority of grade 3/4 adverse<br />
events in the every-3-week docetaxel arm was related<br />
to neutropenia (46%), infection (13%), and neuropathy<br />
(4%). Neuropathy of grade 2, 3, and 4 was<br />
more common in the weekly paclitaxel group compared<br />
with paclitaxel every 3 weeks (27% vs 20%).<br />
Other adverse effects were similar in the weekly and<br />
every-3-week paclitaxel groups.<br />
Discussion<br />
In women with lymph node–positive or high-risk<br />
lymph node–negative breast cancer, weekly paclitaxel<br />
compared with standard taxane therapy every 3<br />
weeks resulted in a significantly improved overall<br />
and disease-free survival. Patients receiving docetaxel<br />
every 3 weeks also had improved disease-free sur-<br />
Weekly paclitaxel and breast cancer<br />
Table 3<br />
Hazard Ratio for Overall Survival in the Experimental Treatment Arms Compared With Standard<br />
Every-3-Week Paclitaxel<br />
Treatment <strong>Group</strong> Hazard Ratio 95% CI P Value<br />
Weekly paclitaxel 1.32 1.02-1.72 0.01<br />
Every-3-week docetaxel 1.13 0.88-1.46 0.25<br />
Weekly docetaxel 1.02 0.80-1.32 0.80<br />
Table 4<br />
Disease-Free and Overall Survival in HER2-Negative Patients According to Hormone Receptor<br />
(HR) Status<br />
Variable Hazard Ratio 95% CI P Value<br />
Overall survival<br />
HR+ 1.36 0.92-2.00 0.12<br />
HR– 1.33 0.91-1.94 0.14<br />
Disease-free survival<br />
HR+ 1.31 1.00-1.72 0.05<br />
HR– 1.37 0.98-1.93 0.97<br />
vival but not overall survival. These results are consistent<br />
with findings in metastatic breast cancer that<br />
demonstrate a benefit of weekly paclitaxel or every-<br />
3-week docetaxel compared with every-3-week<br />
paclitaxel.<br />
Treatment with doxorubicin and cyclophosphamide<br />
was well tolerated, with 97% of patients completing<br />
all four cycles. The majority of patients in<br />
all treatment arms also completed taxane therapy.<br />
Toxic effects, mainly neutropenia, infection, and<br />
grade 2, 3, or 4 neuropathy, were more common in<br />
the every-3-week docetaxel group compared with<br />
the other groups.<br />
Of particular interest was that the benefit of weekly<br />
paclitaxel was seen in patients with HER2negative<br />
disease irrespective of their hormone receptor<br />
status. This is contradictory to recent data from<br />
Hayes and colleagues, who suggested that the benefit<br />
of adjuvant taxane therapy was not seen in<br />
patients with hormone receptor–positive disease or<br />
HER2-negative disease. 8 The results from the recent<br />
ECOG trial are consistent with those demonstrated<br />
in a subgroup analysis of the GEICAM 9906 trial,<br />
which compared six cycles of fluorouracil, epirubi-<br />
November 2008 • Vol 7 • Supplement 5 13
<strong>Review</strong><br />
cin, and cyclophosphamide (FEC) with four cycles of<br />
FEC followed by eight cycles of weekly paclitaxel. 9<br />
The authors concluded that patients treated with<br />
weekly paclitaxel had improved outcomes regardless<br />
of hormone receptor status.<br />
Conclusion<br />
The randomized trial conducted by ECOG is one<br />
of the first trials to compare standard every-3-week<br />
paclitaxel with weekly paclitaxel and docetaxel<br />
either weekly or every 3 weeks in the adjuvant setting.<br />
A 32% reduction in the hazard ratio for death in<br />
the weekly paclitaxel group compared with standard<br />
therapy was seen. The benefit of disease-free survival<br />
for weekly paclitaxel was seen in women with<br />
HER2-negative disease irrespective of hormone<br />
receptor status. ✦<br />
References<br />
1. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the<br />
adjuvant treatment of breast cancer. N Engl J Med. 2008;358:<br />
1663-1671.<br />
2. Early Breast Cancer Trialist’ Collaborative <strong>Group</strong> (EBCTCG).<br />
Effects of chemotherapy and hormonal therapy for early breast<br />
cancer on recurrence and 15-year survival: an overview of the<br />
randomized trials. Lancet. 2005;365:1687-1717.<br />
3. Mamounas EP, Bryant J, Lembersky B, et al. Paclitaxel after<br />
doxorubicin plus cyclophosphamide as adjuvant chemotherapy<br />
for node-positive breast cancer: results from the NSABP B-<br />
28. J Clin Oncol. 2005;23:3686-3696.<br />
4. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes<br />
from adding sequential paclitaxel but not from escalat-<br />
14 The American Journal of Hematology/Oncology<br />
ing doxorubicin dose in an adjuvant chemotherapy regimen<br />
for patients with node-positive primary breast cancer. J Clin<br />
Oncol. 2003;21:976-983.<br />
5. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel<br />
for node-positive breast cancer. N Engl J Med. 2005;352:<br />
2302-2313.<br />
6. Seidman AD, Berry D, Cirrincione C, et al. CALGB 9840: phase<br />
III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion<br />
versus standard (S) 3h infusion every third week in the treatment<br />
of metastatic breast cancer (MBC), with trastuzumab (T)<br />
for HER2 positive MBC and randomized for T in HER2 normal<br />
MBC. J Clin Oncol. 2004;22(July 15 suppl):6s. Abstract 512.<br />
7. Jones SE, Erban J, Overmeyer B, et al. Randomized phase III<br />
study of docetaxel compared with paclitaxel in metastatic<br />
breast cancer. J Clin Oncol. 2005;23:5542-5551.<br />
8. Hayes DF, Thor AD, Dressler LG, et al. HER 2 and response to<br />
paclitaxel in node-positive breast cancer. N Engl J Med. 2007;<br />
357:1496-1506.<br />
9. Rodriguez-Lescure A, Martin M, Ruiz A, et al. Subgroup analysis<br />
of GEICAM 9906 trial comparing six cycles of FE 90 C<br />
(FEC) to four cycles of FE 90 C followed by 8 weekly paclitaxel<br />
administrations (FECP): relevance of HER2 and hormonal status<br />
(HR). J Clin Oncol. 2007;25(June 20 suppl):589s. Abstract<br />
10598.<br />
Supported by grants from the Department of Health and Human<br />
Services and the National Institutes of Health.<br />
Author disclosures: Dr Sparano: speaker and consultant: Sanofi-<br />
Aventis.<br />
Correspondence address: Rachel E. Raab, MD, East Carolina<br />
University Brody School of Medicine, Department of<br />
Hematology/Oncology, 600 Moye Blvd, Brody 3E 127,<br />
Greenville, NC 27834; phone: (252) 744-3326; fax: (252) 744-<br />
3418; e-mail: raabr@ecu.edu.<br />
Committed to bringing you the latest and most relevant information in cancer management.<br />
Look in an upcoming issue for a review by Dr Henry L. Gomez<br />
of his recent article:<br />
INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH ®<br />
Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced<br />
or metastatic breast cancer. J Clin Oncol. 2008;26:2999-3005.<br />
Commentary by Drs Heather L. McArthur and Maura N. Dickler.<br />
®
Commentary<br />
Optimizing Taxane Therapy for Patients With Primary<br />
Breast Cancer: What Are the Lessons Learned?<br />
Lawrence N. Shulman, MD<br />
Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, Massachusetts<br />
The article by Sparano and colleagues comparing<br />
different taxanes and different dose schedules<br />
represents an important step forward in<br />
the treatment of primary breast cancer and also highlights<br />
some important lessons for drug development<br />
in our field. 1<br />
Since the introduction of paclitaxel nearly 20 years<br />
ago, physicians have struggled to determine the<br />
ideal dosing and schedule. Through much of the<br />
1980s and 1990s, our philosophy on chemotherapy<br />
administration was based on delivering the maximum<br />
dose possible, with the interval of therapy<br />
determined by the time needed for normal organ<br />
recovery. However, a series of dose escalation studies<br />
with paclitaxel in metastatic breast cancer suggested<br />
that higher doses were not necessarily associated<br />
with better outcomes. 2 Prolonged paclitaxel infusions<br />
were also tried based on preclinical data but<br />
failed to show a benefit. In both of these circumstances,<br />
toxicity was considerably worse.<br />
Since the introduction of docetaxel, the younger<br />
sibling of paclitaxel, there has been debate as to<br />
whether one taxane is better than the other for<br />
the treatment of breast cancer (as well as other<br />
diseases). 3-5<br />
The North American Breast Intergroup study<br />
reported by Sparano and colleagues enrolled approximately<br />
5000 patients with node-positive or high-risk<br />
node-negative primary breast cancer comparing the<br />
two taxanes and two schedules following standard<br />
cyclophosphamide and doxorubicin therapy.<br />
Paclitaxel or docetaxel was administered either<br />
weekly or every 3 weeks. Differences in disease-free<br />
and overall survival were small, with a small numerical<br />
advantage favoring weekly paclitaxel. One could<br />
argue that the results with weekly paclitaxel were no<br />
different than those for every-3-week docetaxel, and<br />
either would be acceptable therapy. An important<br />
consideration, however, is toxicity. When cancer outcomes<br />
are similar, toxicity and quality of life should<br />
be of paramount importance. Docetaxel administered<br />
every 3 weeks had a 46% incidence of grade<br />
Since the introduction of docetaxel,<br />
. . . there has been debate as to whether<br />
one taxane is better than the other.<br />
3/4 neutropenia and a 16% likelihood of febrile neutropenia,<br />
whereas weekly paclitaxel had a 2% and<br />
1% incidence of these toxicities, respectively. Grade<br />
3/4 neuropathy was slightly more likely in the<br />
patients receiving weekly paclitaxel versus every-3week<br />
docetaxel, 8% versus 4%. Finally, grade 3/4<br />
fatigue was more likely to occur with every-3-week<br />
docetaxel compared with weekly paclitaxel, 9% versus<br />
3%. Although fatigue is not a life-threatening toxicity,<br />
for these patients it was significant, and the<br />
combination of toxicities caused by docetaxel result-<br />
Dr Lawrence N. Shulman was invited to provide commentary on the following article: Sparano JA, Wang M, Martino S, et al. Weekly<br />
paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358:1663-1671.<br />
November 2008 • Vol 7 • Supplement 5 15
Commentary<br />
ed in a high rate of failure to complete the 12 weeks<br />
of taxane therapy. Some have argued that if a greater<br />
proportion of patients had completed therapy on the<br />
docetaxel arms, the survival for those arms would<br />
have been superior to the paclitaxel arms. I would<br />
argue that survival for patients on the weekly paclitaxel<br />
arm was at least as good as for patients on any<br />
of the other treatment arms, and the toxicity was less,<br />
making it better tolerated and therefore the preferred<br />
treatment.<br />
The results of this study are consistent with other<br />
studies that suggest that weekly paclitaxel is superior<br />
to every-3-week paclitaxel, and that every-3-week<br />
docetaxel is superior to weekly docetaxel. Why the<br />
optimal schedule is different for the two taxanes is<br />
not known. This is supported by the study by<br />
Seidman and colleagues of paclitaxel in the metastatic<br />
setting, as well as by studies of docetaxel in breast<br />
cancer and other diseases. 6,7<br />
One question that remains unanswered is the<br />
comparative efficacy of weekly paclitaxel versus<br />
dose-dense paclitaxel (administered every 2 weeks).<br />
Citron and colleagues demonstrated that cyclophosphamide<br />
and doxorubicin followed by paclitaxel<br />
was more effective if administered every 2 weeks<br />
versus every 3 weeks. 8 Sparano and colleagues<br />
administered the cyclophosphamide/doxorubicin<br />
cycles every 3 weeks and compared weekly taxane<br />
versus every-3-week taxane. Although there is no<br />
direct comparison between weekly and dose-dense<br />
paclitaxel, one might expect them to be roughly<br />
similar based on the relative advantage of each of<br />
these regimens when compared with every-3-week<br />
therapy.<br />
Finally, one must ask why it has taken us so long<br />
to determine optimal dose schedules for one of the<br />
most widely used and effective classes of therapies<br />
16 The American Journal of Hematology/Oncology<br />
for breast cancer – the taxanes – which has been in<br />
our armamentarium for quite a long time. F<br />
References<br />
1. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the<br />
adjuvant treatment of breast cancer. N Engl J Med. 2008;358:<br />
1663-1671.<br />
2. Winer E, Berry D, Woolf S, et al. Failure of higher-dose paclitaxel<br />
to improve outcome in patients with metastatic breast<br />
cancer: Cancer and Leukemia <strong>Group</strong> B trial 9342. J Clin Oncol.<br />
2004;22:2061-2068.<br />
3. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III<br />
study of docetaxel compared with paclitaxel in metastatic<br />
breast cancer. J Clin Oncol. 2005;23:5542-5551.<br />
4. Valero V, Jones S, Von Hoff D, et al. A phase II study of docetaxel<br />
in patients with paclitaxel-resistant metastatic breast cancer.<br />
J Clin Oncol. 1998;16:3362-3368.<br />
5. Chevallier B, Fumoleau P, Kerbrat P, et al. Docetaxel is a major<br />
cytotoxic drug for the treatment of advanced breast cancer: a<br />
phase II trial of the Clinical Screening Cooperative <strong>Group</strong> of<br />
the European Organization for Research and Treatment of<br />
Cancer. J Clin Oncol. 1995;13:314-322.<br />
6. Seidman AD, Berry D, Cirrincione C, et al. CALGB 9840: phase<br />
III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion<br />
versus standard (S) 3h infusion every third week in the treatment<br />
of metastatic breast cancer (MBC), with trastuzumab (T)<br />
for HER2 positive MBC and randomized for T in HER2 normal<br />
MBC. J Clin Oncol. 2004;22(July 15 suppl):6s. Abstract 512.<br />
7. Burstein H, Manola J, Younger J, et al. Docetaxel administered<br />
on a weekly basis for metastatic breast cancer. J Clin Oncol.<br />
2000;18:1212-1219.<br />
8. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of<br />
dose-dense versus conventionally scheduled and sequential<br />
versus concurrent combination chemotherapy as postoperative<br />
adjuvant treatment of node-positive primary breast cancer:<br />
first report of Intergroup Trial C9741/Cancer and<br />
Leukemia <strong>Group</strong> B Trial 9741 [published correction appears in<br />
J Clin Oncol. 2003;21:2226]. J Clin Oncol. 2003;21:1431-1439.<br />
Author disclosures: consultant: EMD Serono, Serenex.<br />
Correspondence address: Lawrence N. Shulman, MD, Dana-<br />
Farber Cancer Institute, 44 Binney Street, Boston, MA 02115;<br />
phone: (617) 632-2277; fax: (617) 632-2260; e-mail: Lawrence_<br />
Shulman@dfci.harvard.edu.
HER2 Status and Inflammatory Breast Cancer:<br />
Evidence of Prognostic Significance and<br />
Trastuzumab Efficacy<br />
Shaheenah Dawood, MRCP(UK), MPH 1 ; Ana M. Gonzalez-Angulo, MD 2<br />
<strong>Review</strong><br />
1 Department of Medical Oncology, Dubai Hospital, U.A.E.; 2 Department of Breast Medical Oncology, The University of Texas<br />
M.D. Anderson Cancer Center, Houston, Texas<br />
Inflammatory breast cancer (IBC) is an aggressive<br />
subset of locally advanced breast cancer that<br />
accounts for approximately 1% to 6% 1 of breast<br />
cancers in the United States. For a disease historically<br />
known to be uniformly fatal, a multimodality<br />
approach to management incorporating primary systemic<br />
chemotherapy, radiation therapy, and surgery<br />
has improved long-term outcomes of patients with<br />
IBC. 2,3 However, prognosis still remains poor compared<br />
with other types of breast cancer, with 5-year<br />
survival rates ranging from 30% to 50%. 1-3 The persistently<br />
poor prognosis associated with this disease<br />
has been attributed to a number of factors, including<br />
an inherently aggressive biology and a lack of insight<br />
into specific prognostic factors associated with the<br />
disease. Moreover, most clinical trials actively<br />
exclude patients with IBC, and due to the rarity of<br />
the disease, most prospective and retrospective studies<br />
attempting to answer specific clinical questions<br />
related to IBC have been small.<br />
HER2 is amplified in approximately 30% of breast<br />
tumors. 4 Its main function is to mediate growth and<br />
survival of cells, thus promoting tumor aggressiveness<br />
that is associated with both poor disease-free<br />
and overall survival. 5,6 Trastuzumab, a monoclonal<br />
antibody targeting the HER2 receptor, has been<br />
shown in randomized clinical trials to significantly<br />
improve survival outcomes of women with HER2positive<br />
breast tumors in both the metastatic 7 and<br />
adjuvant 8,9 setting, thereby altering the natural<br />
course of the disease. Although several studies have<br />
observed an increased incidence of HER2 amplification<br />
and/or overexpression of its protein, with rates<br />
ranging from 50% to 100% of IBC tumors tested, its<br />
prognostic significance in this aggressive subtype of<br />
breast cancer had as yet not been established. 10-12<br />
Moreover, the efficacy of trastuzumab in women<br />
with HER2-positive IBC was also not known. We<br />
Most clinical trials actively<br />
exclude patients with<br />
inflammatory breast cancer.<br />
thus embarked on a study 13 involving a cohort of<br />
patients with stage III IBC to primarily study the<br />
prognostic impact of HER2 status. In addition, we<br />
sought to determine whether trastuzumab was an<br />
efficacious agent in this cohort.<br />
Study Design and Results<br />
A cohort of 179 women with stage III IBC diagnosed<br />
between 1989 and 2005 with known HER2 status<br />
were identified from the prospectively maintained<br />
M.D. Anderson breast cancer systems database. For<br />
the purposes of this study, women were identified<br />
as having IBC if they presented with rapidly developing<br />
signs and symptoms, over less than 3<br />
months, that included breast enlargement, erythe-<br />
For a more detailed discussion, please see the following: Dawood S, Broglio K, Gong Y, et al. Prognostic significance of HER-2 status in<br />
women with inflammatory breast cancer. Cancer. 2008;112:1905-1911.<br />
November 2008 • Vol 7 • Supplement 5 17
<strong>Review</strong><br />
ma and/or peau d’orange, and biopsy-confirmed<br />
invasive carcinoma with or without evidence of<br />
dermal lymphatic invasion. Tumors were classified<br />
as HER2 positive if they exhibited 3+ staining by<br />
immunohistochemistry (IHC) and/or gene amplification<br />
by fluorescence in situ hybridization (FISH)<br />
technique. Tumors were classified as HER2 negative<br />
if they exhibited 1+ or negative staining by<br />
HER2 is amplified<br />
in approximately<br />
30% of breast tumors.<br />
IHC and/or no gene amplification by FISH. All<br />
patients received adjuvant anthracycline-based<br />
chemotherapy regimens followed by a mastectomy,<br />
comprehensive radiation therapy to chest wall and<br />
axilla, and adjuvant hormonal therapy when appropriate.<br />
Patients with HER2-positive tumors did not<br />
receive adjuvant trastuzumab as the monoclonal<br />
antibody had not received approval for use in the<br />
Unadjusted estimates*<br />
18 The American Journal of Hematology/Oncology<br />
adjuvant setting at the time of diagnosis. Upon<br />
recurrence, patients with HER2-positive tumors<br />
were allowed to have received trastuzumab.<br />
Recurrence-free survival (RFS), defined from the<br />
date of diagnosis to the date of local or distant<br />
recurrence or last follow-up, and overall survival<br />
(OS), defined from the date of diagnosis to death<br />
from any cause or last follow-up, was computed.<br />
The Kaplan-Meier product limit method was used<br />
to determine 5-year survival estimates, which were<br />
compared across groups using log-rank statistics.<br />
Cox proportional hazards models were then fitted<br />
to determine the association of HER2 status to survival<br />
outcomes after adjusting for patient and<br />
tumor characteristics.<br />
Of the 179 patients, 111 (62%) had HER2-negative<br />
disease and 68 (38%) had HER2-positive disease.<br />
<strong>Media</strong>n age for the cohort was 51 years (range, 28-78<br />
years), and median follow-up among all patients still<br />
alive at last follow-up was 41 months (range, 3-198<br />
months). At the time of the analysis a total of 104<br />
patients had recurred; 62 of 111 (55.9%) with HER2negative<br />
disease and 42 of 68 (61.8%) with HER2positive<br />
disease. Of the 42 patients with HER2-positive<br />
disease who recurred, 31 (73.8%) received<br />
trastuzumab in the metastatic setting. The Table<br />
summarizes the unadjusted and adjusted RFS and<br />
OS estimates. Overall Kaplan-Meier estimates for 5year<br />
RFS was 37.8% (95% CI, 29.9%-45.7%), and 5-<br />
Table<br />
Unadjusted and Adjusted 5-Year Recurrence-Free and Overall Survival Estimates<br />
Recurrence- Overall<br />
Free Survival P Value Survival P Value<br />
HER2 negative 38.8% 49.8%<br />
(28.7%-48.8%) (38.0%-60.6%)<br />
HER2 positive 36.5% 0.750 57.8% 0.245<br />
(24.0%-49.0%) (43.4%-69.8%)<br />
Adjusted estimates †<br />
HER2 0.75 0.241 0.56 0.024<br />
(positive vs negative) (0.46-1.22) (0.34-0.93)<br />
*These are Kaplan-Meier estimates that have been compared across groups using log-rank statistics.<br />
† These are adjusted hazard ratios. The models were adjusted for age (continuous), estrogen receptor status (positive vs negative),<br />
progesterone receptor status (positive vs negative), lymphovascular invasion (yes vs no), grade of tumor (3 vs 1 and 2), lymph node<br />
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<br />
analysis, no significant differences were<br />
observed in both survival end points when stratified<br />
by HER2 status, although a nonsignificant trend that<br />
favored patients with HER2-positive disease compared<br />
to those with HER2-negative disease was<br />
noted for OS. After adjusting for age, grade, hormone<br />
receptor status, pathological complete<br />
response, lymph node status, and lymphovascular<br />
invasion, HER2 status was not observed to significantly<br />
affect RFS. In the multivariate model for OS,<br />
patients with HER2-positive disease had a 44%<br />
decreased risk of death that was statistically significant<br />
(HR=0.56; 95% CI, 0.34-0.93; P=0.024) compared<br />
with patients with HER2-negative disease.<br />
Discussion<br />
The study we conducted is unique for a number of<br />
reasons. First, most studies have been hampered by<br />
nonspecific clinical diagnostic criteria used to identify<br />
patients with IBC, making interpretation and comparisons<br />
difficult. Using standard institutional criteria<br />
for IBC, which conform to the American Joint<br />
Committee on Cancer definition of IBC, allowed us<br />
to clearly identify patients with IBC and separate<br />
them from women with locally advanced non-IBC<br />
tumors. Second, our sample size was relatively large<br />
compared with previously published studies involving<br />
patients with IBC. Third, by using a cohort that<br />
did not receive trastuzumab in the adjuvant setting<br />
but was allowed to use the agent upon recurrence,<br />
we were uniquely able to study both the prognostic<br />
impact of HER2 status as well as the efficacy of<br />
trastuzumab in patients with IBC.<br />
The results of our study indicate that HER2 status<br />
did not impact RFS, even after controlling for patient<br />
and tumor characteristics in the multivariate model.<br />
This is in sharp contrast to the initial observations<br />
made by Slamon and colleagues, 4 who reported<br />
HER2 amplification not only as being associated<br />
with worse RFS and OS outcomes compared with<br />
women whose tumors did not exhibit HER2 amplification<br />
but also as being of superior prognostic significance<br />
to other well-established factors such as hormone<br />
receptor status and the presence of lymph<br />
node involvement. As such, we hypothesize that<br />
prognostic factors typically used for non-IBC tumors<br />
may not confer the same information in IBC tumors.<br />
Studies have shown that factors such as increased<br />
expression of the epidermal growth factor receptor<br />
and p53 and loss of p27 may be indicative of poor<br />
HER2 status and inflammatory breast cancer<br />
prognosis in the IBC cohort, although larger studies<br />
are required to confirm this. 14,15<br />
When assessing overall survival, results from our<br />
multivariate model indicated that women with<br />
HER2-positive tumors had a 44% decreased risk of<br />
death that was statistically significant (HR=0.56; 95%<br />
CI, 0.34-0.93; P=0.024) compared with women with<br />
The results of our study<br />
indicate that HER2 status did<br />
not impact relapse-free survival.<br />
HER2-negative tumors. The improved survival<br />
observed is attributed to the fact that the majority of<br />
women with HER2-positive disease who relapsed<br />
received trastuzumab. This observation indicates<br />
that trastuzumab is indeed efficacious when administered<br />
to women with IBC tumors. It also provides<br />
evidence of the fact that when trastuzumab is administered<br />
to patients with HER2-positive IBC, they<br />
attain superior outcomes compared to patients with<br />
HER2-negative tumors.<br />
Conclusion<br />
The results of this study are important and applicable<br />
to the clinical management of women with IBC.<br />
Randomized clinical trials that have assessed the<br />
efficacy of trastuzumab have been unable to determine<br />
its efficacy in women with IBC tumors. The<br />
results of this study provide evidence of the efficacy<br />
of this agent in this cohort despite the lack of<br />
prognostic difference observed between women<br />
with HER2-positive and HER2-negative tumors in<br />
the absence of trastuzumab administration. It is<br />
well known that the natural history of this aggressive<br />
subtype of breast cancer is different compared<br />
with other types of breast cancer, making it important<br />
for future research to focus on conducting clinical<br />
trials specifically aimed at this cohort. Until<br />
such initiatives are undertaken, results from studies<br />
such as ours will be an important component in<br />
guiding physician management of women with<br />
IBC. F<br />
(continued on page 22)<br />
November 2008 • Vol 7 • Supplement 5 19
Commentary<br />
Inflammatory Breast Cancer: Still a Challenge<br />
Nancy U. Lin, MD<br />
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts<br />
Inflammatory breast cancer (IBC) is a relatively<br />
rare disease, comprising less than 3% of breast<br />
cancer cases in the United States. 1 Compared<br />
with locally advanced, noninflammatory breast cancer,<br />
IBC appears to be a distinct entity with a unique<br />
mode of presentation and underlying biology.<br />
Unfortunately, even with multimodality therapy, the<br />
prognosis for patients with IBC remains poor. 2<br />
Overexpression and/or amplification of HER2 is<br />
present in 25% to 30% of primary breast carcinomas. 3<br />
In contrast, HER2 is overexpressed in approximately<br />
half of IBC cases. 4,5 In all patients with breast cancer,<br />
Inflammatory breast cancer<br />
appears to be a distinct entity with<br />
a unique mode of presentation<br />
and underlying biology.<br />
overexpression of HER2 is associated with a higher<br />
risk of relapse and worse overall survival (OS) 3 ; however,<br />
the contribution of HER2 overexpression to the<br />
prognosis of patients with IBC is not well defined.<br />
Dawood and colleagues therefore set out to examine<br />
the prognostic significance of HER2 status in<br />
women with IBC diagnosed between 1989 and 2005<br />
20 The American Journal of Hematology/Oncology<br />
at the University of Texas M.D. Anderson Cancer<br />
Center. 6 In all, 179 patients fulfilled the inclusion/<br />
exclusion criteria for this retrospective analysis. A<br />
strength of the study is the relatively uniform treatment<br />
of the patients: all patients received an anthracycline,<br />
and nearly 80% received a taxane as part of<br />
their primary systemic chemotherapy. In addition,<br />
the exclusion of patients who received trastuzumab<br />
in the neoadjuvant or adjuvant setting allowed the<br />
authors to describe the impact of HER2 upon relapsefree<br />
survival (RFS) independent of an effective targeted<br />
therapy. Chemotherapy was followed by mastectomy<br />
and comprehensive radiotherapy in all patients,<br />
and hormonal therapy was given to patients with<br />
hormone receptor–positive disease. There was no difference<br />
in the rate of pathologic complete response<br />
(pCR) by HER2 status. After a median follow-up of 35<br />
months, 56% of patients with HER2-negative disease<br />
and 62% of patients with HER2-positive disease<br />
developed a disease recurrence, a difference that was<br />
not statistically significant.<br />
What could account for the lack of prognostic significance<br />
of HER2 for RFS described in this study<br />
compared with the reproducible influence of HER2<br />
status on prognosis in all-comers with breast cancer?<br />
One possibility relates to common characteristics of<br />
IBC present across breast cancer subtypes that lead to<br />
a more aggressive clinical phenotype. Using expression<br />
profiling, Bertucci and colleagues identified the<br />
same five molecular subtypes (luminal A and B,<br />
basal, HER2 positive, and normal breast-like) in IBC<br />
as have been observed in non-IBC. 7 At the same time,<br />
a single 109-gene set was able to distinguish between<br />
IBC and non-IBC within each subtype. These genes<br />
Dr Nancy U. Lin was invited to provide commentary on the following article: Dawood S, Broglio K, Gong Y, et al. Prognostic significance of<br />
HER-2 status in women with inflammatory breast cancer. Cancer. 2008;112:1905-1911.
include those related to cell motility, invasion, proliferation,<br />
and angiogenesis. Van Laere and colleagues<br />
reported similar findings: a set of 50 discriminator<br />
genes distinguished IBC from non-IBC even after<br />
excluding estrogen receptor (ER)- or HER2-related<br />
genes. 8 When IBC-related genes are activated, tumor<br />
behavior may be more aggressive regardless of subtype,<br />
and the influence of HER2 status may be less<br />
relevant. Another possibility relates to the distribution<br />
of molecular subtypes within the Dawood study.<br />
Sixty percent of the HER2-negative tumors were also<br />
ER negative. Although progesterone receptor status<br />
was not reported, one can assume that the majority<br />
of these tumors would probably fall into the “triplenegative”<br />
subtype. Thus, triple-negative tumors<br />
were overrepresented compared with their incidence<br />
in non-IBC tumors, and a binary comparison of the<br />
prognosis of HER2-positive and HER2 negative<br />
patients would be heavily influenced by the prognosis<br />
of patients with triple-negative IBC. In this light,<br />
it would be of interest to explore the prognosis of the<br />
IBC patients according to molecular subtype (ie,<br />
luminal A, luminal B, basal-like, HER2-positive).<br />
Third, as the authors point out, the use of anthracyclines<br />
across all patients may have preferentially benefited<br />
those with HER2-positive tumors. In a pooled<br />
analysis of eight randomized trials for early breast<br />
cancer, anthracyclines were superior to nonanthracycline-containing<br />
regimens in patients with HER2positive<br />
but not HER2-negative tumors. 9 Thus, any<br />
difference in natural history between HER2-positive<br />
versus HER2-negative IBC may have been attenuated<br />
by treatment effect.<br />
With respect to OS, HER2-positive status was a<br />
favorable prognostic factor in this study, likely due to<br />
the availability of effective targeted therapy (eg,<br />
trastuzumab) for patients with HER2-positive IBC at<br />
the time of recurrence. Nevertheless, it is sobering<br />
that even in a group of women treated in a comprehensive<br />
fashion at a highly regarded cancer center<br />
that the 5-year overall survival rate for the entire<br />
cohort was only 53.1%. How can we improve? First,<br />
given the impact of trastuzumab on OS after IBC<br />
recurrence, as demonstrated by Dawood and colleagues,<br />
and the proven benefits of trastuzumab in<br />
the adjuvant setting for early breast cancer, it is likely<br />
that the current standard use of trastuzumab in the<br />
preoperative setting for patients with IBC is already<br />
having a favorable effect upon outcomes in patients<br />
with HER2-positive disease. Preliminary results<br />
from the NOAH (NeOAdjuvant Herceptin) study<br />
The challenge of IBC<br />
indicate that the addition of trastuzumab substantially<br />
improves the rate of pCR in patients with IBC<br />
compared with chemotherapy alone. 10 Given that<br />
pCR is highly correlated with RFS and OS, these<br />
results are highly encouraging. Next, there is also<br />
early evidence of efficacy from a phase II study of the<br />
oral epidermal growth factor receptor/HER2<br />
inhibitor lapatinib in patients with recurrent or<br />
anthracycline-refractory IBC in which 50% of<br />
patients experienced a clinical response. 11 Ongoing<br />
trials will further clarify whether lapatinib has a role<br />
in patients with newly diagnosed IBC.<br />
Looking beyond HER2, a number of other biologic<br />
characteristics appear to be strongly associated<br />
with both RFS and OS in patients with IBC. These<br />
include molecules related to angiogenesis (hypoxiainducible<br />
factor 1, vascular endothelial growth factor,<br />
etc), cytoskeletal organization and cell motility<br />
(eg, Rho proteins), and chemokines (CXCR4,<br />
CCR7). 7,12 Several small studies have already been<br />
completed evaluating the safety of angiogenic blockade<br />
in patients with IBC, and these studies have also<br />
demonstrated associated changes in tumor blood<br />
flow. 13,14 In the future, pharmacologic targeting of the<br />
angiogenesis and other pathways may improve outcomes<br />
in both HER2-positive and HER2-negative<br />
IBC.<br />
In summary, while Dawood and colleagues did<br />
not observe a relationship between HER2 status and<br />
RFS, the observed association between HER2 positivity<br />
and improved OS is powerful evidence that<br />
effective targeted therapy can yield meaningful<br />
improvements in outcomes from IBC. The elucidation<br />
of pathways important in the development and<br />
maintenance of the IBC phenotype and the development<br />
of drugs to target these pathways continue to<br />
move forward. However, because of the relative rarity<br />
of IBC, the pace of further advances in the field<br />
will depend not only on the pipeline of new targeted<br />
drugs but upon a concerted effort to sustain multidisciplinary<br />
and cross-institutional collaborations. ✦<br />
References<br />
1. Levine PH, Veneroso C. The epidemiology of inflammatory<br />
breast cancer. Semin Oncol. 2008;35:11-16.<br />
2. Gonzalez-Angulo AM, Hennessy BT, Broglio K, et al. Trends<br />
for inflammatory breast cancer: is survival improving?<br />
Oncologist. 2007;12:904-912.<br />
3. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer:<br />
correlation of relapse and survival with amplification of the<br />
HER-2/neu oncogene. Science. 1987;235:177-182.<br />
4. Cabioglu N, Gong Y, Islam R, et al. Expression of growth factor<br />
November 2008 • Vol 7 • Supplement 5 21
Commentary<br />
and chemokine receptors: new insights in the biology of<br />
inflammatory breast cancer. Ann Oncol. 2007;18:1021-1029.<br />
5. Parton M, Dowsett M, Ashley S, et al. High incidence of HER-<br />
2 positivity in inflammatory breast cancer. Breast. 2004;13:97-<br />
103.<br />
6. Dawood S, Broglio K, Gong Y, et al. Prognostic significance of<br />
HER-2 status in women with inflammatory breast cancer.<br />
Cancer. 2008;112:1905-1911.<br />
7. Bertucci F, Finetti P, Rougemont J, et al. Gene expression profiling<br />
identifies molecular subtypes of inflammatory breast cancer.<br />
Cancer Res. 2005;65:2170-2178.<br />
8. Van Laere S, Van der Auwera I, Van den Eynden GG, et al.<br />
Distinct molecular signature of inflammatory breast cancer by<br />
cDNA microarray analysis. Breast Cancer Res Treat. 2005;93:237-<br />
246.<br />
9. Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy<br />
of adjuvant anthracyclines in early breast cancer: a pooled<br />
analysis of randomized trials. J Natl Cancer Inst. 2008;100:14-20.<br />
10. Gianni L, Semiglazov V, Manikhas GM, et al. Neoadjuvant<br />
trastuzumab in locally advanced breast cancer (NOAH): antitumor<br />
and safety analysis. J Clin Oncol. 2007;25(June 20 supplement).<br />
Abstract 532.<br />
11. Johnston S, Trudeau M, Kaufman B, et al. Phase II study of pre-<br />
HER2 status and inflammatory breast cancer<br />
(continued from page 19)<br />
References<br />
1. Jaiyesimi IA, Buzdar AU, Hortobagyi G. Inflammatory breast<br />
cancer: a review. J Clin Oncol. 1992;10:1014-1024.<br />
2. Cristofanilli M, Buzdar AU, Hortobagyi GN. Update on the<br />
management of inflammatory breast cancer. Oncologist.<br />
2003;8:141-148.<br />
3. Buzdar AU, Singeltary SE, Booser DJ, et al. Combined modality<br />
treatment of stage III and inflammatory breast cancer. M.D.<br />
Anderson Cancer Center experience. Surg Oncol Clin N Am.<br />
1995;4:715-734.<br />
4. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer:<br />
correlation of relapse and survival with amplification of the<br />
HER-2/neu oncogene. Science. 1987;235:177-182.<br />
5. Borg A, Tandon AK, Sigurdsson H, et al. HER-2/neu amplification<br />
predicts poor survival in node-positive breast cancer.<br />
Cancer Res. 1990;50:4322-4327.<br />
6. Winstanley J, Cooke T, Murray GD, et al. The long term prognostic<br />
significance of c-erb-2 in primary breast cancer. Br J<br />
Cancer. 1991;63:447-450.<br />
7. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy<br />
plus a monoclonal antibody against HER2 for metastatic<br />
breast cancer that overexpresses HER2. N Engl J Med.<br />
2001;344:783-792.<br />
8. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant<br />
chemotherapy for operable HER2-positive breast cancer.<br />
N Engl J Med. 2005;353:1673-1684.<br />
9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.<br />
Trastuzumab after adjuvant chemotherapy in HER2-positive<br />
breast cancer. N Engl J Med. 2005;353:1659-1672.<br />
22 The American Journal of Hematology/Oncology<br />
dictive biomarker profiles for response targeting human epidermal<br />
growth factor receptor 2 (HER-2) in advanced inflammatory<br />
breast cancer with lapatinib monotherapy. J Clin Oncol.<br />
2008;26:1066-1072.<br />
12. Kleer CG, van Golen KL, Merajver SD. Molecular biology of<br />
breast cancer metastasis. Inflammatory breast cancer: clinical<br />
syndrome and molecular determinants. Breast Cancer Res.<br />
2000;2:423-429.<br />
13. Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor<br />
effects of bevacizumab in patients with inflammatory and<br />
locally advanced breast cancer. J Clin Oncol. 2006;24:769-777.<br />
14. Overmoyer B, Fu P, Hoppel C, et al. Inflammatory breast cancer<br />
as a model disease to study tumor angiogenesis: results of<br />
a phase IB trial of combination SU5416 and doxorubicin. Clin<br />
Cancer Res. 2007;13:5862-5868.<br />
Author disclosures: Research support: Genentech, Glaxo-<br />
SmithKline; consultant: GlaxoSmithKline (
CaseStudy<br />
Risk of Local Recurrence for Breast Cancer Subtypes<br />
Defined by ER, PR, and HER2 Status<br />
Paul L. Nguyen, MD 1,2 ; Alphonse G. Taghian, MD, PhD 2,3 ; Jay R. Harris, MD 2,4<br />
1 Harvard Radiation Oncology Program; 2 Harvard Medical School; 3 Department of Radiation Oncology, Massachusetts<br />
General Hospital; 4 Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital;<br />
all Boston, Massachusetts<br />
A60-year-old female had a routine screening<br />
mammogram that showed a 1 cm density<br />
with associated microcalcifications in the<br />
upper outer quadrant of the patient’s left breast. A<br />
core biopsy revealed an infiltrating ductal carcinoma<br />
(IDC), grade 2, with associated ductal carcinoma in<br />
situ (DCIS). The tumor was estrogen receptor (ER)<br />
positive, progesterone receptor (PR) positive, and<br />
HER2 negative. The patient elected breast-conserving<br />
therapy and had a negative sentinel lymph node<br />
biopsy. Pathology from the lumpectomy showed a<br />
1.2 cm grade 2 IDC without evidence of extensive<br />
intraductal component (EIC). There was no lymphovascular<br />
invasion. There was a focally positive inferior<br />
margin, but all other margins were >2 mm. The<br />
Oncotype DX recurrence score was 11 (low risk). A<br />
reexcision of the inferior margin was performed and<br />
was negative except for a single 1 mm focus of DCIS<br />
that came within 1 mm of the final inferior reexcision<br />
margin. The issue of a second reexcision to achieve a<br />
>2 mm inferior margin was discussed, but both the<br />
patient and surgeon were concerned that this might<br />
lead to a poor cosmetic result given the patient’s relatively<br />
small breast size.<br />
Discussion<br />
Classic Predictors of Local Recurrence After Breast-<br />
Conserving Therapy<br />
For women who undergo breast-conserving therapy<br />
for invasive breast cancer, the risk of local recurrence<br />
has been shown in several studies to be based on factors<br />
such as margin status, nodal status, young age,<br />
and presence or absence of EIC (defined as an infiltrating<br />
ductal cancer in which greater than 25% of<br />
the tumor volume is DCIS, and DCIS extends beyond<br />
the invasive cancer into surrounding breast<br />
parenchyma). 1-3<br />
While the exact relative importance of each of the<br />
factors is not always consistent across studies, most<br />
have agreed that margin status is one of the most<br />
important predictors of local recurrence for women<br />
undergoing breast-conserving therapy, and patients<br />
are almost always advised to undergo reexcision if<br />
the tumor involves an inked margin (ie, a positive<br />
margin), unless that positive margin is at the skin or<br />
is a deep margin that has already extended to the<br />
pectoral fascia. The issue of whether a “close margin,”<br />
as our patient has, is a risk factor for local recurrence<br />
is less clear. Investigators have variably<br />
. . . most have agreed that margin<br />
status is one of the most important<br />
predictors of local recurrence.<br />
defined a close margin as having tumor within 1 or 2<br />
mm of the inked surface, and while several studies<br />
have found an association between increasing margin<br />
width and lower local recurrence, only three published<br />
studies have subdivided this width enough to<br />
make finer comparisons. 2,4 One study from Tufts-<br />
New England Medical Center showed a 12-year local<br />
recurrence rate of 9% for margins 0.1 to 2.0 mm, 5%<br />
for 2.1 to 5.0 mm, and 0% for >5 mm. 5 Also, the<br />
Harvard Joint Center for Radiation Therapy found<br />
that 8-year rates of local recurrence were 7% for margins<br />
0.1 to 1.0 mm, 6% for 1.1 to 2.0 mm, and 4% for<br />
November 2008 • Vol 7 • Supplement 5 23
CaseStudy<br />
2.1 to 5 mm. 6 However, a William Beaumont study<br />
found that 12-year local recurrence was 17% for margins<br />
0.1 to 1.0 mm, 14% for 1.1 to 2.0 mm, and 15%<br />
for 2.1 to 3.0 mm, making the impact of a
factors such as age and margin status were not significant,<br />
although there may have been too few<br />
patients with positive margins (3.3%) or age
CaseStudy<br />
References<br />
1. Zhou P, Recht A. Young age and outcome for women with<br />
early-stage invasive breast carcinoma. Cancer. 2004;101:1264-<br />
1274.<br />
2. Recht A. Lessons of studies of breast-conserving therapy with<br />
and without whole-breast irradiation for patient selection for<br />
partial-breast irradiation. Semin Radiat Oncol. 2005;15:123-132.<br />
3. Schnitt SJ, Connolly JL. Processing and evaluation of breast<br />
excision specimens. A clinically oriented approach. Am J Clin<br />
Pathol. 1992;98:125-137.<br />
4. Recht A. Breast Cancer: Stages T1 and T2. In: Gunderson LL,<br />
Tepper JE, eds. Clinical Radiation Oncology. 2nd ed.<br />
Philadelphia, PA: Churchill Livingstone; 2007:1475-1502.<br />
5. Neuschatz AC, DiPetrillo T, Safaii H, et al. Long-term followup<br />
of a prospective policy of margin-directed radiation dose<br />
escalation in breast-conserving therapy. Cancer. 2003;97:30-39.<br />
6. Park CC, Mitsumori M, Nixon A, et al. Outcome at 8 years after<br />
breast-conserving surgery and radiation therapy for invasive<br />
breast cancer: influence of margin status and systemic therapy<br />
on local recurrence. J Clin Oncol. 2000;18:1668-1675.<br />
7. Goldstein NS, Kestin L, Vicini F. Factors associated with ipsilateral<br />
breast failure and distant metastases in patients with<br />
invasive breast carcinoma treated with breast-conserving therapy.<br />
A clinicopathologic study of 607 neoplasms from 583<br />
patients. Am J Clin Pathol. 2003;120:500-527.<br />
8. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of<br />
human breast tumours. Nature. 2000;406:747-752.<br />
9. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns<br />
of breast carcinomas distinguish tumor subclasses with<br />
clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869-<br />
10874.<br />
10. Brenton JD, Carey LA, Ahmed AA, et al. Molecular classification<br />
and molecular forecasting of breast cancer: ready for clinical<br />
application? J Clin Oncol. 2005;23:7350-7360.<br />
26 The American Journal of Hematology/Oncology<br />
11. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of<br />
breast tumor subtypes in independent gene expression data<br />
sets. Proc Natl Acad Sci U S A. 2003;100:8418-8423.<br />
12. Sotiriou C, Neo SY, McShane LM, et al. Breast cancer classification<br />
and prognosis based on gene expression profiles from a<br />
population-based study. Proc Natl Acad Sci U S A. 2003;100:<br />
10393-10398.<br />
13. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes,<br />
and survival in the Carolina Breast Cancer Study. JAMA.<br />
2006;295:2492-2502.<br />
14. Nguyen PL, Taghian AG, Katz MS, et al. Breast cancer subtype<br />
approximated by estrogen receptor, progesterone receptor, and<br />
HER-2 is associated with local and distant recurrence after<br />
breast-conserving therapy. J Clin Oncol. 2008;26:2373-2378.<br />
15. Kyndi M, Sorensen FB, Knudsen H, et al. Estrogen receptor,<br />
progesterone receptor, HER-2, and response to postmastectomy<br />
radiotherapy in high-risk breast cancer: the Danish Breast<br />
Cancer Cooperative <strong>Group</strong>. J Clin Oncol. 2008;26:1419-1426.<br />
16. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.<br />
Trastuzumab after adjuvant chemotherapy in HER2-positive<br />
breast cancer. N Engl J Med. 2005;353:1659-1672.<br />
17. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant<br />
chemotherapy for operable HER2-positive breast cancer.<br />
N Engl J Med. 2005;353:1673-1684.<br />
Author disclosures: No relationships with industry were reported.<br />
Correspondence address: Paul L. Nguyen, MD, Harvard<br />
Radiation Oncology Program, 75 Francis Street, L2, Boston,<br />
MA 02115; phone: (617) 732-6310; e-mail: pnguyen@<br />
LROC.harvard.edu.<br />
Committed to bringing you the latest and most relevant information in cancer management.<br />
Look in an upcoming issue for a review by Dr Giorgio Zavagno<br />
of his recent article:<br />
INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH ®<br />
Role of resection margins in patients treated with breast conservation surgery. Cancer. 2008;<br />
112:1923-1931.<br />
Commentary by Drs Laurie Kirstein and David August.<br />
®