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November 2008 • Vol 7 • Supplement 5

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INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH

Special Breast Cancer Issue TRENDS IN BREAST CANCER

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HER2 Status and 17 Inflammatory Breast Cancer: Evidence of Prognostic Significance and Trastuzumab Efficacy

Weekly Paclitaxel Improves 10 Disease-Free and Overall Survival in the Adjuvant Treatment of Breast Cancer

REVIEW

Cancer

REVIEW

Inflammatory Breast Cancer: Still a Challenge

The New England Journal of Medicine Optimizing Taxane Therapy for Patients With Primary Breast Cancer: What Are the Lessons Learned? COMMENTARY

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COMMENTARY

Risk of Local Recurrence for Breast Cancer Subtypes Defined by ER, PR, and HER2 Status CASE STUDY

THE NATION’S MOST REQUESTED HEMATOLOGY/ONCOLOGY PUBLICATION ©2008 Haymarket Media Inc.

Supplement to The American Journal of Hematology/Oncology

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November 2008 • Vol 7 • Supplement 5

TABLE OF CONTENTS

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INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH

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Trends in Breast Cancer Weekly Paclitaxel Improves Disease-Free and Overall Survival in the Adjuvant Treatment of Breast Cancer

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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

REVIEW

The New England Journal of Medicine

Senior Editorial Director Kristin Lee Siyahian Kristinlee.siyahian@haymarketmedia.com

Rachel E. Raab, MD; Joseph A. Sparano, MD ➢ Montefiore-Einstein Cancer Center, Bronx, New York

Optimizing Taxane Therapy for Patients With Primary Breast Cancer: What Are the Lessons Learned?

Editor in Chief, Medical Oncology Lawrence N. Shulman, MD

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Editorial Director Kristen Olafson Kristen.olafson@haymarketmedia.com Senior Copy Editor Bjarne Hansen

COMMENTARY

Production Editor Rick Maffei

Lawrence N. Shulman, MD ➢ Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, Massachusetts

Art Director Robert Mancuso

HER2 Status and Inflammatory Breast Cancer: Evidence of Prognostic Significance and Trastuzumab Efficacy

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Director of Sales Chad Holloway 201-799-4878 Chad.holloway@haymarketmedia.com

REVIEW

Circulation Department ajhosubs@haymarketmedia.com

Cancer Shaheenah Dawood, MRCP(UK), MPH; Ana M. Gonzalez-Angulo, MD ➢ Dubai Hospital, U.A.E.

Inflammatory Breast Cancer: Still a Challenge

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COMMENTARY

CASE STUDY Paul L. Nguyen, MD, et al ➢ Harvard Medical School, Boston, Massachusetts

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The American Journal of Hematology/Oncology

For reprints contact: Greg Rucker 212-221-9595 ext 105 Greg.rucker@parsintl.com Haymarket Media Inc. CEO Lee Maniscalco

Nancy U. Lin, MD ➢ Dana-Farber Cancer Institute, Boston, Massachusetts

Risk of Local Recurrence for Breast Cancer Subtypes Defined by ER, PR, and HER2 Status

Production Inquiries Leslie Carsman 646-638-6075

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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

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By Beverly Moy, MD, MPH

Trends

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.

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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/m2 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.

Lapatinib Alone or in Combination With Trastuzumab in Heavily Pretreated HER2+ Metastatic Breast Cancer That Progressed on Trastuzumab Therapy

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.

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.

Cristofanilli M, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1012.

O’Shaughnessy J, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1015.

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

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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

T

he 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-

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 paclitaxel6 or every3-week docetaxel7 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.

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Weekly paclitaxel and breast cancer

Figure Operable breast cancer, lymph node positive or high-risk node negative N=4950

Doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 every 21 days for 4 cycles

Paclitaxel 175 mg/m2 every 21 days for 4 doses n=1253

Paclitaxel 80 mg/m2 weekly for 12 doses n=1231

Docetaxel 100 mg/m2 every 21 days for 4 doses n=1236

Docetaxel 35 mg/m2 every 21 days for 12 doses n=1230

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/m2 of body surface area) and cyclophosphamide (600 mg/m2 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.

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

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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

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

Table 1 5-Year Disease-Free Survival and Overall Survival in Four Treatment Arms 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

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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

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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 Hazard Ratio

95% CI

P Value

HR+

1.36

0.92-2.00

0.12

HR–

1.33

0.91-1.94

0.14

HR+

1.31

1.00-1.72

0.05

HR–

1.37

0.98-1.93

0.97

Variable Overall survival

Disease-free survival

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-

vival but not overall survival. These results are consistent with findings in metastatic breast cancer that demonstrate a benefit of weekly paclitaxel or every3-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-

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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. ✦

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 FE90C (FEC) to four cycles of FE90C 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.

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 B28. 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-

Supported by grants from the Department of Health and Human Services and the National Institutes of Health. Author disclosures: Dr Sparano: speaker and consultant: SanofiAventis. 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) 7443418; e-mail: raabr@ecu.edu.

®

INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH

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: 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.

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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

T

he 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.

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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

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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, DanaFarber Cancer Institute, 44 Binney Street, Boston, MA 02115; phone: (617) 632-2277; fax: (617) 632-2260; e-mail: Lawrence_ Shulman@dfci.harvard.edu.


Review

HER2 Status and Inflammatory Breast Cancer: Evidence of Prognostic Significance and Trastuzumab Efficacy Shaheenah Dawood, MRCP(UK), MPH1; Ana M. Gonzalez-Angulo, MD2 1 Department of Medical Oncology, Dubai Hospital, U.A.E.; 2Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

I

nflammatory 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 metastatic7 and adjuvant8,9 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 study13 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.

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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

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 RecurrenceFree Survival

P Value

Overall Survival

P Value

Unadjusted estimates* HER2 negative

38.8% (28.7%-48.8%)

49.8% (38.0%-60.6%)

HER2 positive

36.5% (24.0%-49.0%)

0.750

57.8% (43.4%-69.8%)

0.245

0.75 (0.46-1.22)

0.241

0.56 (0.34-0.93)

0.024

Adjusted estimates† HER2 (positive vs negative)

*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).

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HER2 status and inflammatory breast cancer

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

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)

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Commentary

Inflammatory Breast Cancer: Still a Challenge Nancy U. Lin, MD Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts

I

nflammatory 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

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.

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The challenge of IBC

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

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

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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 HER2 positivity in inflammatory breast cancer. Breast. 2004;13:97103. 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;93:237246. 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-

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, GlaxoSmithKline; consultant: GlaxoSmithKline (<$10,000). Correspondence address: Nancy U. Lin, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: nlin@partners.org.

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.

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10. Sawaki M, Ito Y, Akiyama F, et al. High prevalence of HER2/neu and p53 overexpression in inflammatory breast cancer. Breast Cancer. 2006;13:172-178. 11. Guerin M, Gabillot M, Mathieu MC, et al. Structure and expression of c-erbB2-2 and EGF receptor genes in inflammatory and non-inflammatory breast cancer: prognostic significance. Int J Cancer. 1989;43:201-208. 12. Turpin E, Bièche I, Bertheau P, et al. Increased incidence of ERBB2 overexpression and TP53 mutation in inflammatory breast cancer. Oncogene. 2002;21;7593-7597. 13. 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. 14. Resetkova E, Gonzalez-Angulo AM, Sneige N, et al. Prognostic value of p53, MDM-2, and MUC-1 for patients with inflammatory breast carcinoma. Cancer. 2004;101:913-917. 15. Cabioglu N, Gong Y, Islam R, et al. Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer. Ann Oncol. 2007;17:1021-1029.

Author disclosures: No relationships with industry were reported. Correspondence address: Ana M. Gonzalez-Angulo, MD, MSc, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; phone: (713) 792-2817; fax: (713) 794-4385; e-mail: agonzalez@mdanderson.org.


CaseStudy

Risk of Local Recurrence for Breast Cancer Subtypes Defined by ER, PR, and HER2 Status Paul L. Nguyen, MD1,2; Alphonse G. Taghian, MD, PhD2,3; Jay R. Harris, MD2,4 1 Harvard Radiation Oncology Program; 2Harvard Medical School; 3Department of Radiation Oncology, Massachusetts General Hospital; 4Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital; all Boston, Massachusetts

A

60-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.

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

Discussion Classic Predictors of Local Recurrence After BreastConserving 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

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 TuftsNew 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

. . . most have agreed that margin status is one of the most important predictors of local recurrence.

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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 <1 mm margin in our patient unclear.7 The Beaumont study also observed that the risk of local recurrence increased as the amount of disease close to a margin increased. Breast Cancer Subtypes: A New Prognostic Factor for Local Recurrence In 2008, a new prognostic factor for local recurrence, breast cancer subtype, emerged. The biological breast cancer subtypes were initially identified through gene expression profiling, which found that the various breast cancers studied appeared to cluster into separate groups.8,9 They included two luminal variants, luminal A and luminal B, which

In 2008, a new prognostic factor for local recurrence, breast cancer subtype, emerged.

tended to be ER positive; however, they differed in that luminal A cancers tended to have a higher expression of ER-related genes and a lower expression of proliferative genes than luminal B.9-12 There were also two nonluminal variants that tended to be ER negative. These included the HER2 group, which tended to also be HER2 positive, and the “basal” group, which generally showed low expression of ER, PR, and HER2 and is similar to what is known clinically as the “triple-negative” group.12 These biological subtypes also seemed to have clinical relevance as they divided patients into groups with distinct clinical outcomes. Specifically, the luminal A patients appeared to have the lowest distant recurrence rates and best survival, while the HER2 and basal groups had the poorest survival and highest recurrence rates.11-13 However, the impact of these subtypes on local recurrence remained unknown.

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Impact of Breast Cancer Subtypes After BreastConserving Therapy Earlier this year, we examined the results from 793 consecutive women with early-stage invasive breast cancer who received breast-conserving therapy at Dana-Farber Cancer Institute/Brigham and Women’s Hospital (n=447) or Massachusetts General Hospital (n=346) from July 1998 to December 2001.14 Information about the ER, PR, and HER2 status of the primary tumor was required for inclusion. The purpose of the study was to determine whether the breast cancer subtype, as approximated by the ER, PR, and HER2 receptor status, was significantly associated with time to local and distant recurrence. We used the receptor status because it was readily available for most patients, and some investigators have proposed that the biological subtype could be approximated by the receptor status in the following way: luminal A (ER+ or PR+ and HER2–), luminal B (ER+ or PR+ and HER2+), HER2 (ER– and PR– and HER2+), and basal (ER– and PR– and HER2–).13 Reflective of many modern-era patients receiving breast-conserving therapy, we found this cohort to have highly favorable clinical characteristics, as 80% had T1 disease and more than 70% were node negative. Ninety-eight percent of the patients with nodepositive disease received some form of systemic therapy, as did 86% of those with node-negative disease. Of note, none of the patients in the study received adjuvant trastuzumab, as this was not yet part of the standard of care during the years in which the patients were studied. As expected from prior studies, the breast cancer subtypes significantly differed in terms of their 5year cumulative incidence of distant metastases; luminal A was the lowest at 3.3%, while the others were higher: luminal B 12%, HER2 19%, and basal 16%. Interestingly, the cumulative incidence of local (ie, in-breast) recurrence for the overall cohort was only 1.8% at 5 years, perhaps reflecting patient selection, more careful attention to margins, and widespread use of systemic therapy. However, as with distant recurrence, the 5-year rate of local recurrence was significantly different for the various subtypes, with luminal A being lowest at 0.8%, while luminal B was 1.5%, HER2 8.4%, and basal 7.1%. Strikingly, on multivariate analysis, the breast cancer subtype was the only factor significantly associated with local recurrence (HER2 vs luminal A adjusted hazard ratio [AHR]=9.2; 95% CI, 1.6-51; P=0.012) and basal vs luminal A (AHR=7.1; 95% CI, 1.6-31; P=0.009), while


Breast cancer subtypes and local recurrence

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 <35 years (3.5%) to detect a difference. Impact of Breast Cancer Subtypes on Local Recurrence After Mastectomy Evidence for the prognostic impact of breast cancer subtype on local recurrence was also reported this year among patients who received mastectomy. In a subgroup of 1000 women who underwent mastectomy with or without radiation therapy as part of the Danish 82b/c randomized trials and had tissue available for ER, PR, and HER2 evaluation, Kyndi and colleagues similarly reported that both the HER2 and basal subtypes were significantly associated on multivariate analysis with an increased risk of locoregional recurrence compared with luminal subtypes.15 Additionally, on an analysis performed of the 486 patients randomly assigned to mastectomy plus postmastectomy radiation, the multivariate analysis found that having a HER2 tumor or a basal tumor were the two factors most strongly associated with the risk of locoregional recurrence, outperforming traditional parameters such as nodal status and tumor size. To highlight the impact of breast cancer subtype on local recurrence, the Table shows the 5-year risk of local recurrence for patients treated with lumpectomy and radiation in the Harvard series or with mastectomy and radiation in the Danish series. While differences in patient selection and use of systemic therapy do not allow for direct comparisons between lumpectomy and mastectomy, this table shows strikingly similar trends in the 5-year rates of local recurrence, with HER2 and basal subtypes having substantially higher local rates than their luminal counterparts. As in the Harvard

series, none of the patients in the Danish series received trastuzumab; because trastuzumab may be associated with a lower rate of local recurrence, it is likely that the local recurrence numbers for the luminal B and HER2 patients would be somewhat lower for modern patients who would receive trastuzumab.16,17 Case Outcome Recent evidence suggests that breast cancer subtype is an important predictor of local recurrence after both breast-conserving therapy and mastecto-

Recent evidence suggests that breast cancer subtype . . . may even outperform more traditional predictors of recurrence.

my and may even outperform more traditional predictors of recurrence among contemporary patients with generally favorable characteristics. Besides a focally close margin, our patient had overall favorable characteristics that placed her at low risk for local recurrence, including a luminal A subtype, which was found to be associated with only a 0.8% risk of local recurrence at 5 years. Therefore, it was recommended that she not have a second reexcision but that she be treated with breast irradiation and hormonal therapy alone, with planned initial tamoxifen and switching to an aromatase inhibitor after 2 to 3 years. ✦

Table 5-Year Rates of Local Recurrence by Breast Cancer Subtype Lumpectomy + Radiation14

Mastectomy + Radiation15

Luminal A (ER+ or PR+/HER2–)

0.8%

2%

Luminal B (ER+ or PR+/HER2+)

1.5%

3%

HER2 (ER– and PR–/HER2+)

8.4%

13%

Basal (ER– and PR–/HER2–)

7.1%

21%

November 2008 • Vol 7 • Supplement 5

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CaseStudy

References 1. Zhou P, Recht A. Young age and outcome for women with early-stage invasive breast carcinoma. Cancer. 2004;101:12641274. 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;98:1086910874. 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.

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.

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INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH

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: Role of resection margins in patients treated with breast conservation surgery. Cancer. 2008; 112:1923-1931. Commentary by Drs Laurie Kirstein and David August.

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AJHO Special Breast Cancer Issue