Management of Breast Cancer in the Adjuvant and Metastatic ...John Carpenter, MD Professor of Medicine Division of Hematology/Oncology University of Alabama at Birmingham Birmingham,

CMECertified

FROM THE PUBLISHERS OF:

2008 . Vol 5 . Issue 1

PRSRT STD U.S. POSTAGE

PAID MIAMI, FL

PERMIT #1317

Sponsored by Research To Practice.

Last review date: June 2008 Release date: June 2008

Expiration date: June 2009 Estimated time to complete: 3 hours

Management of Breast Cancer in the Adjuvant and Metastatic Settings

Editor Neil Love, MD

Faculty Kathy D Miller, MD

Hyman B Muss, MD

A Survey Comparing Practices of Breast Cancer Investigators and General Oncologists

Copyright © 2008 Research To Practice. This program is supported by educational grants

from Abraxis BioScience, AstraZeneca Pharmaceuticals LP, Genentech BioOncology, Genomic Health Inc and Sanofi-Aventis.

POCB1_08_Cover_Final2jc.indd 1 6/6/08 2:46:20 PM

ISSUE 1 JUNE 2008 1

Table of Contents

PowerPoint files of the graphics contained in this document can be downloaded at www.PatternsOfCare.com.

2 Continuing Medical Education Information

5 Editor’s Note: Dr Frankenstein…or is it Frankensteen?

9 Adjuvant Systemic Therapy

25 Systemic Therapy for Metastatic Disease

35 Educational Assessment and Credit Form

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2 PATTERNS OF CARE

Continuing Medical Education (CME) Information

FACULTY — The following faculty (and their spouses/partners) reported real or apparent conflicts of interest, which have been resolved through a conflict of interest resolution process: Dr Miller — Consulting Agreements: Eli Lilly and Company, Genentech BioOncology, Roche Laboratories Inc; Paid Research: Pfizer Inc, Roche Laboratories Inc; Speakers Bureau: Genentech BioOncology, Roche Laborato-ries Inc. Dr Muss — Consulting Agreements: Amgen Inc, Bristol-Myers Squibb Company, Pfizer Inc, Roche Laboratories Inc.RESEARCH TO PRACTICE STAFF AND EXTERNAL REVIEWERS — The scientific staff and reviewers for Research To Practice have no real or apparent conflicts of interest to disclose.

CME DISCLOSURES FOR QUOTED FACULTYDrs Burstein, Geyer, Giordano, Lin, Morrow, Peto and Winer had no real or apparent conflicts of interest to disclose. The following faculty (and their spouses/partners) reported real or apparent conflicts of interest, which have been resolved through a conflict of interest resolution process: Dr Albain — Consulting Fees: Bristol-Myers Squibb Company, Eli Lilly and Company, Genentech BioOncology, Genomic Health Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc; Contracted Research: Abraxis BioScience, Genentech BioOncology, Genomic Health Inc. Dr Budd — Consulting Fees: AstraZeneca Pharmaceuticals LP, Pfizer Inc. Dr Burris — Consulting Fees: Celgene Corporation, Keryx Biopharmaceuticals Inc, Novartis Pharmaceuticals Corporation; Fees for Non-CME Services Received Directly from Commercial Interest or Their Agents: Sanofi-Aventis. Dr Carlson — Advisory Committee: Genomic Health Inc; Consulting Agreements: AstraZeneca Pharmaceuticals LP, Pfizer Inc; Paid Research: AstraZeneca Pharmaceuti-cals LP, Genentech BioOncology. Prof Forbes — Consulting Fees: Novartis Pharmaceuti-cals Corporation; Fees for Non-CME Services Received Directly from Commercial Interest or Their Agents: AstraZeneca Pharmaceuticals LP, Novartis Pharmaceuticals Corporation. Dr Goss — Consulting Fees and Fees for Non-CME Services Received Directly from Commer-cial Interest or Their Agents: AstraZeneca Pharmaceuticals LP, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Pfizer Inc. Dr Gradishar — Consulting Fees and Fees for Non-CME Services Received Directly from Commercial Interest or Their Agents: Abraxis BioScience, AstraZeneca Pharma-

STATEMENT OF NEED/TARGET AUDIENCEIt is important for practicing oncologists to be aware of similarities and differences between his or her practice patterns, those of others in community practice and those of breast cancer clinical investigators. It is also important for oncologists to recognize that heterogeneity exists in the oncology community, especially in clinical situations for which there is suboptimal research evidence.

This program focuses on the self-described practice patterns of randomly selected medical oncologists on a variety of key clinical issues in cancer. Also included are clinical investigator commentary and references addressing these issues. This CME program will provide medical oncologists with information on national cancer patterns of care to assist with the development of clinical management strategies.

LEARNING OBJECTIVES FOR THE PATTERNS OF CARE SERIES• Compare management strategies of

community oncologists and cancer clinical investigators in the adjuvant and metastatic settings, and apply relevant information to the treatment of patients with breast cancer.

• Evaluate management issues for patients with cancer for which relative agreement and heterogeneity exist in patterns of care, and make treatment decisions considering this information.

• Counsel patients with cancer about multiple acceptable treatment options when they exist.

PURPOSE OF THIS ISSUEThe purpose of this issue of Patterns of Care is to support these objectives by comparing the perspectives of 100 community medical oncol-ogists to those of 43 breast cancer specialists and to offer in-depth commentary from faculty regarding their practice patterns in the manage-ment of breast cancer.

ACCREDITATION STATEMENTResearch To Practice is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical educa-tion for physicians.

CREDIT DESIGNATION STATEMENTResearch To Practice designates this educa-tional activity for a maximum of 3 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

HOW TO USE THIS CME ACTIVITYThis monograph is one issue of a CME series activity. To receive credit for this activity, the participant should read the monograph and complete the Educational Assessment and Credit Form located in the back of this book or on our website www.PatternsOfCare.com. PowerPoint files of the graphics contained in this document can be downloaded at www.PatternsOfCare.com.

COMMERCIAL SUPPORTThis program is supported by educational grants from Abraxis BioScience, AstraZeneca Pharmaceuticals LP, Genentech BioOncology, Genomic Health Inc and Sanofi-Aventis.

PHARMACEUTICAL AGENTS DISCUSSED IN THIS PROGRAMThis educational activity includes discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. Research To Practice does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

CONTENT VALIDATION AND DISCLOSURESResearch To Practice is committed to providing its participants with high-quality, unbiased and state-of-the-art education. We assess potential conflicts of interest with faculty, planners and managers of CME activities. Real or apparent conflicts of interest are identified and resolved through a conflict of interest resolution process. In addition, all activity content is reviewed by both a member of the Research To Practice scientific staff and an external, independent reviewer for fair balance, scientific objectivity of studies refer-enced and patient care recommendations.

COMMENTS IN THIS MONOGRAPH

To highlight the practice issues presented in this survey, a number of excerpts are included from CME publications. For the related audio programs from Research To Practice, please visit www.BreastCancerUpdate.com.

ABOUT THIS SURVEY

This survey was completed in March 2008 by 100 community-based medical oncologists and 43 oncologists who specialize in breast cancer management (see list on pages 3-4) in the United States. The community-based oncologists were selected from a proprietary mail list used by Research To Practice for distribution of its CME programs, and the specialists included physicians who have participated in education programs with Research To Practice and others referred for this project.

Continued on page 4


ISSUE 1 JUNE 2008 3

Clinical Investigators Completing the Survey (March 2008, Medical Oncologists Who Devote Greater than 50 Percent of Their Practice to Breast Cancer)

FACULTY

Kathy D Miller, MD Sheila D Ward Scholar of Medicine Associate Professor of Medicine Indiana University Simon Cancer Center Indianapolis, Indiana

Hyman B Muss, MD Professor of Medicine University of Vermont and Vermont Cancer Center Hematology Oncology Unit Burlington, Vermont

CLINICAL INVESTIGATORS COMPLETING THE SURVEY

Mary Ann K Allison, MD Member, USON Breast Cancer Committee Member, TORI/UCLA Research Network Comprehensive Cancer Centers of Nevada Henderson, Nevada

Alan B Astrow, MD Director, Division of Hematology/Medical Oncology Maimonides Medical Center Brooklyn, New York

Kimberly L Blackwell, MD Associate Professor of Medicine Assistant Professor of Radiation Oncology Duke University Medical Center Durham, North Carolina

Joanne L Blum, MD, PhD Director, Hereditary Cancer Risk Program at Baylor-Sammons Cancer Center US Oncology Research Site Leader Texas Oncology, PA at the Baylor-Sammons Cancer Center Dallas, Texas

Adam M Brufsky, MD, PhD Associate Professor of Medicine University of Pittsburgh Member, University of Pittsburgh Cancer Institute Director, Comprehensive Breast Cancer Center Associate Division Chief, University of Pittsburgh, Department of Medicine Division of Hematology/Oncology Pittsburgh, Pennsylvania

Daniel R Budman, MD Professor of Medicine New York University School of Medicine Associate Chief, Don Monti Division of Medical Oncology Monter Cancer Center of North Shore University Hospital Lake Success, New York

Howard A Burris III, MD CMO, Director, Drug Development Sarah Cannon Research Institute Nashville, Tennessee

Harold J Burstein, MD, PhD Assistant Professor of Medicine Harvard Medical School Breast Oncology Center Dana-Farber Cancer Institute Boston, Massachusetts

Lisa A Carey, MD Medical Director, UNC Breast Center University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center Chapel Hill, North Carolina

Robert W Carlson, MD Professor of Medicine Division of Oncology and Stanford Medical Informatics Stanford University Medical Center Stanford, California

John Carpenter, MD Professor of Medicine Division of Hematology/Oncology University of Alabama at Birmingham Birmingham, Alabama

Jenny C Chang, MD Dan L Duncan Professor Lester and Sue Smith Breast Center Baylor College of Medicine Houston, Texas

Rowan T Chlebowski, MD, PhD Professor of Medicine David Geffen School of Medicine at UCLA Chief, Division of Medical Oncology and Hematology Harbor-UCLA Medical Center Torrance, California

Ellen Chuang, MD Assistant Professor of Clinical Medicine Weill Cornell Breast Center Division of Hematology and Medical Oncology Weill Cornell Medical College New York, New York

Marc L Citron, MD Clinical Professor of Medicine Albert Einstein College of Medicine Yeshiva University Lake Success, New York

Generosa Grana, MD Associate Professor of Medicine UMDNJ/Robert Wood Johnson School of Medicine Director, Breast Cancer Program Cooper Hospital Camden, New Jersey

Jennifer J Griggs, MD, MPH Associate Professor Department of Medicine Hematology/Oncology University of Michigan Ann Arbor, Michigan

Clifford Hudis, MD Chief, Breast Cancer Medicine Service Solid Tumor Division Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Peter A Kaufman, MD Associate Professor of Medicine Breast Oncology Section of Hematology/Oncology Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

Allan Lipton, MD Professor of Medicine and Oncology Division of Hematology/Oncology MS Hershey Medical Center The Pennsylvania State University Hershey, Pennsylvania

Charles L Loprinzi, MD Director, NCCTG Cancer Control Program Co-Director, Mayo Cancer Center Prevention and Control Program Professor of Oncology Mayo Clinic Rochester, Minnesota

Gary H Lyman, MD, MPH Professor of Medicine and Director Health Services and Outcomes Research Program — Oncology Duke University Medical Center and the Duke Comprehensive Cancer Center Senior Fellow, Duke Center for Clinical Health Policy Research Durham, North Carolina

Anne Moore, MD Professor of Clinical Medicine Attending Physician New York Presbyterian Hospital Weill-Cornell Medical Center New York, New York

Ruth O’Regan, MD Associate Professor of Hematology and Oncology Director, Translational Breast Cancer Research Program Director, Hematology and Oncology Fellowship Program Emory University Winship Cancer Institute Atlanta, Georgia

Beth Overmoyer, MD Dana-Farber Cancer Institute Boston, Massachusetts

Leroy M Parker, MD Associate Clinical Professor of Medicine Dana-Farber Cancer Institute Harvard Medical School Boston, Massachusetts


4 PATTERNS OF CARE

Continuing Medical Education (CME) Information (Continued)

ceuticals LP, Bristol-Myers Squibb Company, Genomic Health Inc, Novartis Pharmaceuti-cals Corporation, Pfizer Inc, Sanofi-Aventis. Dr Gralow — Consulting Agreements: Amgen Inc, Genentech BioOncology, Genomic Health Inc, GlaxoSmithKline, Novartis Pharma-ceuticals Corporation, Roche Laboratories Inc, Sanofi-Aventis. Dr Hayes — Contracted Research: AstraZeneca Pharmaceuticals LP. Dr Hudis — Advisory Committee: Amgen Inc, GlaxoSmithKline, Novartis Pharmaceuti-cals Corporation, Pfizer Inc, Sanofi-Aventis; Consulting Agreements: Bristol-Myers Squibb Company, Genentech BioOncology, Wyeth; Paid Research: AstraZeneca Pharmaceuticals LP, Onyx Pharmaceuticals Inc, Roche Labora-tories Inc; Stock Ownership: Genomic Health Inc. Dr Jones — Consulting Fees: Pfizer Inc, Sanofi-Aventis; Fees for Non-CME Services Received Directly from Commercial Interest or Their Agents: AstraZeneca Pharmaceuticals LP, Genentech BioOncology, GlaxoSmithKline, Pfizer Inc, Sanofi-Aventis. Dr Mackey — Honoraria: Amgen Inc, AstraZeneca Pharmaceuticals LP, Roche Laboratories Inc, Sanofi-Aventis. Dr O’Shaughnessy — Consulting Fees: Biogen Idec, Bristol-Myers Squibb Company, Eisai Inc, Eli Lilly and Company, Genentech BioOncology, Genzyme Corporation, Novartis Pharmaceu-ticals Corporation, Ortho Biotech Products

LP, Pfizer Inc; Fees for Non-CME Services Received Directly from Commercial Interest or Their Agents: Abraxis BioScience, Eli Lilly and Company, Sanofi-Aventis. Dr Pegram — Advisory Committee: Amgen Inc, Bristol-Myers Squibb Company, Genentech BioOncology, Genomic Health Inc, GlaxoSmithKline, Pfizer Inc; Speakers Bureau: Genentech BioOncology, GlaxoSmithKline, Sanofi-Aventis. Dr Perez — Paid Research: Bristol-Myers Squibb Company, Genentech BioOncology, GlaxoSmithKline, Novartis Pharmaceuticals Corporation. Dr Ravdin — Consulting Agreement: Genomic Health Inc; Speakers Bureau: AstraZeneca Pharmaceuticals LP; Stock Ownership: Adjuvant! Inc, Bristol-Myers Squibb Company, Pfizer Inc, Wyeth. Dr Robert — Advisory Committee: Novartis Pharmaceuticals Corpo-ration, Pfizer Inc, Sanofi-Aventis; Consulting Agreements: Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation; Speakers Bureau: Novartis Pharmaceuticals Corporation. Dr Slamon — Fees for Non-CME Services Received Directly from Commer-cial Interest or Their Agents: Genentech BioOncology, GlaxoSmithKline, Sanofi-Aventis; Ownership Interest: Amgen Inc, Pfizer Inc. Dr Sledge — Consulting Fees: Genentech BioOncology; Contracted Research: Sanofi-Aventis. Prof Smith — Advisory Committee:

AstraZeneca Pharmaceuticals LP, Eli Lilly and Company, GlaxoSmithKline, Novartis Pharma-ceuticals Corporation, Roche Laboratories Inc, Sanofi-Aventis; Lecturing: AstraZeneca Pharmaceuticals LP, Eli Lilly and Company, GlaxoSmithKline; Speakers Bureau: AstraZeneca Pharmaceuticals LP, Eli Lilly and Company, Novartis Pharmaceuticals Corpo-ration, Pfizer Inc, Roche Laboratories Inc, Sanofi-Aventis. Dr Sparano — Consulting Fees: Bristol-Myers Squibb Company, Eisai Inc, Genentech BioOncology, GlaxoSmithKline, Johnson & Johnson Pharmaceuticals, Merck and Company Inc, Sanofi-Aventis. Dr Swain — Consulting Fees: Johnson & Johnson Pharmaceuticals, Roche Laboratories Inc; Travel for Clinical Investigator Meeting: Genentech BioOncology, Sanofi-Aventis. Dr Whitworth — Consulting Fees and Fees for Non-CME Services Received Directly from Commercial Interest or Their Agents: AstraZeneca Pharma-ceuticals LP, Ethicon Endo-Surgery Inc, General Electric Company, Genomic Health Inc, Myriad Genetics Inc, Novartis Pharmaceuticals Corpo-ration, Sanarus Medical Inc, Sanofi-Aventis, SenoRx Inc, SonoSite Inc, Veridex LLC; Owner-ship Interest: SenoRx Inc. Dr Wolff — Paid Research: Roche Laboratories Inc.

Clinical Investigators Completing the Survey (March 2008, Medical Oncologists Who Devote Greater than 50 Percent of Their Practice to Breast Cancer)

Ann H Partridge, MD, MPH Assistant Professor of Medicine Harvard Medical School Medical Oncologist Dana-Farber Cancer Institute Brigham and Women’s Hospital Boston, Massachusetts

Edith A Perez, MD Serene M and Frances C Professor of Medicine Director, Cancer Clinical Study Unit Director, Breast Cancer Program Division of Hematology and Oncology Mayo Clinic Jacksonville, Florida

John E Pippen Jr, MD Baylor-Charles A Sammons Cancer Center Chair, Breast Tumor Site Committee Texas Oncology Dallas, Texas

Peter M Ravdin, MD, PhD Research Professor of Biostatistics The University of Texas MD Anderson Cancer Center Houston, Texas

Nicholas J Robert, MD Co-Chair, Breast Cancer Committee US Oncology Research Network Chairman, Cancer Committee Cancer Center, Inova Fairfax Hospital Fairfax, Virginia

Bryan P Schneider, MD Assistant Professor Department of Medicine Division of Hematology/Oncology Indiana University School of Medicine Indianapolis, Indiana

Lee S Schwartzberg, MD Medical Director, The West Clinic Clinical Professor of Medicine University of Tennessee School of Medicine Memphis, Tennessee

Michelle Shayne, MD Assistant Professor of Medicine James P Wilmot Cancer Center University of Rochester School of Medicine and Dentistry Rochester, New York

George W Sledge Jr, MD Ballve-Lantero Professor of Oncology Professor of Medicine and Pathology Melvin and Bren Simon Indiana University Cancer Center Indianapolis, Indiana

Vered Stearns, MD Associate Professor of Oncology Breast Cancer Research Program Sidney Kimmel Comprehensive Cancer Center Johns Hopkins School of Medicine Baltimore, Maryland

Anna Maria Storniolo, MD Director, Catherine Peachey Breast Cancer Prevention Program Professor of Clinical Medicine Department of Medicine Division of Hematology/Oncology Indiana University School of Medicine Indianapolis, Indiana

Richard L Theriault, DO, MBA Professor, Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Vicente Valero, MD Professor of Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

Charles L Vogel, MD Senior Research Advisor for Breast Cancer, Aptium Oncology Lynn Regional Cancer Center West Campus Boca Raton Community Hospital Scientific Advisor Cancer Research Network Inc Boca Raton, Florida

Victor G Vogel, MD, MHS Director, Magee/UPCI Breast Cancer Prevention Program Professor of Medicine and Epidemiology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania


ISSUE 1 JUNE 2008 5

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Editor’s Note: Dr Frankenstein…or is it Frankensteen?

Our main office in Miami is currently the scene of complete and total mayhem, as dozens of dusty construction workers tear apart our previously

nondescript academic environs high in the sky to make way for the world’s first international CME audio production and Podcasting studio. The work is slated to be complete in time for a series of scheduled events in July, including several Think Tanks and Meet The Professors recording sessions. Until then, we continue to push ahead attempting to ignore a cacophony of sounds that often makes it hard just to think.

Some might question our business acumen in taking this bold step forward in the midst of a crashing economy, a dearth of new cancer drugs in the so-called pipeline and mounting concerns about congress-people and bean-counting, nine-to-five university-based “educators” trying to shut down the totally legitimate and pretty decently functioning private-sector busi-ness of CME. With all of this and more to worry about, we decided to further spice up the mix with an interesting educa-tion experiment for our first Patterns of Care study of 2008.

By way of background, we’ve spent the last year rebuilding our website, and a key aspect of this unexpectedly complex undertaking was how to optimally categorize the seemingly infinite pieces of content in our programs to facilitate high-quality search functionality. Out of these discussions we began to consider whether CME might be most effectively organized based on specific clinical decisions encountered by physicians — in this case, medical oncologists.

With that in mind, and using invasive breast cancer as a pilot in a mad effort to go inside the brain of the monster called evidence-based oncology, we developed a list of the most chal-lenging management decisions in both the adjuvant and meta-static settings. In January, during our most recent breast cancer Think Tank, we asked the learned faculty to weigh in on our selections and based on their input arrived at a “Top 20” list.

In March, as part of the enclosed national Patterns of Care survey, we asked 100 practicing oncologists and 43 breast cancer investigators (all US based) to think very carefully about these identified issues and then provide three numbers for each, as follows:1. About how often they encounter the situation in their

practice.2. Their level of interest (0 to 10 rating) in CME related to

the particular clinical decision. It is important to note that when we say CME, we are not referring to your average local dinner meeting but to Socratic CME — our name for what we have been doing for 20 years — specifically, asking investigators and docs in practice what they know, think and believe.

3. Their level of support (0 to 10 rating) for clinical research to further define the optimal management strategies for patients in the described situation.Our co-conspirators in this educational adventure were

Drs Kathy Miller and Hy Muss, both of whom helped a great deal in shaping the methods. On the following pages, we sum-


6 PATTERNS OF CARE

Editor’s Note (Continued)

EDIT

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we call the “Table-Graph,” in which…well, look at it and tell us if it works. Here are a few of the team’s thoughts about our initial attempt to bring quantitation to education and research needs assessment:HY MUSS…was pleased that most of the high-priority research issues are being addressed in ongoing clinical trials. He was particularly intrigued by the answers to a scenario he came up with — the patient with prior anthracycline/taxane adjuvant therapy who now has a second primary tumor that is triple-negative. This question broke our record for recommended responses, as there were 33 different regimens listed by the 100 practicing docs. Understanding that a level 3 evidence-based answer is unlikely to ever be determined, Hy would choose between TC (docetaxel/cyclophosphamide) and XT (or is it TC2?) (docetaxel/capecitabine).KATHY MILLER…thinks these docs likely overestimated the number of patients they see under age 40 with ER-positive, node-positive disease, noting that “these young women stand out in our minds because of the compelling human issues with this situation.” Good point, Kathy. She also expressed “curios-ity” that so much interest was expressed in this issue, when trials like TEXT and SOFT that are geared toward exactly this patient population are withering away like neglected plants because of poor accrual. However, as we go to press, Mike Gnant and the Austrian Breast Cancer Trialists Group completely turned this issue on its ear with a stunning ASCO plenary presentation that demonstrated little difference in choice of endocrine therapy in patients on an LHRH agonist but an eye-opening 35 percent reduction in relapse rate in women receiving zoledronic acid every six months, and you can hear Dr Gnant and others talk all about it in the current issue of the Breast Cancer Update audio series.

Dr Miller was particularly fascinated by the relatively high level of support for clinical research addressing the issue of con-tinuation of a biologic — in this case, bevacizumab — in spite of tumor progression. In colon cancer, Axel Grothey’s BRiTE tumor registry analysis has led to the launch of the iBET trial, evaluating a question that was never settled for trastuzumab.

Kathy noted that as part of this type of clinical trial, trans-lational studies could be employed to look at the potential for rebound VEGF expression upon withdrawal of bevacizumab that might explain why her pivotal trial of bev/paclitaxel dem-onstrated an impressive progression-free survival but no overall survival advantage.YOUR HUMBLE EDITOR…is desperate to figure out whether others will think this is as interesting and relevant as we do. From the perspective of CME, we have long believed that a more scientific and research-like platform is essential to move the field forward, and the impressive number of oncologists who rate their interest in “Socratic” CME as a “9” or “10” supports the fact that docs in practice value the perspectives of their colleagues on critical decisions. It is particularly striking that this thirst for input regarding common tumors like breast cancer seems unquenchable.

So as our editorial staff huddles together in temporarily cramped working conditions with hard hats ripping our walls

down to build the studio, we amuse ourselves by coming up with slightly bizarre, pseudo-scientific graphs that perhaps in their own unique way tell a simple but powerful story, which is that docs in practice want input on many important decisions in breast oncology, and the more frequently they encounter a situ-ation, the more pressing is the need for answers.

Our ever-evolving ideas laboratory continues to put together interesting new education adventures and creations, and in the very near future we will ask investigators, practicing docs, nurses and patients to join us in our new special recording digs overlooking beautiful Biscayne Bay and Miami Beach beyond, and perhaps as we gaze out to the ocean, ideas and solutions will emerge that might finally have a meaningful impact on this horrendous disease.

— Neil Love, MD [email protected]

FIGURE 1

The top 5 breast cancer clinical decisions as ranked by 100 practicing oncologists and 43 breast cancer investigators, sorted by:

FREQUENCY OF THE CLINICAL DECISION IN MEDICAL ONCOLOGY PRACTICE (100 practicing oncologists)

1. ER+, HER2-negative, node-negative — Chemo?

2. ER+, HER2-negative, node+ — Chemo?

3. HER2-negative MBC — Chemo? Bevacizumab?

4. <Age 40, ER+, multiple node+ — Endocrine choice

5. AIs beyond five years?

INTEREST IN SOCRATIC OR QUESTION-BASED CME RELATED TO THESE DECISIONS (100 practicing oncologists)


2. ER+, HER2-negative, node-negative — Chemo?


4. Triple-negative with residual tumor after neoadjuvant AC taxane — Postop Rx

5. ER+, HER2-negative, node+ — Chemo?

INTEREST IN CLINICAL RESEARCH FOCUSING ON MANAGING THIS SITUATION (43 investigators)



3. Triple-negative with residual tumor after neoadjuvant AC taxane — Postop Rx

4. HER2-negative MBC with response to chemo/bev but chemo stopped from toxicity — Continuation of bev alone or with other chemo?

5. HER2-negative MBC with response to chemo/bev then progression — Continuation of bev alone or with other chemo?


ISSUE 1 JUNE 2008 7

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75%

5%

10%

30%

25%

20%

15%

35%

40%

55%

50%

45%

60%

65%

70%

28%

40%

36%

30%

44%

46%

42%

38%

34%

32%

ER+, HER2-negative, node-negative — Chemo?75% <Age 40, ER+, multiple node+ — Endocrine choice 46%

ER+, HER2-negative, node+ — Chemo?72%

HER2-negative MBC — Chemo? Bevacizumab?63%

AIs beyond five years?51%

HER2+, small node-negative — Chemo?45%

HER2+ MBC (no prior Rx) — Anti-HER2 agent39%

>Age 65, HER2+, node+ — Choice of chemo29%

ER+ relapse on AI — Endocrine choice27%

Triple-negative with residual tumor after neoadjuvant AC taxane — Postop Rx22%

Postmenopausal patient with prior tamoxifen — AI?22%

Premenopausal patient with relapse on tamoxifen — Endocrine choice21%

HER2+ MBC (prior adjuvant trastuzumab) — Choice of anti-HER2 agent19%

Premenopausal woman with positive nodes — More than 5 years of tamoxifen?19%

ER+, HER2+ asymptomatic MBC — Systemic therapy?17%

HER2-negative MBC with response to chemo/bev but chemo stopped from toxicity — Continuation of bev alone or with other chemo?

13%

8%

ER+, HER2-negative, node-negative — Chemo? 44%

AIs beyond five years? 42%

ER+, HER2-negative, node+ — Chemo? 40%

HER2-negative MBC — Chemo? Bevacizumab? 40%

HER2+, small node-negative — Chemo? 38%

HER2-negative MBC with response to chemo/bev then progression — Continuation

of bev alone or with other chemo?38%

ER+ relapse on AI — Endocrine choice 36%

HER2-negative MBC with response to chemo/bev but chemo stopped from toxicity — Continuation

of bev alone or with other chemo?36%

HER2+ MBC with progression on trastuzumab — Anti-HER2 agent? 35%

HER2+ MBC (no prior Rx) — Anti-HER2 agent 33%

>Age 65, HER2+, node+ — Choice of chemo 33%

>Age 75, HER2+, node+ — Chemo? 32%

Postmenopausal patient with prior tamoxifen — AI? 28%

HER2+ MBC with progression on trastuzumab — Anti-HER2 agent?15%

<Age 40, ER+, multiple node+ — Endocrine choice54%

Triple-negative with residual tumor after neoadjuvant AC taxane — Postop Rx 41%

Premenopausal woman with positive nodes — More than 5 years of tamoxifen? 33%

HER2+ MBC (prior adjuvant trastuzumab) — Choice of anti-HER2 agent 39%

Prior dose-dense AC T; now with triple-negative new cancer — Chemo? 35%

Premenopausal patient with relapse on tamoxifen — Endocrine choice? 34%

>Age 75, HER2+, node+ — Chemo?27%

HER2-negative MBC with response to chemo/bev then progression — Continuation of bev alone or with other chemo?

10%

ER+, HER2+ asymptomatic MBC — Systemic therapy? 35%

Prior dose-dense AC T; now with triple-negative new cancer — Chemo?

Frequency of clinical situations (% of practicing oncologists who encounter this situation at least monthly); interest in Socratic or question-based CME (responses of 100 practicing oncologists; % who rate 9 or 10)

CLINICAL QUESTIONFREQUENCY CLINICAL QUESTION INTEREST IN CME

FIGURE 2

METASTATIC CLINICAL SITUATIONS ADJUVANT CLINICAL SITUATIONS


8 PATTERNS OF CARE

Editor’s Note (Continued)

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16%

20%

28%

40%

38%

30%

48%

58%

56%

54%

52%

50%

46%

44%

42%

36%

34%

32%

26%

24%

22%

18%

75%

5%

10%

30%

25%

20%

15%

35%

40%

55%

50%

45%

60%

65%

70%

AIs beyond five years? 58%

<Age 40, ER+, multiple node+ — Endocrine choice 56%

Triple-negative with residual tumor after neoadjuvant AC taxane — Postop Rx 53%

HER2-negative MBC with response to chemo/bev then progression — Continuation

of bev alone or with other chemo? 47%

ER+, HER2-negative, node-negative — Chemo? 44%

HER2+ MBC (prior adjuvant trastuzumab) — Choice of anti-HER2 agent 37%

ER+, HER2-negative, node+ — Chemo? 35%

HER2-negative MBC — Chemo? Bevacizumab? 33%

>Age 75, HER2+, node+ — Chemo? 30%

Prior dose-dense AC T; now with triple-negative new cancer — Chemo? 30%

Premenopausal woman with positive nodes — More than 5 years of tamoxifen? 28%

HER2-negative MBC with response to chemo/bev but chemo stopped from toxicity — Continuation

of bev alone or with other chemo? 47%

HER2+, small node-negative — Chemo? 37%

>Age 65, HER2+, node+ — Choice of chemo 26%

ER+ relapse on AI — Endocrine choice 23%

Premenopausal patient with relapse on tamoxifen — Endocrine choice? 23%

HER2+ MBC with progression on trastuzumab — Anti-HER2 agent? 23%

HER2+ MBC (no prior Rx) — Anti-HER2 agent 21%

ER+, HER2+ asymptomatic MBC — Systemic therapy? 19%

Postmenopausal patient with prior tamoxifen — AI? 16%

ER+, HER2-negative, node-negative — Chemo?75%

ER+, HER2-negative, node+ — Chemo?72%

HER2-negative MBC — Chemo? Bevacizumab?63%

AIs beyond five years?51%

HER2+, small node-negative — Chemo?45%

HER2+ MBC (no prior Rx) — Anti-HER2 agent39%

>Age 65, HER2+, node+ — Choice of chemo29%

ER+ relapse on AI — Endocrine choice27%

Triple-negative with residual tumor after neoadjuvant AC taxane — Postop Rx22%

Postmenopausal patient with prior tamoxifen — AI?22%

Premenopausal patient with relapse on tamoxifen — Endocrine choice21%

HER2+ MBC (prior adjuvant trastuzumab) — Choice of anti-HER2 agent19%

Premenopausal woman with positive nodes — More than 5 years of tamoxifen?19%

ER+, HER2+ asymptomatic MBC — Systemic therapy?17%

HER2-negative MBC with response to chemo/bev but chemo stopped from toxicity — Continuation of bev alone or with other chemo?

13%

8%

HER2+ MBC with progression on trastuzumab — Anti-HER2 agent?15%

<Age 40, ER+, multiple node+ — Endocrine choice54%

>Age 75, HER2+, node+ — Chemo?27%

HER2-negative MBC with response to chemo/bev then progression — Continuation of bev alone or with other chemo?

10%


Frequency of clinical situations (% of practicing oncologists who encounter this situation at least monthly); support for more clinical research related to this scenario (responses of 43 clinical investigators; % who rate 9 or 10)

CLINICAL QUESTIONFREQUENCY CLINICAL QUESTION INTEREST IN RESEARCH

FIGURE 3

ADJUVANT CLINICAL SITUATIONS METASTATIC CLINICAL SITUATIONS


ISSUE 1 JUNE 2008 9

Adjuvant Systemic Therapy

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Breast Cancer Update Issue 1, 2008

DR CHARLES E GEYER JR: Our first choice for postmenopausal patients with hormone receptor-positive disease who have completed a standard five-year duration of hormonal therapy is to enroll them on the NSABP-B-42 study with a randomization to either letrozole or placebo. If this cannot be done, we try to attain a sense of the patients’ residual risk to decide whether to stop or continue therapy. We infer that based on their baseline risk from their disease at presen-tation — a larger tumor, a larger number of nodes and so on indicate a higher risk for recurrence. The assumption is that the relative reduction is fixed, so the residual risk beyond five years is higher.

If I have a patient with a large num-ber of positive nodes, I discuss with that patient the uncertainties regarding benefits of additional therapy, toxicities and so on. I believe that you also have to assess how the patient tolerates the aromatase inhibitor.


DR KATHY D MILLER: I tell patients that I have no clue if aromatase inhibitors should be continued beyond five years. We have available the rerandomization of the MA17 trial that evaluates 10 versus five years of an aromatase inhibitor in aggregate, and I’ve been talking to patients about the trial even though I must admit I’ve been surprised that I have not had a lot of patients who were interested.

I certainly could not argue with some-one who had a patient at high risk who was tolerating the aromatase inhibitor well, who wanted to continue it and thought that was reasonable. But I believe that the patients in that situation need to know that we have absolutely no data to advise them as to whether that will provide a greater benefit, greater

0 10 20 30 40 50 60 70

0 10 20 30 40 50 60 70 80

Yes

Yes, individualizing based on risk of recurrence

Yes, but only in an exceptional circumstance

No

58%

50%

16%

12%

7%

11%

27%

19%

3 positive nodes

A 2.8-cm tumor and negative nodes



49%

34%

19%

72%

60%

5%

8%

23%

In general, do you continue an aromatase inhibitor (AI) in a patient who is completing the fifth year of an adjuvant AI and is tolerating it well?

FIGURE 4

AIs beyond five years?CLINICAL QUESTION

For a 67-year-old patient, would you continue an AI after five years of treatment with an AI if the patient originally had:

FIGURE 5

CLINICAL INVESTIGATORS (CI)

PRACTICING ONCOLOGISTS (PO)


10 PATTERNS OF CARE

Adjuvant Systemic Therapy (Continued)

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bone toxicity or if it will all be a wash in the end.

Breast Cancer Update Think Tank Issue 1, 2008

DR JULIE R GRALOW: It’s not unusual to evaluate premenopausal patients with positive nodes and ER-positive, HER2-negative disease who request “anything to try to reduce the risk of relapse.” Younger patients have a chance of regaining ovar-ian function. If the patient is close to menopause, I have less of an issue with ovarian suppression because I think she’ll go through menopause regardless.

If she has chemotherapy and goes into a temporary menopause, I would want to enroll her in a trial. I don’t know what’s

correct and incorrect with long-term fol-low-up. Hopefully, she will survive and will reach age 70 and beyond. The higher the number of nodes, the more com-fortable I am with ovarian suppression and an aromatase inhibitor. That said, I would consider enrolling a patient like her in a trial such as SOFT. I would not say, “I am sure you shouldn’t have your ovaries suppressed.” I don’t know.


DR JOHN MACKEY: If a premenopausal woman came to me with ER-positive, HER2-negative disease and five posi-tive nodes I don’t think ovarian function suppression with an aromatase inhibitor

is appropriate — the evidence doesn’t exist. We know that if you use goserelin or other analogs, some patients actually have substantial levels of estradiol. In fact, we have anecdotes of women with metastatic disease who undergo ovarian function suppression and continue to menstruate. You can’t trust an ovary not to wake up again simply because some-one’s received chemotherapy and has a temporary loss of menses.

At the end of the day, if a premeno-pausal patient was insistent on such an approach, I’d say that she might con-sider a laparoscopic oophorectomy, par-ticularly if she has a family history by which you could bolster that argument. However, generally speaking I would

0 10 20 30 40 50 60 0 10 20 30 40 50 60

AI + LHRH agonist or OA

Tamoxifen for 5 years then

switch to an AI

Tamoxifen + LHRH agonist or OA*

Tamoxifen for up to 3 years then switch to an AI

14%

24%

Tamoxifen for 5 years then no

further treatment

LHRH agonist or OA alone

0%

4%

19%

11%

37%

14%

21%

33%

9%

14%

Tamoxifen for 5 years then no

further treatment

Tamoxifen for 5 years then

switch to an AI

Tamoxifen for up to 3 years then switch to an AI†

Tamoxifen + LHRH agonist or OA

AI alone

AI + LHRH agonist or OA

47%

43%

5%

8%

2%

8%

9%

5%

28%

22%

9%

14%

What would be your most common recommendation for a premenopausal patient with a multiple node-positive, ER-positive tumor in the following clinical situations?

Continues menstruating after adjuvant chemotherapy

* OA = ovarian ablation; † If patient becomes postmenopausal

Ceases menstruation with adjuvant chemotherapy

FIGURE 6

<Age 40, ER+, multiple node+ — Endocrine choice?CLINICAL QUESTION


ISSUE 1 JUNE 2008 11

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suggest five years of tamoxifen as the standard and would say that clinical tri-als are attempting to address this issue, but the data are not at all definitive.


DR FORBES: We learned some impor-tant concepts with this new 100-month follow-up data from the ATAC trial. First, the advantage of anastrozole over tamoxifen is maintained at least through nine years. Is has a carryover effect — the benefit continues after the treat-ment is stopped. In particular for the post-treatment period from years five to nine, the advantage of anastrozole compared to tamoxifen remains signifi-cant. Furthermore, the absolute differ-ence in the rate of breast cancer relapse increases in magnitude from 2.8 percent at five years to 4.8 percent at nine years.

A somewhat unexpected and espe-cially pleasing finding was that upon completion of the treatment, no differ-ence was apparent in the risk of frac-ture between tamoxifen and anastrozole. The other surprising finding was the much lower rate of endometrial cancer in women receiving anastrozole compared to those on tamoxifen.

Breast Cancer Update for Surgeons Issue 1, 2008

DR ROBERT W CARLSON: The 100-month follow-up of the ATAC trial was one of the most important abstracts presented at San Antonio. The results were encouraging and reassuring. From the Early Breast Cancer Trialists’ Collab-orative Group (EBCTCG) analysis, we know that the benefits of tamoxifen, in terms of risk reduction for recur-rence and death, persist well beyond the period of actual tamoxifen administra-tion. Some were concerned that this might not be the case with the aromatase inhibitors — that you might win the short game but lose the long game.

The efficacy data from the ATAC trial suggest substantial benefit from anastrozole beyond the five years of actual therapy. The long-term differ-ences were larger in the ATAC trial than in the EBCTCG analysis of the

0 10 20 30 40 50 60

0 1 2 3 4 5 6 7 8 9

>6 months to 1 year

6 months or less

>1-3 years

>3-5 years

>5-10 years14%

3%

Would not use an AI for those patients 10%

5%

21%

44%

44%

32%

12%

10%

0%

5%

Disease-free survival

Recurrence rate

Time to distant recurrence

Contralateral breast

4.8%

2.8%

1.3%

4.1%

2.5%

1.7%

0.8%

2.4%

SOURCE: Forbes JF et al. Lancet Oncol 2008;9(1):45-53. Abstract

Nine years

Five years

In general, for a postmenopausal patient who has previously received 5 years of tamoxifen, what would be the longest duration off tamoxifen after which you would consider starting an AI off protocol?

FIGURE 7

Postmenopausal patient with prior tamoxifen — AI?CLINICAL QUESTION

ATAC trial 100-month update — Carryover effect: Increased absolute differ-ence between tamoxifen and anastrozole that favors anastrozole at five years and nine years of follow-up

FIGURE 8

CLINICAL INVESTIGATORS (CI) PRACTICING ONCOLOGISTS (PO)


12 PATTERNS OF CARE


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tamoxifen carryover effect. It is an indi-rect comparison, so we have to be cau-tious, but it is reassuring to observe

sustained benefits from anastrozole after treatment is completed.

Breast Cancer Update for Surgeons Issue 1, 2008

DR MONICA MORROW: Clearly, the results from the ATAC trial are holding up long term. A question was whether there would be a “carryover” effect with the aromatase inhibitors, as we’ve seen with tamoxifen, in terms of the long-term reduction in contralateral breast cancer and survival benefits. The 100-month ATAC trial data suggest that the same carryover effect is present, which is reassuring.

The idea that the osteoporosis and fracture problems appear to stabilize over time is also reassuring, although it doesn’t obviate the increased risk of osteoporo-sis in the early treatment period. This needs to be monitored and is an issue in the chemoprevention setting. Most of the side-effect profile of the aromatase inhibitors appears to be preferable to that of tamoxifen, with the exception of the bone and joint problems, which for some women can be significantly disabling.


SIR RICHARD PETO: The ATLAS study compares 10 years of tamoxifen to five years in terms of the 15-year outcome. It involves a large international group with about 400 centers in 38 countries and is run by Christina Davies. They’ve randomly assigned 11,500 women who have completed five years of adjuvant tamoxifen. About half of the women had ER-positive disease, and half didn’t have their ER status tested, but most of them would have been ER-positive.

Christina followed the patients for an average of four years, so these are prelim-inary results. But it’s clear that further reduction in recurrence is achieved by continuing tamoxifen beyond five years. It decreases it further by about 15 per-cent. This decrease is in addition to the decrease from the carryover effect of the first five years. In terms of pre-venting recurrence, 10 years of adjuvant tamoxifen is better than five years. It’s too early to determine how 10 years of tamoxifen will affect breast cancer

0 10 20 30 40 50 60 70

0 10 20 30 40 50 60 70

Yes, always or almost always

Yes, sometimes

Yes, rarely

No

21%

23%

14%

5%

9%

53%

54%

21%

Fewer recurrences

No impact

More recurrences

I don’t know

26%

62%

17%

44%

19%

16%

2%

14%

Would you continue the tamoxifen in a premenopausal patient with positive nodes who has recently completed 5 years of tamoxifen and is eligible for a clinical trial?

FIGURE 9

Premenopausal woman with positive nodes — More than 5 years of tamoxifen?

CLINICAL QUESTION

In your opinion, what is the impact on cancer recurrence when adjuvant therapy with tamoxifen is extended beyond 5 years?

FIGURE 10



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her with neoadjuvant therapy. Rather, it’s for the patients with large tumors that I employ neoadjuvant therapy, and these patients usually agree to no further treatment because they are often reas-sured when they feel their tumor shrink from therapy prior to surgery.

A number of papers are being pub-lished evaluating response to neoadjuvant therapy and the risk of recurrence in patients with triple-negative breast can-cer. Anderson and colleagues, in the Journal of Clinical Oncology, found that many of these patients fared well unless they had a large tumor and little response to treatment, which we would all agree is a bad scenario. However, I don’t believe we have a good enough database to accu-rately inform patients of their likelihood of relapse in this situation.

mortality. Also, longer treatment will increase the incidence of the significant side effect of uterine cancer. There are disadvantages in continuing tamoxifen, but certainly the myth that tamoxifen beyond five years will start stimulating breast cancer is wrong. This was a mis-take that emerged in the mid-90s.

Interview, April 2008

DR HYMAN B MUSS: Like the majority of survey responders, typically I don’t use further systemic therapy for a patient with residual triple-negative disease after neoadjuvant therapy. Generally, if a patient has a tumor that can be managed with breast conservation, I don’t treat

0 10 20 30 40 50 60 70 80 90

0 10 20 30 40 50 60 70 80 90

Placebo PO qd x 1y

Sunitinib PO qd x 1y

Eligibility

Patients with resected residual disease after neoadjuvant chemo-therapy

69%

36%

19%

32%

10%

10%

2%

8%

0%

14%

72%

42%

23%

3%

16%

2%

5%

Bevacizumab alone or with other

chemotherapy*

Capecitabine alone or with other

chemotherapy

No systemic treatment

Platinum-based regimen

Other

Very likely

Somewhat likely

Not very likely

Not at all likely

37%

R

NSABP-B-45 schema (proposed trial)

FIGURE 12

Patients will be stratified by hormone receptor status, number of positive nodes and administration of postoperative chemotherapy.

What would be your most common recommendation for a patient with significant residual triple-negative tumor at surgery after neoadjuvant chemotherapy?

* Excludes platinum-based regimens

FIGURE 11

Triple-negative with residual tumor after neoadjuvant AC taxane — Postop Rx?CLINICAL QUESTION

How likely would you be to enroll this patient in a clinical trial that randomly assigns patients to further systemic therapy or no further systemic therapy?



14 PATTERNS OF CARE


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DR O’SHAUGHNESSY: For a patient with significant residual triple-negative disease at surgery after neoadjuvant chemother-apy, I order a PET scan up front. It is particularly useful in highly proliferative tumors with a lot of axillary adenopathy, where we sometimes observe lymphade-nopathy in the intramammary chain, in the low cervical nodes and even in the mediastinum. If the disease is chemo-therapy sensitive and you have a chance for a decent prognosis, then you can include those nodal beds in the radia-tion port.

Off protocol, I generally recommend noncross-resistant chemotherapy agents in cases like this. In the absence of other data, I turn to agents with either a proven track record in the adjuvant setting or for which we have evidence of some preoperative activity.

I would probably choose capecitabine combined with a platinum agent and bevacizumab. Capecitabine is a noncross-resistant drug, and work from Farber and others suggests that it has some activity in triple-negative disease. I would try to give the patient the best chance for cyto-reduction and disruption of any micro-metastatic niche she might have.


DR SHARON GIORDANO: Increasingly, data suggest that patients with ER-posi-tive tumors benefit less from chemo-therapy than patients with ER-negative tumors, but I’m not convinced at this point that they receive no benefit. Stud-ies like TAILORx, in which we are strat-ifying patients with ER-positive disease by risk as determined with the Oncotype DX assay, might help establish whether there is a subset of patients who don’t need chemotherapy. For patients who are borderline candidates for chemotherapy, if they have ER-positive disease, I’m less inclined to use chemotherapy. I believe, however, that patients who have high-risk disease, even if it’s ER-positive, still clearly benefit.

In the TAILORx trial, which we are participating in, if a patient’s tumor is

BONE AND AROMATASE INHIBI-TORS

0 10 20 30 40 50 60 70 80

Yes, depending on tumor factors

65%

56%


No0%

3%

35%

41%

Select Eligibility Criteria • ER-positive and/or PR-positive breast cancer• Negative axillary nodes• Tissue from primary tumor available for

Oncotype DX assay• 18 to 75 years of age• HER2-negative

• Tumor size 1.1 to 5.0 centimeters (tumors 5 millimeters to 1.0 centimeter allowed if intermediate or poor nuclear and/or histologic grade or lymphovascular invasion)

Study ContactEastern Cooperative Oncology GroupJoseph Sparano, MDTel: 718-920-4826

SOURCES: PACCT-1 Protocol, August 23, 2006; www.ecog.org.

Current Accrual: 3,660 (4/27/2008); Target n = 11,000 Date Activated: April 7, 2006

Hormonal therapy†

Hormonal therapy†

Combination chemotherapy† + hormonal therapy†

Combination chemotherapy† + hormonal therapy†

Group I (RS* < 11)

Group III (RS* > 25)

Group II (RS* 11-25)ARM 1

ARM 2R

* Oncotype DX recurrence score† Physician’s choice for hormonal therapy and chemotherapy

In general, for a patient with an ER-positive, node-negative, HER2-negative tumor, do you have the tumor tested by the Oncotype DX™ assay?

FIGURE 13

ER+, HER2-negative, node-negative — Chemo?CLINICAL QUESTION

TAILORx: A Phase III randomized trial of adjuvant combination chemo-therapy and hormonal therapy versus adjuvant hormonal therapy alone in women with previously resected axillary node-negative breast cancer with an intermediate score of the Oncotype DX assay

FIGURE 14



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categorized as presenting intermediate risk, then she is randomly assigned to hormonal therapy with or without che-motherapy. If the patient’s tumor is in the low-risk category, she receives hormonal therapy alone. If the patient’s tumor is in the high-risk category, she receives che-motherapy and hormonal therapy.

I’ve used the Oncotype DX assay off protocol — to help both myself and the patient make a decision as to whether to use chemotherapy — for patients who are borderline candidates for chemo-therapy because they do not want che-motherapy or they have comorbidities or fairly low-risk tumors.

I can’t say that I have a clear cutoff, but for patients with tumors larger than

two centimeters, I’m inclined to use che-motherapy. I typically don’t order the Oncotype DX assay in that situation.


DR NICHOLAS J ROBERT: I tend to order the test for patients with node-negative disease, with whom I would be comfort-able administering endocrine therapy and there’s a question mark — such as a case in which the ER is not highly positive.

I’m a fan of Allred’s scoring, but frankly our pathologists don’t use it, so it’s not very helpful. In addition, I believe that the Oncotype DX test provides me with better insight in terms of the endo-crine status of the tumor, because if the

ER is low-positive and the PR is nega-tive, if the recurrence score comes back as intermediate or high, that pushes the chemotherapy button for me.

Interview, May 2008

DR PETER M RAVDIN: The Oncotype DX assay truly has a role for smaller tumors, larger tumors and 2- to 3-cm tumors. However, the degree of accu-racy changes. One of the limitations of Oncotype DX with regard to smaller tumors is that the assay was developed largely from the NSABP-B-14 and B-20 trials. These trials enrolled relatively few patients whose tumors were 10 millime-ters or smaller in size. They were not excluded, but they made up a very small

0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100

0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100

1.0-2.0 cm

2.1-4.0 cm

4.1-5.0 cm

7%

52%

53%

32%

40%

16%

<0.5 cm

0.5-1.0 cm

1.1-2.0 cm

55%

45%

45%

5%

0%

50%

Yes70%

63%Yes

95%

64%

Is there a tumor size above or below which you would not recommend testing with the Oncotype DX assay?

What is the size of the:

* CI n = 30; PO n = 63; † CI n = 41; PO n = 65

FIGURE 15


Upper limit?* Lower limit?†

Above Below



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percentage of the patient population. Having said that, it can be argued that for the patients with smaller tumors, we are less confident that the Oncotype DX assay is valid.

I think the Oncotype DX assay is valid because a gene signature should help you tell the difference between low risk and high risk — in other words, high proliferation state or low prolifera-

tion state tumors. Additionally, I would expect this to apply to small node-nega-tive tumors, larger node-negative tumors and node-positive tumors also. So far, the evidence seems to support this view.

One portion of the gene signature that needs to be better defined is whether other factors should be used in addition to the Oncotype DX assay. All things equal, a tumor with a given signature that had been around long enough to involve regional nodes will almost cer-tainly have a worse prognosis. This is evi-denced in the Southwestern Oncology Group 8814 trial.


DR MACKEY: In deciding whether to use an anthracycline for patients with HER2-negative disease, my prefer-ence and what I discuss with patients is that we proceed with TC. I’m not administering anthracyclines to patients with HER2-negative disease unless the patient is adamant that she wants one of the older regimens. It’s clear that TC has achieved a survival advantage over AC, which is exciting because this popula-tion is unselected and includes patients with HER2-positive disease who did not receive trastuzumab. So in a sense this trial was stacked against the TC regi-men, but TC is still outperforming AC in terms of safety and efficacy. With the survival advantage, I don’t see where the anthracyclines fit into the treatment of HER2-negative disease.

Breast Cancer Update Think Tank Live 2007

DR DENNIS J SLAMON: The US Oncol-ogy adjuvant trial evaluating patients with node-negative and node-positive disease demonstrated the superiority of the nonanthracycline-containing regi-men over an anthracycline. At UCLA, most of the investigators and clinicians, including myself, are using docetaxel and cyclophosphamide (TC) instead of AC.DR SANDRA M SWAIN: I feel comfort-able not using an anthracycline for patients with node-negative disease. Perhaps it’s not rational, but I make a distinction for patients with higher-

0 10 20 30 40 50 60 70 80 90

0 10 20 30 40 50 60 70 80 90


Yes, sometimes

Yes, rarely

No

14%

34%

2%

2%

79%

59%

5%

5%


Yes, sometimes

Yes, rarely

No

28%

37%

17%

9%

23%

44%

23%

19%

Oncotype DX recurrence score is high but risk of relapse as determined by Adjuvant! Online is substantially lower (<10%)

Would you recommend chemotherapy for patients who are not eligible for a clinical trial and are in each of the following clinical situations?

Oncotype DX recurrence score is low but risk of relapse as determined by Adjuvant! Online is substantially higher (>20%)

FIGURE 16




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risk disease. Furthermore, Mike Press and Soon Paik have demonstrated that TOPO II isn’t overexpressed in patients with HER2-negative disease. Therefore, I don’t believe we need the anthracyclines for these patients.

DR MARK D PEGRAM: You must have a balanced discussion with the patient, and evaluate her comorbid medical conditions, et cetera. We have nice data comparing nonanthracycline regimens to anthracycline regimens, and clearly the nonanthracycline regimens are prefer-able. It boils down to a patient’s relative risk and which regimen she’s likely to

tolerate. I use a lot of TC for patients with node-negative disease. Moreover, we participated in the Phase III trials of TAC versus FAC in the metastatic and adjuvant settings, so we have quite a lot of experience with docetaxel-based regi-mens at our institution. I feel comfort-able using TC.

DR SLAMON: It’s clear that physicians are using TC now. The benefits are the same for patients with higher-risk disease as for those with node-negative disease. TC is easy to administer, and the patients finish their chemotherapy in 12 weeks.


DR KATHY S ALBAIN: I use the Oncotype DX assay when I am on the fence about chemotherapy, but I also order it when I think I know the answer. At ASCO 2007, we presented a multicenter study for women with node-negative disease of the impact of the Oncotype DX assay results on prospective decision-making by doctors and patients.

When you thought you knew what you were doing, you changed your mind in a third of the cases, either to use therapy when you hadn’t expected to or vice versa.

0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90

AC

AC/taxane regimens

Other

41%*

15%

6%

8%

10%

0%

TC(docetaxel/

cyclophosphamide)39%

75%

CMF

2%

4%

16%

60%

7%

9%

8%

2006

2007

2008

AC

AC/taxane regimens

Other

TC(docetaxel/

cyclophosphamide)

CMF

65%

52%*

19%

20%

9%

2%

5%

4%

50%

24%

24%

1%

1%

3%

21%

2006

2007

2008

FIGURE 17

What would be your most common chemotherapy treatment recommendation for a patient with an ER-positive, node-negative, HER2-negative tumor who is not eligible for a clinical trial and for whom chemotherapy will be used?

* 14% of CIs and 9% of POs use dose-dense AC





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I’m not ready to say it will only be used when the patient and/or doctor are unde-cided about the use of chemotherapy, but those may be the types of patients with node-positive disease that we should start with. A woman with 15 positive nodes is not someone for whom I will order a recurrence score assay right off the bat.


DR DANIEL F HAYES: Kathy Albain led a study (SWOG-8814) for post-menopausal patients with node-positive, ER-positive disease who were randomly assigned to tamoxifen alone, tamoxifen concurrent with CAF or CAF followed by tamoxifen. This trial demonstrated that chemotherapy concurrent with tamoxifen was not as effective as chemo-therapy followed by tamoxifen. Tissue blocks were available from approximately 40 percent of those patients, so we evalu-ated whether or not we could correlate a benefit of treatment with the Onco-type DX recurrence score. We compared tamoxifen alone to CAF/tamoxifen. To our pleasure, we saw exactly what we predicted: Among the patients treated with tamoxifen alone, those with low recurrence scores as determined by Oncotype DX fared better than those with high recurrence scores.

However, nodes are still a prognostic factor. In fact, as many as 40 percent of patients with node-positive disease and low recurrence scores will experience a recurrence on tamoxifen alone. Among the patients with node-positive disease and high recurrence scores, a statistically significant benefit was seen in disease-free survival with CAF/tamoxifen versus tamoxifen alone. For the patients with low recurrence scores, the curves over-lapped. Even in node-positive disease, chemotherapy may not be effective for patients with high ER, low HER2 or low Ki-67 — the components of the Oncotype DX assay.

For patients with node-positive dis-ease, adjuvant chemotherapy is of proven benefit regardless of biological subsets. Almost every guideline recommends che-motherapy for patients with node-positive disease. The stakes are high in this situa-tion. I don’t believe nodal status indicates whether chemotherapy will work — biol-ogy tells you whether chemotherapy will work. I am not sure whether this is the assay we should use to decide whether to withhold adjuvant chemotherapy from patients with node-positive disease.

The question is whether we should run yet another prospective randomized trial. It would be a large trial because it would

be an equivalency trial. Patients with low recurrence scores who received adjuvant tamoxifen would be randomly assigned to modern chemotherapy versus none.


DR GRALOW: For a select group of patients with positive nodes, such as those with low nodal burden, I use the Oncotype DX assay to determine whether they should receive adjuvant chemotherapy. I am not ready to order it for a patient with 10 posi-tive nodes and use it to trump the other features of her disease. For a patient who I believe is highly sensitive to endocrine therapy and has a little nodal disease, I would consider it.

DR CLIFFORD HUDIS: I recently saw a 78-year-old woman in otherwise good health with a 2-cm, ER-positive (100 percent), PR-negative (zero), HER2-normal tumor and a single positive lymph node out of 14. Her attitude was that she would accept chemotherapy if it was needed. That was one of the first times I’ve ordered an Oncotype DX assay for a patient with node-positive disease.

Conversely, I believe it is risky to with-hold adjuvant chemotherapy from cohorts of patients for whom it’s been recom-mended, especially among those with node-positive disease, based on relatively small absolute numbers of events. When the patient is on the fence about receiving chemotherapy and you’re having a discus-sion, that’s a different situation.

DR MUSS: It is reasonable to use Onco-type DX for a patient with one posi-tive node who is on the fence about whether or not to take chemotherapy. Like Cliff, I would be nervous about using this routinely, except for an occa-sional patient. Also, these studies we’re discussing have notably small numbers of patients. We’re pruning them down and ending up with 200 patients in a subset analysis. We need to be cautious.


DR JOYCE O’SHAUGHNESSY: People aren’t wrong to use TC for higher-risk, node-positive disease, but the question

0 10 20 30 40 50 60 70 80

Yes, depending on tumor factors

49%

29%


No

0%

64%

51%

7%

In general, for a patient with an ER-positive, node-positive, HER2-negative tumor, do you have the tumor tested by the Oncotype DX assay?

FIGURE 18

ER+, HER2-negative, node+ — Chemo?CLINICAL QUESTION



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of duration remains for patients with a higher nodal burden and presum-ably a higher micrometastatic burden. The question is whether four cycles are enough, so most of us will err on the side of six or eight.

I use TC all the time in cases for which I used to use AC, which were for the patients at lower risk, such as those with ER-positive, node-negative disease or the patients with tiny triple-negative disease, who will gain that one to four percent absolute benefit from chemotherapy.


SIR PETO: In 2007, we presented the updated meta-analysis of trial results at the San Antonio Breast Cancer Sympo-sium. We don’t have trials of taxane-based regimens versus no adjuvant ther-apy, but we have trials of taxane-based regimens versus anthracycline-based regimens. These regimens will not be so different, but the taxanes are better.

From the data we have at the moment, taxane-based regimens appear to involve about a 15 percent lower recur-

rence rate and lower breast cancer mor-tality rate versus anthracycline-based regimens. With anthracycline-based reg-imens versus CMF, about a 15 percent lower recurrence rate is evident. I don’t mean a 15 percent absolute reduction: These are proportional risk reductions.

To evaluate chemotherapy, we have to put various trials together. CMF versus nothing provided a moderate gain. Anthracycline-based therapy ver-sus CMF provided another moderate gain. Taxane-based regimens versus

0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90

Other

9%

10%

6%

12%

Dose-dense AC paclitaxel

q2wk

TC

AC taxane q3wk

71%

4%

0%

51%

54%

13%

12%

30%

14%

50%

0%

10%

TAC

16%

19%

21% 2006

2007

2008

63%

Other

Dose-dense AC paclitaxel

q2wk

TC

AC taxane q3wk

TAC

16%

9%

20%

25%

2006

2007

2008

0%

0%

7%

0%

1%

17%

AC paclitaxel qwk

0% 0%

7%

12%

AC paclitaxel qwk

13%

8%

What would be your most common chemotherapy treatment recommendation for a patient with an ER-positive, node-positive, HER2-negative tumor who is not eligible for a clinical trial and for whom chemotherapy will be used?

FIGURE 19

ER+, HER2-negative, node+ — Chemo?CLINICAL QUESTION




20 PATTERNS OF CARE


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anthracycline-based regimens provided yet another moderate gain.

If you combine all of these, then you conclude that if we had been comparing taxane-based regimens to no adjuvant therapy, for women in their fifties and sixties we’d probably be reducing breast cancer mortality by about one third and recurrence rates by about half. For the younger women, the effects are even greater. Taxane-based regimens would be reducing breast cancer mortality by

about half and recurrence rates by more than half.


DR MILLER: When I see a patient with a HER2-negative tumor with multiple positive nodes, I generally administer AC/paclitaxel, evenly split between dose-dense administration and using the paclitaxel weekly.


DR MUSS: If presented with a patient who has had prior breast cancer, was treated with an anthracycline and a taxane and now presents with triple-negative contralateral disease, I would probably use TC now. I’d be repeating one drug that she’s already had, but I don’t think that’s risky for leukemia, and perhaps there is synergy for TC, so that is what I would recommend.

Another option in this situation, although I haven’t seen this much, might be docetaxel/capecitabine. I’ve also seen vignettes of platinum data in this situa-tion and the in vitro work of Lisa Carey, but I’m not sure that’s worked out so well. I’ve never been a great platinum fan, but it’s interesting to see.


DR GOSS: Treatment of triple-negative breast cancer is a special interest of ours at MGH Cancer Center. Everyone recognizes that triple-negative disease is a disproportionately fatal form of breast cancer and that it’s particularly refrac-tory to our current anticancer therapies, and we are frustrated by the lack of progress with this dangerous subtype. Cisplatin was previously tried in breast cancer and produced a low response rate in an “all-comers” setting, so it was taken off the table as a single agent or even as an active drug in breast cancer.

However, Leif Ellisen, the head of translational research at MGH Cancer Center, is investigating cell survival path-ways in breast cancer, and he has discov-ered a p63/p73 marker that we believe identifies 30 to 40 percent of patients with triple-negative breast cancer who are exquisitely and specifically sensitive to cisplatin. These genes are in the same family and pathway as p53.

So it makes biological sense that a platinum agent would be particularly effective in this subgroup of patients. It is more than simply a predictor of response — it’s actually involved in the response mechanism.

In the clinical setting, I would not use single-agent cisplatin before standard chemotherapy, but I would afterward.

0 10 20 30 40 50

Taxane + platinum

TC

Capecitabine alone or with other chemotherapy

Taxane + other chemotherapy*

5%

11%

Taxane alone

Taxane + bevacizumab2%

5%

27%

7%

17%

17%

34%

34%

7%

14%

Other platinum-based regimen

Other3%

7%

5%

5%

What would be your most common treatment recommendation for a patient who received dose-dense AC followed by a taxane for a triple-negative tumor approximately 2 years ago and now presents with a triple-negative tumor in the contralateral breast and who is not eligible for a clinical trial?

* Excluding platinums and capecitabine

FIGURE 20


CLINICAL QUESTION



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I’ve seen responses with the strategy, and I believe that this will be one of these phenomena in which the marker may be found in only 15 or 20 percent of patients. Among those patients, we’ll see an 80 or 85 percent response rate with this drug, which would be fantastic.


DR ROBERT: You have to be careful in how you approach adjuvant chemo-therapy in patients with smaller HER2-positive, node-negative tumors. Age is key, as is making sure the tumor is truly HER2-positive. As a former pathologist, I like to see the grade to be at least II or III. However, I have a low threshold for intervening with a HER2-based regimen for tumors larger than five millimeters. For tumors smaller than five millime-ters, the data are sparse. If it’s hormone receptor-negative, I struggle.


DR NANCY U LIN: One area in which we need more data in terms of actual prog-

nosis or natural history is for the patients with HER2-positive, T1N0 tumors. HER2 wasn’t routinely tested until about 1999 or 2000, after trastuzumab was approved, so it’s difficult to obtain, for example, 10-year follow-up data on a large cohort of patients. I believe that’s part of what has limited our ability to answer this question.

At any given tumor board, the rec-ommendations range from four cycles of AC to AC followed by trastuzumab, similar to the HERA regimen. Most of us would not treat someone with a low resurgent positive tumor with the full North American regimen of AC/paclitaxel/trastuzumab and then trastuzumab maintenance.


DR HUDIS: I would treat an older patient with a 2-cm, HER2-positive, node-nega-tive tumor conventionally with AC/taxane/trastuzumab, if she were inter-ested and willing.

DR GRALOW: The studies support an anthracycline- and taxane-containing regimen that is more aggressive than I want to administer. However, docetaxel/carboplatin/trastuzumab (TCH) is a tough regimen. Even though the patient might experience less cardiotoxicity, I believe that you trade it for other toxici-ties. I would try to enroll an older patient in our Phase II trial of weekly paclitaxel/trastuzumab, but I don’t have data to do that off study. Off study, I would probably use AC/weekly paclitaxel with trastuzumab.DR MACKEY: Off study, I would offer a patient like this TCH. I believe that the anthracyclines are a major confounding problem with the cardiotoxicity that we see with trastuzumab. I have found that TCH is reasonably well tolerated.DR ROBERT: I was involved with BCIRG 006, and we’ve prescribed a fair amount of TCH. I believe that we find some comfort in using less chemotherapy. So off study I would administer TCH, but I wouldn’t be wedded to six cycles.

0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70

Less than 1.0 cm

1.0-1.5 cm

Greater than 1.5 cm

Regardless of tumor size

26%

19%

55%

39%

10%

8%

9%

34%

Less than 1.0 cm

1.0-1.5 cm

Greater than 1.5 cm

Regardless of tumor size

46%

23%

35%

27%

0%

2%

19%

48%

Would you recommend chemotherapy with trastuzumab for a patient with a node-negative, HER2-positive tumor (who is not eligible for a clinical trial) if the tumor is:

* Percent responding yes; CI n = 42; PO n = 94; † Percent responding yes; CI n = 43; PO n = 94

ER-positive* ER-negative†

FIGURE 21

HER2+, small node-negative — Chemo?CLINICAL QUESTION



22 PATTERNS OF CARE


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DR GEYER: The statistical design for BETH is chemotherapy with trastuz-umab with or without bevacizumab, and the protocol basically provides for two chemotherapy regimens. One is the TCH regimen that was used in the BCIRG 006 trial.

The other regimen uses docetaxel at 100 mg/m2 every three weeks times three cycles followed by FEC with the epirubicin at 90 mg/m2. Patients on the docetaxel/FEC regimen receive the targeted therapy with the docetaxel. It is suspended during FEC and then resumed after FEC. Obviously, the tar-geted therapy with TCH begins concur-rently with the chemotherapy in both arms. All patients entered through the CIRG and NSABP will receive TC. The idea of the two arms and the TCH justification arrive from the current

0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90

Carb/doc/trast trastuzumab

Carb/doc/trast trastuzumab

Cyclophosph/doc/trast trastuzumab

Cyclophosph/doc/trast trastuzumab

AC TH16%

28%AC TH

Anthracycline taxane/

trastuzumab trastuzumab

Anthracycline taxane/

trastuzumab trastuzumab

Other Other

5%

22%

9%

0%

9%

65%

41%

7%

23%

9%

25%

7%

0%

2%

6%

75%

46%

5%

Eligibility • Node-positive or high-risk,

node-negative early breast cancer• HER2-positive by central FISH testing

Stratification • Number of positive nodes• Hormone receptor status

SOURCE: Slamon D. The Art of Oncology Satellite Symposium at ECCO 14, Barcelona, Spain. September 26, 2007.

TCH Docetaxel/carboplatin x 6 + trastuzumab x 1 year

TCHBDocetaxel/carboplatin x 6 + trastuzumab x 1 year + bevacizumab x 1 year

R

Target Accrual: 2,875

What is the optimal chemotherapy/trastuzumab regimen for a patient older than age 65 with a HER2-positive, node-positive or larger node-negative tumor who is not eligible for a clinical trial and who is:

FIGURE 22

>Age 65, HER2+, node+ — Choice of chemoCLINICAL QUESTION

BETH: Proposed NSABP/CIRG adjuvant trial in patients with HER2-positive breast cancer

FIGURE 23

In good healthUndergoing treatment

for hypertension



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results that Dr Slamon presented at the 2006 San Antonio meeting show-ing that outcomes with TCH versus AC TH were statistically indistin-guishable. The confidence intervals over-lapped tremendously, and no statisti-cally discernible difference in efficacy is apparent at this point, with a substantial number of events already reported.

The other compelling part of the 006 trial relates to the cardiac toxicity issue. All the trials with trastuzumab after anthracyclines have shown a low tolerable rate of cardiac dysfunction, but clearly the lowest cardiotoxicity rates of any of the trials were seen on the TCH arm. So I believe the TCH is show-ing efficacy on a similar magnitude to the anthracycline and does have a more favorable safety profile.


DR STEPHEN E JONES: The issue of adju-vant trastuzumab without chemotherapy in older or frail women does come up, and it makes sense, particularly for a woman with hormone receptor-positive breast cancer with whom you are planning to use an aromatase inhibitor. Although data from the TAnDEM trial of anastrozole with or without trastuzumab for patients with hormone receptor-positive, HER2-positive metastatic breast cancer were disappointing, they are open to interpre-tation.

Most patients with HER2-positive tumors tend to express ER at lower lev-els. These are not patients who we expect to respond well to endocrine therapy. My interpretation is that approximately 20 percent of patients fared well, even

at three years, and were still respond-ing to both the aromatase inhibitor and trastuzumab.

That subpopulation of patients with relatively indolent, HER2-overexpressing — probably ER-positive and PR-positive — breast cancer may fare well. Having said that, some older women will refuse chemotherapy. In those instances you have to consider trastuzumab monotherapy.


DR O’SHAUGHNESSY: I have treated healthy older patients, even women with T1 tumors, with the combination of trastuzumab and chemotherapy. As for adjuvant trastuzumab alone in the elderly, I can only think of one case — an 88-year-old woman with a node-positive, HER2-positive tumor whom I treated with capecitabine and trastuzumab. She didn’t tolerate the capecitabine well, so I used an aromatase inhibitor and trastuzumab.

I am currently treating a patient who is in her late seventies with a favorable tumor — T1N0, ER-positive — with weekly paclitaxel and trastuzumab, and she is faring well. As patients age, they are delicately balanced, so we’re increas-ingly concerned about harming them and I won’t use doublet chemotherapy with trastuzumab.

I haven’t tried nab paclitaxel with trastuzumab in the adjuvant setting, but it’s a thought for patients who are diabetic or are weak in the muscles, for whom ste-roid premedication is a problem.

Meet The Professors Breast Cancer Issue 1, 2008

DR GRALOW: I would love to feel comfortable administering antiestrogen therapy along with trastuzumab and omitting the chemotherapy, but I have to say that I believe in the synergy between trastuzumab and chemotherapy, and I also believe that the combination is better than trastuzumab alone.

If I truly felt that I couldn’t administer chemotherapy, with no study to back me up, I would do that. But I think that if she could handle a taxane, that would be my preference. Also, sometimes for patients like this I’ll say, “Let’s try it and see how it

0 10 20 30 40 50 60 70 80 90 100

0 10 20 30 40 50 60 70 80 90 100

Yes44%

48%

Age 76-80

Age 81-85

Age 86-9011%

8%

84%

79%

5%

13%

For a patient older than age 75 with a HER2-positive, ER-positive tumor and positive nodes, is there an age at which you would recommend trastuzumab with endocrine therapy but without chemotherapy?

If yes, at what age?*

* CI n = 19; PO n = 48

FIGURE 24

>Age 75, ER+, HER2+, node+ — Chemo?CLINICAL QUESTION



24 PATTERNS OF CARE


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goes. If we have to stop the chemotherapy after one or two cycles, then at least we’ve tried it and now we know.”

I believe the regimen that has the most data to back it up would be docetaxel/carboplatin/trastuzumab.

I do believe the data are good, if I’m doing something off study and I’m alter-ing tested regimens anyway, in terms of the synergy between paclitaxel and trastuzumab.

Weekly paclitaxel is much more toler-able, especially in an elderly population, than the classic TCH regimen.

So I’m going totally off what the stud-ies have shown, searching for a regimen that I think she can tolerate and one that makes sense. I might lean toward weekly paclitaxel with trastuzumab.

SELECT PUBLICATIONS

Albain K et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmeno-pausal, node-positive, ER-positive breast cancer (S8814,INT0100). San Antonio Breast Cancer Symposium 2007;Abstract 10.

Albain K et al. Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-f luorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or proges-terone (PgR) receptor-positive breast cancer: Mature outcomes and new biologic correlates on Phase III Intergroup trial 0100 (SWOG-8814). San Antonio Breast Cancer Symposium 2004;Abstract 37.

Buzdar A et al. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treat-ment for early-stage breast cancer: Long-term safety analysis of the ATAC trial. Lancet Oncol 2006;7(8):633-43. Abstract

Cronin M et al. Analytical validation of the Oncotype DX genomic diagnostic test for recur-rence prognosis and therapeutic response predic-tion in node-negative, estrogen receptor-positive breast cancer. Clin Chem 2007;53(6):1084-91. Abstract

Eastell R et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol 2008;26(7):1051-7. Abstract

Fisher B et al. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: Updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. JNCI 2001;93(2):684-90. Abstract

Forbes JF et al. Effect of anastrozole and tamoxifen as adjuvant treatment for earlystage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9(1):45-53. Abstract

Goss PE et al. Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Cancer Institute of Canada Clinical Trials Group MA.17. J Clin Oncol 2007;25(15):2006-11. Abstract

Jones S et al. Extended follow-up and analysis by age of the US Oncology adjuvant trial 9735: Docetaxel/cyclophosphamide is associated with an overall survival benefit compared to doxorubicin/cyclophosphamide and is well-toler-ated in women 65 or older. San Antonio Breast Cancer Symposium 2007;Abstract 12.

Lo SS et al. Prospective multicenter study of the impact of the 21-gene recurrence score (RS) assay on medical oncologist (MO) and patient (pt) adjuvant breast cancer (BC) treatment selec-tion. Proc ASCO 2007;Abstract 577.

Mamounas EP et al. NSABP B-42: A clinical trial to determine the efficacy of five years of letrozole compared with placebo in patients completing five years of hormonal therapy consisting of an aromatase inhibitor (AI) or tamoxifen followed by an AI in prolonging disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Clin Breast Cancer 2006;7(5):416-21. Abstract

Paik S et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006;24(23):3726-34. Abstract

Peto R et al. ATLAS (Adjuvant Tamoxifen, Longer Against Shorter): International random-ized trial of 10 versus 5 years of adjuvant tamoxifen among 11,500 women preliminary results. San Antonio Breast Cancer Symposium 2007;Abstract 48.

Slamon D et al. Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2 positive early breast cancer patients: Second interim efficacy analysis. San Antonio Breast Cancer Symposium 2006;Abstract 52.

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45-53. Abstract

0 10 20 30 40 50 60 70 80 90

0 10 20 30 40 50 60 70 80 90

Yes33%

35%

Age 76-80

Age 81-8515%

20%

69%

Age 86-9011%

71%

14%

For a patient older than age 75 with a HER2-positive, ER-negative tumor and positive nodes, is there an age at which you would recommend trastuzumab without chemotherapy?

If yes, at what age?*

* CI n = 14; PO n = 35

FIGURE 25

>Age 75, ER-negative, HER2+, node+ — Chemo?CLINICAL QUESTION



Systemic Therapy for Metastatic Disease

SYSTEM

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DR WILLIAM J GRADISHAR: EFECT was an effort to address the issue of what to do for patients who receive nonsteroidal aromatase inhibitors as treatment in the adjuvant or metastatic setting and then develop progressive disease. We want to know if an optimal sequence exists for endocrine therapy.

Other pilot studies suggested that you could switch from a nonsteroidal aromatase inhibitor to fulvestrant, a selective estrogen receptor regulator, and obtain a clinical response. EFECT attempted to rigorously address the issues of which agent to employ in this setting and whether using a loading dose of fulvestrant might lead to a more rapid achievement of steady-state drug levels.

Regarding efficacy, nearly every end-point was superimposable. Whether you compare response rate, time to disease progression or tolerability and adverse events, patients who received either fulvestrant or exemestane had identical outcomes in all of those categories.

The conclusion is that one could legitimately approach a patient who has experienced progression on a nonsteroidal aromatase inhibitor with either one of these agents. It’s not abso-lutely clear whether a superior sequence exists, however.


PROFESSOR JOHN F R ROBERTSON: I believe it is reasonable to consider ovarian suppression in combination with fulvestrant for a premenopausal patient with metastatic breast cancer. Gunter Steger’s work shows response rates in the range that one would expect from an effective endocrine agent. I believe that if you’ve used other, perhaps more estab-lished, options, such as goserelin and tamoxifen or goserelin and anastrozole, and you’re searching for an alternative,

0 10 20 30 40 50 60

0 10 20 30 40 50 60 70 80 90 100

Tamoxifen29%

18%

Fulvestrant48%

49%

Exemestane23%

33%

85%

67%

AI + LHRH agonist or ovarian ablation

AI alone

LHRH agonist or ovarian ablation alone

Fulvestrant + LHRH agonist or ovarian ablation

2%

15%

7%

0%

11%

13%

What would be your most common endocrine treatment recommendation for a postmenopausal patient who experiences a cancer relapse while receiving a nonsteroidal AI and who is not eligible for a clinical trial?

What would be your most common endocrine treatment recommendation for a premenopausal patient who experiences a cancer relapse while receiving adjuvant tamoxifen and who is not eligible for a clinical trial?*

* Those who would recommend endocrine therapy in this situation; CI n = 40; PO n = 89

FIGURE 26

ER+ relapse on AI — Endocrine choice?CLINICAL QUESTION

FIGURE 27

Premenopausal patient with relapse on tamoxifen — Endocrine choice?

CLINICAL QUESTION

CLINICAL INVESTIGATORS (CI)

PRACTICING ONCOLOGISTS (PO)


26 PATTERNS OF CARE

Systemic Therapy for Metastatic Disease (Continued)

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then that’s reasonable for a patient with hormone-sensitive disease.


DR CARLSON: Currently, the use of bevacizumab and paclitaxel in the first-line treatment of metastatic disease is included in the NCCN guidelines as an option. The NCCN panel does not require FDA approval of an agent and a specific indication to incorporate it into the guidelines, nor does FDA approval mean that it is incorporated into the guidelines. The NCCN Breast Cancer Committee to date does not focus specifi-cally on progression-free survival, overall survival or toxicity. It’s more a gestalt or a balance between the experts on the panel in terms of weighing the different advantages.

Breast Cancer Update SABCS Satellite Symposium 2008

DR HUDIS: ECOG-E2100 is the infor-mative study for the question at hand. The trial demonstrated that the addition of bevacizumab to a three-out-of-four-week paclitaxel schedule was associated with a near doubling of progression-free survival, a remarkable increase in response rate and a nonstatistically significant trend in favor of an improve-ment in overall survival.

We have nonrandomized trial data with several of the first-line agents and several of the taxanes. Albumin-bound paclitaxel was studied in a retrospec-tive fashion along with the bevacizumab, suggesting a reasonable response rate of approximately 50 percent.DR G THOMAS BUDD: For a patient with visceral disease who has not received

adjuvant chemotherapy, I would think of a taxane, and I would use bevacizumab. I usually use paclitaxel. I think nab paclitaxel is a perfect alternative — we have safety data with it.

DR GEORGE W SLEDGE JR: A taxane-based regimen with bevacizumab would certainly be my front choice, assuming the insurance paid for it.


PROFESSOR IAN E SMITH: In the United Kingdom, the bevacizumab data haven’t inf luenced the use of capecitabine. I believe capecitabine is a useful drug for metastatic breast cancer for all the obvi-ous reasons.

Women who’ve already experienced relapse after standard adjuvant therapy are demoralized, and the problems of

0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70

Capecitabine Taxane† + bevacizumab

Taxane + bevacizumab

Taxane + other chemotherapy

Taxane alone9%

18%

Taxane + other chemotherapy +

bevacizumab

Taxane + other chemotherapy Taxane alone

Other Other

25%

20%

3%

14%

60%

38%

9%

12%

21%

40%

5%

7%

8%

58%

23%

3%

10%* 17%‡

* AC + bevacizumab = 1%; † CI paclitaxel = 47%, nab paclitaxel = 11%; PO paclitaxel = 15%, nab paclitaxel = 5%, docetaxel = 3%; ‡ AC + bevacizumab = 2%

What would be your most common treatment recommendation for a patient in this clinical situation with HER2-negative metastatic breast cancer, who has received no prior systemic therapy and is not eligible for a clinical trial, with:

FIGURE 28

HER2-negative MBC — Chemo? Bevacizumab?CLINICAL QUESTION

Nonlife-threatening, nonvisceral, minimally symptomatic or asymptomatic MBC

Life-threatening, symptomatic liver metastases



SYSTEM

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TIC D

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returning to all the standard chemother-apy options are obvious. Capecitabine is, by and large, well tolerated.

I believe dose is important. To be technical, the standard dose is 2,500 mg/m2 in divided doses (ie, 1,250 mg/m2 twice a day). That dose can cause a lot of toxicity. MD Anderson published data a few years ago showing outcomes if the dose was reduced a little, to 1,000 mg/m2 twice daily.

This wasn’t a randomized trial — they simply reviewed the data — but the outcome was as good, and the toxicity with capecitabine is dose dependent. We now start patients with a dose of 1,000 mg/m2 twice daily for 14 days, and most people tolerate that well.

We published a study describing a series of patients who received that dose of capecitabine, and I believe the efficacy was similar to what we would see at a higher dose. In adjuvant therapy with curative intent, the dose is crucial. You don’t want to shortchange patients. Once you’re dealing with metastatic disease, it’s a balance.

Obviously, patients want to stay alive, but patients can stay alive using a little dose reduction — it is difficult for me to imagine that a small dose reduction will make a big difference in terms of survival. However, you can see that the lower dose makes a big difference in terms of quality of life.


DR SLEDGE: We launched a multicenter study, XCaliBr, with patients who were similar to the patients from ECOG-E2100. They had HER2-negative breast cancer and were receiving their first chemotherapy for metastatic disease. These patients were treated in a Phase II, single-arm setting, and all received the combination of bevacizumab and capecitabine until progression. At the time of progression, they crossed over and continued to receive bevacizumab with either a taxane — paclitaxel — or vinorelbine.

We have data from the first portion of that trial, and the median progression-

0 10 20 30 40 50 60 70 80

0 10 20 30 40 50 60 70 80

Capecitabine alone or with bevacizumab

Taxane* + bevacizumab



bevacizumab

Taxane alone12%

25%

Taxane + other chemotherapy


bevacizumabTaxane alone

Taxane + other chemotherapy Other

33%

19%

2%

1%

50%

35%

12%

30%

13%

13%

0%

5%

21%

70%

27%

3%

14% 9%†

Other6%

0%

* CI paclitaxel + bevacizumab = 56%, nab paclitaxel + bevacizumab = 14%; PO paclitaxel + bevacizumab = 13%, nab paclitaxel + bevacizumab = 10%, docetaxel + bevacizumab = 4%; † Capecitabine + platinum + bevacizumab = 1%; capecitabine + bevacizumab = 2%

What would be your most common treatment recommendation for a patient in this clinical situation, who received prior adjuvant AC approximately 2 years ago and is not eligible for a clinical trial, with:

FIGURE 29






28 PATTERNS OF CARE


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free survival for patients receiving bevaci-zumab and capecitabine was 5.7 months, which is a disappointing result compared to the 11 months we saw with the com-

bination of paclitaxel/bevacizumab in ECOG-E2100.


DR JOSEPH A SPARANO: For a patient with visceral disease who has received an adjuvant anthracycline, paclitaxel/beva-cizumab would be an appropriate choice. It would be my choice. If bevacizumab were not available, then this is the type of patient for whom I would recommend a couplet that includes a taxane.


DR O’SHAUGHNESSY: When a patient who has previously received an anthracycline and a taxane presents with metastatic visceral disease and needs a response to first-line therapy, I turn to a bevacizumab regimen. I want to use it up front, when the safety is the best, and I want to obtain prolonged progres-

0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70

Capecitabine Taxane* + bevacizumab



bevacizumab

Capecitabine + bevacizumab

10%

6%

Taxane alone or with other

chemotherapy

Taxane alone or with other

chemotherapy

Capecitabine + bevacizumab

Other Other

24%

15%

6%

28%

55%

40%

17%

36%

14%

7%

20%

7%

7%

42%

21%

5%

11% 29%†

* CI paclitaxel + bevacizumab = 26%, nab paclitaxel + bevacizumab = 14%, docetaxel + bevacizumab = 2%; PO paclitaxel + bevacizumab = 6%, nab paclitaxel + bevacizumab = 7%, docetaxel + bevacizumab = 8%; † 13 different chemotherapy regimens

What would be your most common treatment recommendation for a patient in this clinical situation who received prior adjuvant AC paclitaxel approximately 2 years ago and who is not eligible for a clinical trial with:

FIGURE 30


FIGURE 31

AVADO trial: A Phase III randomized study of docetaxel with bevaci-zumab or placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer

Docetaxel + Docetaxel + Docetaxel + placebo bev 7.5 mg/kg bev 15 mg/kg (n = 241) (n = 248) (n = 247)

Median PFS 8 months 8.7 months* 8.8 months†

One-year survival 73% 78% 83%

Bev = bevacizumab* Hazard ratio [95% confidence interval] = 0.79 [0.63-0.98], p = 0.0318† Hazard ratio [95% confidence interval] = 0.72 [0.57-0.90], p = 0.0099

SOURCE: Miles D et al. Proc ASCO 2008;Abstract LBA1011.





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sion-free survival. I don’t have a strong preference between paclitaxel and nab paclitaxel. All things equal, I’d probably use nab paclitaxel with the idea of trying to provide a longer run on the taxane before causing toxicity.


DR ERIC P WINER: Typically, for a patient with triple-negative breast cancer who develops a relapse soon after receiv-ing adjuvant chemotherapy, I would

administer bevacizumab and weekly paclitaxel, with the exception of a patient who had a particularly short disease-free interval (less than one year) and had received a taxane in the adjuvant setting. In that situation, we don’t have a clear answer, and I would be inclined to use another chemotherapeutic agent with bevacizumab. I would pick an agent for which we have toxicity data because from an efficacy standpoint, I don’t believe we can answer the question.

DR SWAIN: I would use paclitaxel and bevacizumab. The patients in ECOG-E2100 who had received adjuvant taxanes were required to have had a disease-free interval of at least 12 months, and they derived a significant benefit from paclitaxel and bevacizumab.DR SLEDGE: Approximately one in five patients entering the trial had received an adjuvant taxane for one year or more in the past. The hazard ratio for those patients was the best hazard ratio of any subgroup in the forest plot, almost as if bevacizumab in that setting is at least partially reversing taxane resistance.

I believe this is a case in which you sit down and discuss the factors with the patient. An 11-month progression-free survival is good in the metastatic setting. I do not see a lot of evidence indicating that we should be using bevacizumab further along. We have no evidence for benefit with this agent for anything other than front-line metastatic breast cancer. If I were going to use bevacizumab, I would use it up front.


DR HUDIS: Until the ECOG-E2100 data were reported, I was consistently choos-ing capecitabine as first-line chemother-apy for patients who have received both an anthracycline and a taxane as adju-vant therapy. In ECOG-E2100, the delta gain and the point estimates with bevaci-zumab were similar for the patients who were pretreated and those who were not. If patients have completed more than a six-month or a one-year interval from their adjuvant taxane, I’m comfortable — if they’re tolerant of the toxicity — resuming it and using bevacizumab.


DR HUDIS: In an effort to address the question of which chemotherapy to combine with bevacizumab in the meta-static setting, the CALGB has proposed a trial evaluating first-line therapy with bevacizumab in combination with paclitaxel, nab palcitaxel or ixabepilone. Hope Rugo is a principal investigator

0 10 20 30 40 50

101%

0%

3

4

2

5%

19%

28%

29%

6%

610%

0%

21%

537%

31%

73%

2%

81%

7%

90%

0%

Mean 5.1 4.4

Median 5.0 4.0

Approximately how many total lines of chemotherapy were received by the last 5 patients you treated who died of metastatic breast cancer (average of the 5 patients)?

FIGURE 32




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of this prospective, randomized, Phase III trial along with Alvaro Moreno from the NCCTG. They proposed a Phase II randomized trial of ixabepilone versus paclitaxel in combination with bevaci-zumab. We proposed a Phase III trial of weekly paclitaxel versus nab paclitaxel. CTEP asked us to collaborate and join these two studies.

Weekly paclitaxel, for three weeks out of four, with bevacizumab is the control

regimen. The two experimental arms administer weekly ixabepilone or weekly nab paclitaxel, both with bevacizumab. Significant correlative science studies are also built into the study. The cooperative groups wrote the study with progression-free survival as an endpoint. However, FDA-related discussions are ongoing as to whether or not this study will be ade-quate for drug approval and, therefore, how we should move forward.


DR O’SHAUGHNESSY: The trial compar-ing bevacizumab in combination with ixabepilone, paclitaxel or nab paclitaxel is a great study. I believe the dose of each agent is optimized. It may be difficult to discern large differences in efficacy with those three agents combined with beva-cizumab, because I believe bevacizumab will enhance the activity of all of them. The issue will be toxicity, which I believe may be similar with nab paclitaxel and weekly paclitaxel with regard to neurop-athy, because the dose of nab paclitaxel is being pushed.


DR MILLER: Investigators and clinicians have posed important questions that are not being addressed in clinical trials. One question relates to the continuation of bevacizumab in breast cancer, which we’ve thought to be important for several years. Unfortunately, it is not a trial that the NCI is inclined to support.

For three years now, we’ve heard talk about it and assurance that there is interest, and they’ve been calling it the RIBBON 3 trial. Three years later, there is no final design for the trial and it’s not moving forward. Yet some are inclined to use bevacizumab the way trastuzumab is used.

This brings us to the colon can-cer trial, the BRiTE registry and using bevacizumab beyond disease progres-sion. People tend to refer to the BRiTE registry as if it were a randomized trial. However, it is important to acknowledge the difference.

One issue with extrapolating the colon cancer data is that the patients were selected, suggesting a certain degree of bias. The registry is essentially a col-lection of 2,000 anecdotes. It doesn’t tell us much, except that in the absence of data this is what we have to go by. People see the differences, and the message that they take away from it is, look at this difference in overall survival with beva-cizumab beyond progression. But these are not concrete data, and I still think it’s a crucial issue that needs to be addressed by a randomized trial.

0 10 20 30 40 50

Yes, sometimes


Yes, rarely

30%

42%

9%

15%

35%

24%

No26%

19%

SOURCES: Personal communication. Clifford Hudis, MD, 2007; Interview. O’Shaughnessy J. December 2007.

Paclitaxel qwk + bevacizumab

Nab paclitaxel qwk + bevacizumabR

Ixabepilone qwk + bevacizumab

For a patient who receives chemotherapy and bevacizumab for MBC with a response for approximately 6 months and subsequently develops toxicity from the chemotherapy requiring cessation of chemotherapy, would you continue the bevacizumab alone?

FIGURE 33

HER2-negative MBC with response to chemo/bev but chemo stopped from toxicity — Continuation of bev alone?

CLINICAL QUESTION

Proposed randomized trial of chemotherapy/bevacizumab as first-line treatment for metastatic breast cancer

FIGURE 34



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DR ROBERT: The opportunity to study HER2-based regimens generation after generation, or on different lines, is prob-

ably closed. However, perhaps we can develop bevacizumab in a more responsi-ble way. I support the idea of a RIBBON 3 trial and maybe even a RIBBON 4 trial.

In individualizing care, I would be

tempted to continue bevacizumab for some patients, if money were not an issue. However, to date I have not done so, partly because of the reimbursement issue but also because we don’t have enough data to push me to do so.


DR HOWARD A BURRIS III: The decision whether to continue bevacizumab upon progression is difficult. I see more and more patients who have finished weekly paclitaxel and bevacizumab, and they’re being treated with maintenance bevaci-zumab. If they’re feeling well and their disease is gradually regrowing, I continue bevacizumab and add a second drug. For patients who clearly aren’t benefiting or are fighting the toxicity, it’s easy to think about discontinuing bevacizumab. In general, however, it’s been well tolerated.

DR HAROLD J BURSTEIN: I believe continuing bevacizumab after progres-sion is not a great strategy. We all lapsed into this behavior with trastuzumab, which perhaps was correct or perhaps was incorrect. Considering the concerns about some of bevacizumab’s side effects, the absolute unknowns about its role and the fact that we have a negative study in the second-line setting, it’s hard to believe that a huge clinical advantage exists for continuing bevacizumab.

DR SLAMON: If we had a way to identify a patient who was responding to bevaci-zumab, we’d have little doubt that stay-ing with the agent and adding another drug later would also continue to benefit the patient, as it has with trastuzumab. We don’t have hard data, but that’s what I would do clinically. These drugs are safe, and we know the toxicities. We can administer them safely, and I believe they should be used.


DR GRALOW: Trastuzumab is a large monoclonal antibody that shouldn’t be able to cross the intact blood-brain barrier. However, some anecdotal case reports indicate that once you have a large metastasis that disrupts the blood-

0 10 20 30 40 50 60 70 80

0 10 20 30 40 50 60 70 80

Somewhat likely

Very likely

Not very likely

26%

37%

0%

12%

72%

44%

Not at all likely2%

7%

Yes, sometimes


Yes, rarely

21%

41%

12%

18%

9%

17%

No58%

24%

For a patient who receives chemotherapy and bevacizumab for MBC with a response for approximately 12 months but then develops gradual tumor progression, would you continue the bevacizumab (with another chemo-therapy agent)?

How likely would you be to enroll a patient in this situation onto a clinical trial that randomly assigns patients to continuation of bevacizumab versus no further bevacizumab?

FIGURE 35

HER2-negative MBC with response to chemo/bev then progression — Continuation of bev with other chemo?

CLINICAL QUESTION



32 PATTERNS OF CARE


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tinib alone has not produced much of a response. It’s making a dent, but it doesn’t meet the classic response criteria.

When patients on those studies experienced disease progression or no response on lapatinib, capecitabine was added and quite a few responses then met conventional criteria. Whether it was the combination of capecitabine/lapatinib or the capecitabine alone, I’m not sure.

I’m also tantalized by evidence in the Phase III trial of capecitabine/lapatinib versus capecitabine, which indicated a numerical trend toward fewer brain metastases with lapatinib.


DR GEYER: Some studies suggest that a substantial proportion of the patients who die from HER2-positive breast cancer are probably dying in part from uncontrolled CNS disease. The hope is that lapatinib, being a small mole-cule, will penetrate. Some studies have evaluated lapatinib in heavily pretreated patients with brain metastases, and they did see activity, but it didn’t meet the study criteria they were hoping for — it’s a tough population.

In our trial comparing capecitabine with or without lapatinib in women with advanced breast cancer who pro-gressed on trastuzumab, 13 patients on capecitabine alone developed symp-tomatic CNS disease as part of their first site of progression, whereas only four patients on the combination did so, which I believe is a notable result.

I see clinicians struggle with what to do when a patient is well systemically on trastuzumab and then develops brain metastases. Do you switch to lapatinib? Do you add lapatinib? A number of cli-nicians choose the combination, but do they know that when they do so, they have to use a lower dose of lapatinib to make it tolerable with trastuzumab? The question is, if we lower the dose of lapatinib, do we know if it is reaching the brain? We don’t have the answer, so I have concerns about the combination.

brain barrier, you can obtain tumor shrinkage with trastuzumab.

Lapatinib certainly penetrates the blood-brain barrier, and we have some anecdotal evidence suggesting that we can achieve tumor shrinkage with lapa-tinib alone. Nancy Lin and the group

at Dana-Farber have conducted elegant studies for patients with HER2-positive brain metastases who received radiation therapy and whose disease was progress-ing. They added lapatinib as a single agent.

Using conventional measures, lapa-

0 10 20 30 40 50 60 70 80 90 100

0 10 20 30 40 50 60 70 80 90 100

Trastuzumab or lapatinib (equal choices)

7%

17%

Lapatinib

Other0%

3%

63%

56%

Trastuzumab30%

24%


7%

8%

Trastuzumab

Lapatinib2%

4%

91%

88%

What would be your most common anti-HER2 treatment recommendation for a patient with HER2-positive MBC who has multiple asymptomatic brain metastases and is not eligible for a clinical trial?

CI n = 43; PO n = 99

What would be your most common anti-HER2 treatment recommendation for a patient with HER2-positive MBC who has not received prior anti-HER2 treatment and is not eligible for a clinical trial?

FIGURE 36

HER2+ MBC (no prior Rx) — Anti-HER2 agent?CLINICAL QUESTION



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we were active participants in NCCTG-N9831. Perhaps the window of relapse will be early, and it may plateau later on. Or maybe some of these patients who have not experienced a relapse never will — that would be wonderful.

The major concern is that we have no idea what prior trastuzumab will mean in this situation. I am not sure what these artificial boundaries of six, 12 or 24 months mean, but at some point you need to draw the line. I believe that if someone has an immediate relapse within the first year after trastuzumab, I would be more nervous about attempt-ing to use a trastuzumab-containing reg-imen and may proceed to lapatinib. But again, we are making artificial decisions.


DR SLAMON: If a patient has received a trastuzumab regimen and has experi-enced a relapse quickly — within a year after receiving adjuvant trastuzumab — I consider an alternative targeting agent such as lapatinib.

If a year, 18 months or more has passed, I consider using trastuzumab with another therapeutic agent — vinorelbine or gemcitabine. A number of agents can be used while still on trastuzumab.


DR WINER: A patient who develops a recurrence while receiving or soon after receiving a combination of adju-vant trastuzumab and chemotherapy, in my mind, is no different from the patient who, in the metastatic setting, has received a first-line regimen of trastuzumab and paclitaxel or docetaxel, and you’re considering a second-line regi-men.

Capecitabine and lapatinib would be my choice for patients who experi-ence relapse during adjuvant therapy. For a patient who has a cancer relapse three years after receiving adjuvant trastuzumab, I would probably re-treat with trastuzumab.

At this point the patient’s disease is likely to be sensitive to trastuzumab, so I would not approach this situation


DR ANTONIO C WOLFF: I’m surprised

that, thus far, I haven’t had any patients who have experienced a cancer relapse after receiving adjuvant trastuzumab, and

0 10 20 30 40 50 60 70

0 10 20 30 40 50 60 70

3-6 months24%

59%

1-3 months12%

7%

3-6 months ago20%

32%

1-3 months ago7%

4%

9-12 months54%

31%

10%

3%

24%

12%

49%

52%9-12 months ago

12 months ago

24-50 months

For a patient with HER2-positive MBC who has received prior adjuvant trastuzumab, I generally recommend lapatinib if the patient completed trastuzumab within the last:*

* CI n = 41; PO n = 96 who would recommend lapatinib in this situation

For patients in this situation, I generally recommend trastuzumab again if the trastuzumab was completed more than:†

† CI n = 41; PO n = 96

FIGURE 37

HER2+ MBC (prior adjuvant trastuzumab) — Choice of anti-HER2 agent

CLINICAL QUESTION



34 PATTERNS OF CARE


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much differently than I would approach a patient who presents with de novo HER2-positive disease.

SELECT PUBLICATIONS

Cameron D et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: Updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008;[Epub ahead of print]. Abstract

Chia S et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: Results from EFECT. J Clin Oncol 2008;26(10):1664-70. Abstract

Geyer CE et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355(26):2733-43. Abstract

Grothey A et al. Association between exposure to bevacizumab (BV) beyond first progression (BBP) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Results from a large observational study (BRiTE). Proc ASCO 2007;Abstract 4036.

Hennessy BT et al. Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: Retrospective analysis of patients treated at MD Anderson Cancer Center and a review of capecitabine toxicity in the literature. Ann Oncol 2005;16(8):1289-96. Abstract

Lin NU et al. EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER2+ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy. Proc ASCO 2007;Abstract 1012.

Link JS et al. Bevacizumab and albumin-bound paclitaxel treatment in metastatic breast cancer. Proc ASCO 2007;Abstract 1101.

Miller K et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357(26):2666-76. Abstract

Miller K et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: A trial coordinated by the Eastern Cooperative Oncology Group (E2100). San Antonio Breast Cancer Symposium 2005;Abstract 3.

Perez EA et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 2008;26(8):1231-8. No abstract available

Sugrue MM et al. Safety and effectiveness of bevacizumab plus chemotherapy in elderly patients with mCRC: Results from the BRiTE registry. Proc ASCO 2006;Abstract 3537.

Yap YS et al. Clinical efficacy of capecitabine as first-line chemotherapy in metastatic breast cancer — How low can you go? The Breast 2007;16(4):420-4. Abstract

0 10 20 30 40 50 60 70 80

0 10 20 30 40 50 60 70

Trastuzumab14%

19%

Lapatinib


23%

14%

67%

63%

Endocrine therapy alone or with chemo

Endocrine therapy and trastuzumab*

Trastuzumab, chemo and endocrine therapy*

28%

18%

5%

12%

60%

39%

Trastuzumab alone or with chemo*

7%

31%

What would be your most common anti-HER2 treatment recommendation for a patient who develops progressive MBC while receiving trastuzumab maintenance after trastuzumab with chemotherapy as first-line therapy for MBC and who is not eligible for a clinical trial?

What would be your most common treatment recommendation for a patient with asymptomatic, nonvisceral, ER-positive, HER2-positive MBC who has received no prior anti-HER2 therapy and who is not eligible for a clinical trial?

* Either combination or in sequence

FIGURE 38

HER2+ metastatic breast cancer (MBC) with progression on trastuzumab — Anti-HER2 agent?

CLINICAL QUESTION

FIGURE 39

ER+, HER2+ asymptomatic MBC — Systemic therapy? CLINICAL QUESTION



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EDUCATIONAL ASSESSMENT AND CREDIT FORM: Patterns of Care 2008 . Vol 5 . Issue 1

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AS A RESULT OF THIS ACTIVITY, I WILL:

• Compare management strategies of community oncologists and cancer clinical investigators in the adjuvant and metastatic settings, and apply relevant information to the treatment of patients with breast cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3 2 1 N/M N/A

• Evaluate management issues for patients with cancer for which relative agreement and heterogeneity exist in patterns of care, and make treatment decisions considering this information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3 2 1 N/M N/A

• Counsel patients with cancer about multiple acceptable treatment options when they exist. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3 2 1 N/M N/A

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What additional information or training do you need on the activity topics or other oncology-related topics?

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PART ONE — Please tell us about your experience with this educational activity


36 PATTERNS OF CARE

EDUCATIONAL ASSESSMENT AND CREDIT FORM (continued)

To what extent do you feel the faculty members’ comments were helpful or not helpful?

Please be as specific as possible about individual faculty.

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Please recommend additional faculty for future activities:

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Other comments about the faculty for this activity:

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Please Print Clearly

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Degree:

MD PharmD NP BS DO RN PA Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Medical License/ME Number.:. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Last 4 Digits of SSN (required): . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Street Address: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Box/Suite:. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Telephone: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fax:. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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PART TWO — Please tell us about the faculty for this educational activity

REQUEST FOR CREDIT — Please print clearly


of Carein Medical Oncology

Patterns EDITOR Neil Love, MD

FACULTY Kathy D Miller, MD Hyman B Muss, MD

MANAGING EDITOR Kathryn Ault Ziel, PhD

CONTRIBUTING EDITOR Melanie Elder

SCIENTIFIC DIRECTOR Richard Kaderman, PhD

WRITERS Lilliam Sklaver Poltorack, PharmD Douglas Paley

CONTINUING EDUCATION ADMINISTRATOR FOR NURSING Sally Bogert, RNC, WHCNP

CONTENT VALIDATION Margaret Peng Erin Wall Clayton Campbell

DIRECTOR, CREATIVE AND COPY EDITING Aura Herrmann

CREATIVE MANAGER Fernando Rendina

GRAPHIC DESIGNERS Jessica Benitez Jason Cunnius Tamara Dabney Claudia Munoz

SENIOR PRODUCTION EDITOR Alexis Oneca

TRAFFIC MANAGER Tere Sosa

COPY EDITORS Dave Amber Margo Harris David Hill Rosemary Hulce Kirsten Miller Pat Morrissey/Havlin Carol Peschke Susan Petrone

PRODUCTION MANAGER Tracy Potter

AUDIO PRODUCTION Frank Cesarano

WEB MASTER John Ribeiro

FACULTY RELATIONS MANAGER Melissa Vives

CME DIRECTOR/CPD DIRECTOR Isabelle Tate

CONTACT INFORMATION Neil Love, MD

Research To Practice One Biscayne Tower 2 South Biscayne Boulevard, Suite 3600 Miami, FL 33131

Fax: (305) 377-9998 Email: [email protected]

FOR CME/CNE INFORMATION Email: [email protected]

The printed material and associ-ated Internet content are protected by copyright. No part of this program may be reproduced or transmit ted in any form or by any means, electronic or mechan-ical, including photocopying, recording or utilizing any information storage and retrieval system, without writ ten permis-sion from the copyright owner.

The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Participants have an implied responsi-bility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management.

Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contrain-dications or dangers in use, review of any applicable manufacturer’s product informa-tion and comparison with recommendations of other authorities.

Copyright © 2008 Research To Practice. All rights reserved.


CMECertified

FROM THE PUBLISHERS OF:

2008 . Vol 5 . Issue 1

PRSRT STD U.S. POSTAGE

PAID MIAMI, FL

PERMIT #1317

Sponsored by Research To Practice.

Last review date: June 2008 Release date: June 2008

Expiration date: June 2009 Estimated time to complete: 3 hours

Management of Breast Cancer in the Adjuvant and Metastatic Settings

Editor Neil Love, MD

Faculty Kathy D Miller, MD

Hyman B Muss, MD

A Survey Comparing Practices of Breast Cancer Investigators and General Oncologists

Copyright © 2008 Research To Practice. This program is supported by educational grants

from Abraxis BioScience, AstraZeneca Pharmaceuticals LP, Genentech BioOncology, Genomic Health Inc and Sanofi-Aventis.


Documents

Management of Breast Cancer in the Adjuvant and Metastatic ...John Carpenter, MD Professor of Medicine Division of Hematology/Oncology University of Alabama at Birmingham Birmingham,