December 2012 Volume 1, Number 6

The official publication of

December 2012 Volume 1 • Number 6 A Peer-Reviewed Journal

PM O

PERSONALIZED MEDICINE IN ONCOLOGY TM

INTERVIEW WITH THE INNOVATORS Lynch Syndrome: An Interview With the Father of Hereditary Cancer Detection and Prevention, Henry T. Lynch, MD.......................................Page 18

COLORECTAL CANCER KRAS and Colorectal Cancer: Shades of Gray............................................. Page 22

HEALTHCARE ECONOMICS Institute of Medicine Report: Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Highlights for the Cancer Community................................................... Page 32

MELANOMA The New Therapeutic Paradigm for Personalized Therapy of Melanoma....................................Page 36

ALSO IN THIS ISSUE… • The Last Word by Robert E. Henry................ Page 44

IMPLEMENTING THE PROMISE OF PROGNOSTIC PRECISION INTO PERSONALIZED CANCER CARE

TM

www.PersonalizedMedOnc.com © 2012 Green Hill Healthcare Communications, LLC

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T

he Global Biomarkers Consortium™ (GBC) is a community of worldrenowned healthcare professionals who will convene in multiple educational forums in order to better understand the clinical application of predictive molecular biomarkers and advanced personalized care for patients.

PM O

December 2012 Volume 1 • Number 6

PERSONALIZED MEDICINE IN ONCOLOGY ™

CONFERENCE NEWS News from ASH, ASTRO, and the San Antonio Breast Cancer Symposium

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Ibrutinib: Proof of Concept Pays Off Two Studies Show That Radiation Extends Survival in Elderly Women With Early-Stage Breast Cancer

Save the date for the Second Annual Conference, October 4-6, 2013 Visit www.globalbiomarkersconsortium.com to register

Newer More Costly Radiation Technologies Adopted in the Elderly Memantine Delays Cognitive Decline in Patients With Brain Metastases Treated With Whole-Brain Radiation Stereotactic Body Radiation Therapy Is Effective, Cost Saving, and Convenient for Patients With Prostate Cancer Activating HER2 Mutations Found in HER2-Negative Patients

Professional Experience of GBC Attendees 56.7%

26.7%

Genetic Targets Identified in Triple-Negative Breast Cancer

INTERVIEW WITH THE INNOVATORS Lynch Syndrome: An Interview With the Father of Hereditary Cancer Detection and Prevention, PAGE 18 Henry T. Lynch, MD PMO talks with the director of the Creighton Cancer Center about the events that led to the discovery of Lynch syndrome, implications of genetic cancers, and his vision for improving care to this patient population.

6.7% 3.3%

COLORECTAL CANCER

6.7%

1-3 years

KRAS and Colorectal Cancer: Shades of Gray

3-5 years

Chloe E. Atreya, MD, PhD; Jonathan M. Ostrem, BS, MD, PhD Candidate; Robin K. Kelley, MD

5-10 years 10-20 years >20 years

Volume 1 • No 6

PAGE 22

The authors place differences between KRAS mutations at codon 12 and 13 in colorectal cancer into scientific and clinical contexts as well as address the potential implications of nonequivalent mutations within the same gene for the pursuit of personalized medicine in oncology.

WWW.PERSONALIZEDMEDONC.COM

December 2012

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PUBLISHING STAFF SENIOR VICE PRESIDENT, SALES AND MARKETING Philip Pawelko phil@greenhillhc.com PUBLISHERS John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com DIRECTOR, CLIENT SERVICES Lou Lesperance Jr lou@greenhillhc.com MANAGING DIRECTOR Pam Rattananont Ferris

Institute of Medicine Report: Best Care at Lower Cost: The Path to Continuously Learning Health Care in America.

Highlights for the Cancer Community

STRATEGIC EDITOR Robert E. Henry SENIOR COPY EDITOR BJ Hansen

PAGE 32

James Conway

PRODUCTION MANAGER Marie RS Borrelli QUALITY CONTROL DIRECTOR Barbara Marino BUSINESS MANAGER Blanche Marchitto

A summary of the Institute of Medicine report identifying how the effectiveness and efficiency of the current healthcare system can be transformed.

MELANOMA The New Therapeutic Paradigm for Personalized Therapy of Melanoma

CIRCULATION DEPARTMENT circulation@greenhillhc.com Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician.

Please convey any errors to the editorial director.

Volume 1 • No 6

PERSONALIZED MEDICINE IN ONCOLOGY ™

HEALTHCARE ECONOMICS

EDITORIAL DIRECTOR Kristin Siyahian kristin@greenhillhc.com

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Sanjiv Agarwala, MD A report from the 2012 conference of the Global Biomarkers Consortium.

THE LAST WORD Companion Diagnostics and the Paradoxical Return of the Blockbuster Drug

PAGE 44

Robert E. Henry If personalized medicine in cancer care is incompatible with blockbuster drugs, could this spell the collapse of the pharmaceutical/biologicals industry?

OUR MISSION The mission of Personalized Medicine in Oncology is to deliver practice-changing information to clinicians about customizing healthcare based on molecular profiling technologies, each patient’s unique genetic blueprint, and their specific, individual psychosocial profile, preferences, and circumstances relevant to the process of care.

OUR VISION Our vision is to transform the current medical model into a new model of personalized care, where decisions and practices are tailored for the individual – beginning with an incremental integration of personalized techniques into the conventional practice paradigm currently in place.

PERSONALIZED MEDICINE

IN

ONCOLOGY

December 2012

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Editorial Board Editor in Chief AL B. BENSON III, MD Northwestern University Chicago, Illinois

SECTION EDITORS Breast Cancer EDITH PEREZ, MD Mayo Clinic Jacksonville, Florida

Gastrointestinal Cancer EUNICE KWAK, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts

Drug Development IGOR PUZANOV, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee

Hematologic Malignancies GAUTAM BORTHAKUR, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Lung Cancer VINCENT A. MILLER, MD Foundation Medicine Cambridge, Massachusetts

Pathology DAVID L. RIMM, MD, PHD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut

Melanoma DOUG SCHWARTZENTRUBER, MD Indiana University Simon Cancer Center Indianapolis, Indiana

Predictive Modeling MICHAEL KATTAN, PHD Case Western Reserve University Cleveland, Ohio

Prostate Cancer OLIVER SARTOR, MD Tulane University New Orleans, Louisiana

EDITORIAL BOARD SANJIV S. AGARWALA, MD St. Luke’s Hospital Bethlehem, Pennsylvania

K. PETER HIRTH, PHD Plexxikon, Inc. Berkeley, California

HOPE S. RUGO, MD University of California, San Francisco San Francisco, California

GREGORY D. AYERS, MS Vanderbilt University School of Medicine Nashville, Tennessee

HOWARD L. KAUFMAN, MD Rush University Chicago, Illinois

DANIELLE SCELFO, MHSA Genomic Health Redwood City, California

LYUDMILA BAZHENOVA, MD University of California, San Diego San Diego, California

KATIE KELLEY, MD UCSF School of Medicine San Francisco, California

LEE SCHWARTZBERG, MD The West Clinic Memphis, Tennessee

LEIF BERGSAGEL, MD Mayo Clinic Scottsdale, Arizona

MINETTA LIU, MD Georgetown University Hospital Washington, DC

JOHN SHAUGHNESSY, PHD University of Arkansas for Medical Sciences Little Rock, Arkansas

KENNETH BLOOM, MD Clarient Inc. Aliso Viejo, California

KIM MARGOLIN, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington

LAWRENCE N. SHULMAN, MD Dana-Farber Cancer Institute Boston, Massachusetts

MARK S. BOGUSKI, MD, PHD Harvard Medical School Boston, Massachusetts GILBERTO CASTRO, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil MADELEINE DUVIC, MD The University of Texas MD Anderson Cancer Center Houston, Texas

STEVEN D. GORE, MD The Johns Hopkins University School of Medicine Baltimore, Maryland

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AFSANEH MOTAMED-KHORASANI, PHD Radient Pharmaceuticals Tustin, California NIKHIL C. MUNSHI, MD Dana-Farber Cancer Institute Boston, Massachusetts

BETH FAIMAN, PHD(C), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio STEPHEN GATELY, MD TGen Drug Development (TD2) Scottsdale, Arizona

GENE MORSE, PHARMD University at Buffalo Buffalo, New York

JAMIE SHUTTER, MD South Beach Medical Consultants, LLC Miami Beach, Florida DARREN SIGAL, MD Scripps Clinic Medical Group San Diego, California DAVID SPIGEL, MD Sarah Cannon Research Institute Nashville, Tennessee MOSHE TALPAZ, MD University of Michigan Medical Center Ann Arbor, Michigan

STEVEN O’DAY, MD John Wayne Cancer Institute Santa Monica, California

SHEILA D. WALCOFF, JD Goldbug Strategies, LLC Rockville, Maryland

DAVID A. PROIA, PHD Synta Pharmaceuticals Lexington, Massachusetts

ANAS YOUNES, MD The University of Texas MD Anderson Cancer Center Houston, Texas

RAFAEL ROSELL, MD, PHD Catalan Institute of Oncology Barcelona, Spain STEVEN T. ROSEN, MD, FACP Northwestern University Chicago, Illinois

PERSONALIZED MEDICINE

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December 2012

Tumor Invasion and Metastasis Co-Chairpersons: Zena Werb and Bruce R. Zetter January 20-23, 2013 • San Diego, CA Ninth AACR-Japanese Cancer Association Joint Conference: Breakthroughs in Basic and Translational Cancer Research Co-Chairpersons: Tyler Jacks and Kohei Miyazono February 21-25, 2013 • Maui, HI Joint AACR-Society of Nuclear Medicine and Molecular Imaging Conference: State-of-the-Art Molecular Imaging in Cancer Biology and Therapy Co-Chairpersons: Carolyn J. Anderson and David Piwnica-Worms February 27-March 2, 2013 • San Diego, CA AACR Annual Meeting 2013 Chairperson: José Baselga April 6-10, 2013 • Washington, DC Synthetic Lethal Approaches to Cancer Vulnerabilities Co-Chairpersons: William C. Hahn, Sebastian Nijman, and Louis M. Staudt May 17-20, 2013 • Bellevue, WA Chromatin and Epigenetics in Cancer Co-Chairpersons: Suzanne J. Baker, Charles W.M. Roberts, and Gerald R. Crabtree June 19-22, 2013 • Atlanta, GA Frontiers in Basic Cancer Research Chairperson: Scott W. Lowe Co-Chairpersons: Joan S. Brugge, Hans Clevers, Carol L. Prives, and Davide Ruggero September 18-22, 2013 • National Harbor, MD

Advances in Ovarian Cancer Research: From Concept to Clinic Co-Chairpersons: David G. Huntsman, Douglas A. Levine, and Sandra Orsulic September 18-21, 2013 • Miami, FL Advances in Breast Cancer Research Co-Chairpersons: Carlos L. Arteaga, Jeffrey M. Rosen, Jane E. Visvader, and Douglas Yee October 3-6, 2013 • San Diego, CA AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Co-Chairpersons: Jeffrey A. Engelman, James H. Doroshow, and Sabine Tejpar October 19-23, 2013 • Boston, MA Twelfth Annual International Conference on Frontiers in Cancer Prevention Research Chairperson: Paul J. Limburg October 27-30, 2013 • National Harbor, MD Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes Co-Chairpersons: John M. Maris, Stella M. Davies, James R. Downing, Lee J. Helman, and Michael B. Kastan November 3-6, 2013 • San Diego, CA The Translational Impact of Model Organisms in Cancer Co-Chairpersons: Cory Abate-Shen, A. Thomas Look, and Terry A. Van Dyke November 5-8, 2013 • San Diego, CA CTRC-AACR San Antonio Breast Cancer Symposium Co-Directors: Carlos L. Arteaga, C. Kent Osborne, and Peter M. Ravdin December 10-14, 2013 • San Antonio, TX

AACR EDUCATIONAL WORKSHOPS Accelerating Anticancer Agent Development and Validation Co-Chairpersons: H. Kim Lyerly and Richard Pazdur May 8-10, 2013 Bethesda, MD

NEW! Integrative Molecular Cancer Epidemiology Director: Thomas A. Sellers; Co-Directors: Peter L. Kraft and Margaret R. Spitz July 15-20, 2013 Boston, MA

Molecular Biology in Clinical Oncology Co-Directors: William G. Kaelin Jr., Mark Geraci, and Suzanne Topalian July 21-28, 2013 Snowmass, CO

ASCO/AACR Methods in Clinical Cancer Research Co-Directors: Jamie H. von Roenn, Neal J. Meropol, and Mithat Gönen July 27-August 2, 2013 Vail, CO

Translational Research for Basic Scientists Co-Directors: Tom Curran, George D. Demetri, and Pasi A. Jänne Fall 2013 Boston, MA

www.aacr.org/Workshops2013

Letter From the Board

PMO: Exploring the New Frontier of Personalizing Cancer Care Dear Colleague,

I

n the new era of personalizing cancer care, a vital issue is raised: the assumption that personalized medicine will be too costly to be part of the healthcare landscape. The content of Personalized Medicine in Oncology (PMO) explores personalized medicine as a frontier – one that, with resourceful exploration and problem solving, can deliver value and not just quality, placing therapeutics within the economic reach of a cost-strained healthcare system. But personalized medicine does not run itself. It is a strategy in perpetual search of new tactics that support its quality with value: healthcare’s “Iron Triangle” of cost, quality, and access.

Doug Payers fear that cancer therapies will pose an unsustainable cost burden. This Schwartzentruber, MD is based in part on a long history of cancer drug usage based solely on populationbased evidence. PMO exists to help oncologists cultivate tactical, value-based approaches to cancer treatments and to integrate them into the full constellation of personalized medicine techniques. We are dedicated to the proposition that new life-saving technologies need not be prohibitively expensive, provided they are used skillfully. Conversely, misuse or overuse of cancer therapies would ensure their extinction. Techniques appropriate to the pretargeted drug era must be supplanted with new ones, for targeted therapies are not just novel: they are game-changing interventions altering the very culture of cancer care whose rules of engagement must be learned, and quickly.

Chemotherapy regimens relied on population-based research suggesting only potential effectiveness, making aggressive but uninformed usage customary and even appropriate in the absence of anything better to offer a dying patient. But such a “frontal attack” strategy is ill suited to targeted therapies and diagnostics and invites payer obstruction, placing unlucky patients in the middle of stakeholder stalemate. Payers are keenly aware that treatment may turn an acute condition into a chronic one, incurring care measured in years rather than weeks or months. Such care must be accurate to justify its expense. We help achieve this goal by bringing the knowledge that replaces frontal-attack drug usage with a sensitive process of patient selection that heals while retaining value, now the defining characteristic of healthcare dynamics.

PMO delivers expert opinion and insight on research breakthroughs and their tactical management via an enriched patient population. This knowledge can transform strategy into practice and turn cost into value. It empowers the iterative process of personalized medicine with techniques that reduce chance and ensure that appropriate treatments reach patients capable of responding to them. This will deliver the value that payers demand and the quality that providers and their patients seek.

We will continue to inform oncologists on the essential “how” of cancer therapies and diagnostics and hope this mission of translational personalized medicine brings the fruits of medicine’s finest research into play.

Sincerely,

Doug Schwartzentruber, MD

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PERSONALIZED MEDICINE

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December 2012

THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS

AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013

Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

PROGRAM OVERVIEW Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

10:30 am - 11:45 am

Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Roy A. Beveridge, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

Session 3: Cost of Cure: When, How, and How Much?

John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

Session 4: Where Is Oncology Care Headed in the Future?

Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery.

• Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered.

• Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively.

• Examine the current trends in personalized care and companion diagnostics.

• Analyze the patient issues around cost, quality, and access to care.

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015?

Linda Bosserman, MD, FACP; John D. Sprandio, MD

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm

Session 7: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

TARGET AUDIENCE

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

SATURDAY, MAY 4, 2013 7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

DESIGNATION OF CREDIT STATEMENTS

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 8: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD Thomas J. Smith, MD, FACP, FASCO

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

LEARNING OBJECTIVES

SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, the Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT

10:00 am - 10:15 am

Break

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

SUNDAY, MAY 5, 2013 7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Large Oncology Group Practices—Successes, Issues, and Challenges

11:45 am - 12:00 pm

Summary and Conclusion of Conference

CONFERENCE REGISTRATION Discounted Pricing Available!

$375.00 until January 15, 2013 $475.00 until March 15, 2013 $675.00 after March 15, 2013

REGISTER TODAY AT

www.regonline.com/avbcc2013

*Agenda is subject to change.

2012 ASH Annual Meeting

Ibrutinib: Proof of Concept Pays Off Phoebe Starr

I

brutinib as a single agent and in combination with rituximab achieved unprecedented response rates in studies of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) presented at the 54th Annual Meeting of the American Society of Hematology (ASH). The drug is being studied in several B-cell malignancies, including CLL/small lymphocytic leukemia (SLL), relapsed/refractory MCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and multiple myeloma. The drug is under development by Pharmacyclics and Janssen Biotech, Inc. Ibrutinib is an investigational Bruton’s tyrosine kinase (BTK) inhibitor. BTK is a key mediator of at least 3 critical B-cell prosurvival mechanisms: regulating B-cell apoptosis, cell adhesion, and lymphocyte migration and homing.

“Ibrutinib is the molecule of the year. This agent represents a revolution in the treatment of lymphomas,” stated Martin Dreyling, professor at the University of Munich in Germany and a lymphoma expert. He cited 2 studies of ibrutinib at ASH as potentially practice changing. One was a study in relapsed/refractory MCL (Abstract 904), and the other was a study in DLBCL (Abstract 686).

The first study was a phase 2 trial in 115 patients (65 bortezomib naive and 50 bortezomib exposed) with relapsed/refractory MCL. Median number of previous treatments was 3. In these difficult-to-treat patients, ibrutinib achieved an overall response rate (ORR) of 70% and a complete response rate of 20%, which increased to 50% at 14 months. Lead author of the study was Michael Wang, MD, from MD Anderson Cancer Center in Houston, TX. A pivotal study of relapsed and refractory MCL following bortezomib treatment has been initiated. At next year’s ASH, Wang is expected to present results of a study of ibrutinib as first-line therapy for MCL. Moving on to the study of 70 patients with relapsed DLBCL presented by Wyndham Wilson, MD, National Cancer Institute in Bethesda, MD, treatment with ibrutinib achieved an ORR of about 28%. However, when

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patients were stratified according to genetic expression, response rates in activated B-cell–like (ABC) DLBCL were 40% (this group has the worst prognosis), and in germinal center B-cell–like DLBCL, 5.3%.

These results in the ABC subgroup of relapsed DLBCL patients are considered unprecedented. Wilson and colleagues concluded that future clinical trials of ibrutinib in DLBCL should be confined to the ABC subtype.

CLL/SLL Phase 2 Studies Two phase 2 trials were reported with ibrutinib in CLL/SLL. The first was with single-agent ibrutinib (Abstract 189), and the second with ibrutinib plus rituximab (Abstract 187).

The first phase 2 trial included 116 CLL/SLL patients in 2 groups: elderly naive, relapsed/refractory patients, and high-risk relapsed/refractory patients. Ibrutinib monotherapy achieved excellent progression-free survival (PFS) at 26 months for both elderly, treatment-naive patients (estimated PFS, 96%) and relapsed/refractory highrisk CLL/SLL patients (estimated PFS, 75%).

“These results with ibrutinib continue to support the possibility that we can address some of the critical unmet needs in CLL/SLL. Rarely does a drug come along that helps patients this much. This drug is highly effective and very well tolerated,” said lead author John R. Byrd, MD, D. Warren Brown Chair of Leukemia Research and director of the Division of Hematology at Ohio State University Comprehensive Cancer Center in Columbus.

ORRs were 68% in the treatment-naive, relapsed/refractory patients at a median follow-up of 20.3 months and 71% in the high-risk relapsed/refractory group at a median follow-up of 15.7 months. At 26 months, estimated overall survival is 96% and 83%, respectively.

In the second phase 2 study, the combination of ibrutinib plus rituximab achieved an ORR of 83% in 40 patients with high-risk CLL, and 38 of the 40 patients have no evidence

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2012 ASTRO Annual Meeting

of disease progression and are continuing on treatment.

“High-risk CLL patients typically have inferior outcomes compared with low- and intermediate-risk patients. This study shows profound activity for this combination in high-risk patients with CLL. The overall response rate is favorable compared with standard treatment, and the toxicity compares favorably to other treatment options,” stated Jan Burger, MD, lead author of this phase 2 trial. Burger is associate professor at the University of Texas MD Anderson Cancer Center.

High risk was defined as having 1 of the following

characteristics: deletion of 17p, TP53 mutation, deletion of 11q, or <3 years of remission after first-line chemoimmunotherapy.

No disease progression was observed in 95% of the entire group and in 90% of those with 17p deletions.

Ibrutinib achieved rapid reduction in the size of lymph nodes and spleen; 84% experienced >50% decrease in lymph node size.

In both phase 2 trials in CLL, treatment was well tolerated, with transient and infrequent grade 3 and 4 toxicities associated with ibrutinib. u

Two Studies Show That Radiation Extends Survival in Elderly Women With Early-Stage Breast Cancer Phoebe Starr

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adiation therapy extends life in older women with early-stage breast cancer, according to 2 studies presented at the 54th Annual Meeting of ASTRO. The first study showed that the addition of radiation to lumpectomy improved overall survival (OS) as well as cause-specific survival (CSS) in women aged 70 or older.

The study population included 29,949 women identified in a SEER Medicare database who were diagnosed with stage I, estrogen receptor–positive (ER+) breast cancer. All women underwent lumpectomy with or without adjuvant radiation and survived at least 1 year after the initial diagnosis. Seventy-six percent received adjuvant radiation therapy.

Median survival was 13.1 years for women treated with surgery plus radiation and 11.1 years for those treated with surgery alone. Five-year CSS was 98.3% for the adjuvant radiation group versus 97.6% for the surgery-alone group. Ten-year CSS was 95.4% versus 93.3%, respectively; 15-year CSS was 91.4% versus 89.5%, respectively.

At all time points, the use of adjuvant radiation improved OS. At 5 years, OS was 88.6% for those who received radiation versus 73.1% for the surgery-alone arm

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(P<.0001); at 10 years, OS was 65% versus 41.7%, respectively (P<.0001); at 15 years, OS was 39.6% versus 20%, respectively.

A related study based on 27,559 patients from a SEER Medicare database found that older women with early-stage, low-risk breast cancer treated with radiation after breast-conserving surgery (BCS) had superior CSS and OS rates compared with women who did not undergo radiation after BCS. The study showed a 6% decline in use of radiation after 2004, coinciding with revised National Comprehensive Cancer Network guidelines allowing omission of radiation therapy as a reasonable option for women over age 70 with small ER+ tumors treated with adjuvant tamoxifen.

CSS favored radiotherapy. At 5 years, CSS was 97% for those who received radiotherapy versus 95% for those who did not, an absolute difference of 2%; by 10 years, the absolute difference was doubled to 4%, favoring radiation: 95% and 91%, respectively.

OS also favored the addition of radiotherapy to surgery. Five-year OS was 87% versus 68%, respectively, with an absolute difference of 19% favoring radiation, and 8-year OS was 73% versus 50%, respectively, for an absolute difference of 23% favoring radiation. u

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Newer More Costly Radiation Technologies Adopted in the Elderly Phoebe Starr

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atterns of use of radiotherapy have changed over time in elderly patients with stage I breast cancer, and these changes have financial implications for the healthcare system. In elderly patients with favorable-risk breast cancer, use of intensity-modulated radiation therapy (IMRT) and brachytherapy steadily increased from 2001 to 2007, while use of standard external beam radiation therapy (EBRT) decreased. Data are lacking on whether the newer technologies improve outcomes in this group of patients. These patterns of utilization led to an increase of 63% per treated patient, according to a study of Medicare patients enrolled in the SEER Medicare database reported at the 54th Annual Meeting of ASTRO. In 2007, 52% of favorable-risk breast cancer patients received EBRT, and 24% received a newer form of therapy. The median cost of EBRT was $6000 per patient, while the costs of IMRT and brachytherapy were twice as high: $12,469 and $13,981, respectively.

“The incremental cost to our nation for new radiation therapy modalities in 2007 was $31 billion. We need to determine if the benefit is commensurate with the increased cost,” stated Kenneth Roberts, MD, Yale University School of Medicine in New Haven, CT. “Further study is needed to explore radiation modalities in this low-risk population.”

The CALGB C9343 trial, published in 2004, included women aged 70 and older with clinical stage T1 N0 treated with lumpectomy with negative margins.

Ten-year follow-up showed that the local recurrence rate was 2% for those treated with radiation versus 9% for those who did not receive radiation.

Roberts coauthored a study showing that this trial had no effect on the usage of radiation in favorablerisk patients. “Radiation use remained stable even

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in patients with low life expectancy,” he said.

Over the past decade new treatments have been adopted, including accelerated partial breast irradiation and brachytherapy, without much evidence to support their use, he said. The present study was conducted to determine temporal trends in usage of technology and the associated cost in elderly, favorable-risk breast cancer patients.

The study included 12,925 women with a mean age of 77.7 years (range, 70-94 years) with stage I breast cancer undergoing lumpectomy. Tumor size was <2 cm, and all cancers were estrogen receptor positive. Seventysix percent were treated with some form of radiation therapy.

Patterns of usage changed over time. In 2007, 24% did not receive radiotherapy, and a progressive increase in brachytherapy (11.2%) and IMRT (12.4%) was seen.

Use of standard EBRT decreased from 76% in 2001 to 52% in 2007.

Fewer women aged 85 and older received radiation therapy, but even in this group there were temporal changes as follows: in 2008, 8.8% were treated with brachytherapy, 5.3% with IMRT, and 21.2% with standard EBRT. The study did not include data on quality of life and toxicity.

Discussant of this abstract, Meena Moran, MD, Yale University School of Medicine, said that this study showed the utilization of EBRT has decreased in older women, yet they are opting for costly newer technologies with no data to show improved outcomes.

The real question, she indicated, is how to define elderly. Also, it is not clear that radiation should be omitted in elderly patients with favorable-risk breast cancer.

“The decision should encompass tumor characteristics, patient anxiety, and patient goals,” she stated. u

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2012 ASTRO Annual Meeting

Memantine Delays Cognitive Decline in Patients With Brain Metastases Treated With Whole-Brain Radiation Phoebe Starr

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emantine delayed cognitive decline in patients treated with whole-brain radiation therapy (WBRT) for brain metastases, according to results of a randomized phase 3 trial presented at the 54th Annual Meeting of ASTRO. Cognitive decline is common with WBRT, occurring in 50% to 60% of patients 4 months following radiation treatment. Since the mechanism of radiation-induced cognitive decline appears to be similar to that of vascular or Alzheimer’s dementia, the researchers postulated that memantine, a drug used to treat Alzheimer’s disease, would be of benefit in patients treated with WBRT. “We are excited to see that adding memantine to the treatment plan for brain tumor patients helps preserve their cognitive function after whole-brain radiotherapy even 6 months after treatment. Our findings suggest that memantine may prevent the changes that occur in the brain following radiation therapy, impacting future treatment practices for these patients, and suggest a role for further study in patients receiving radiation to the brain,” said lead author Nadia N. Laack, MD, radiation oncologist at the Mayo Clinic in Rochester, MN. Formal discussant of this trial, Vinai Gondi, MD, Associate Director of the CDH Proton Center in Warrenville, IL, called this study “a good first step” in understanding the cognitive changes resulting from brain radiation and the role of memantine in preventing or delaying them. He said that the effect of memantine was modest in this trial, and that other strategies to improve cognitive effects of radiation are being pursued by researchers.

The study included 508 patients with brain metastases who received WBRT between March 2008 and June 2010. WBRT was delivered as 37.5 Gy in 15 daily fractions. Patients were randomized to memantine 20 mg/day or placebo within 3 days of the start of radiation therapy.

Six domains of cognitive function (memory, processing speed, executive function, global function, self-reported

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cognitive function, and quality of life) were assessed by different instruments at baseline and weeks 8, 16, 24, and 52. The primary end point was memory as assessed by the Hopkins Verbal Learning Test-Revised (HVLT-R).

Compliance with the cognitive testing protocol was suboptimal, with 32% of patients completing drug therapy and cognitive assessments. The reasons for noncompliance appeared to be death, disease progression, and difficulty in getting patients to stay longer during a clinic visit or in physicians scheduling the extra 20 minutes to 1 hour required for cognitive testing. Of the 508 patients randomized to the 2 arms, only 149 were available for analysis at 24 weeks.

Six domains of cognitive function (memory, processing speed, executive function, global function, self-reported cognitive function, and quality of life) were assessed.

For the primary end point, memantine reduced the decline in HVLT-R delayed recall, with a median decline of 0 versus –2 for placebo at 24 weeks, with a statistical significance of P=.059, “teetering on the edge of significance,” according to Laack.

At 24 weeks, memantine reduced the relative risk of cognitive decline by 17% versus placebo (P=.01) and reduced the rate of decline in cognitive, executive, and global function as well as processing speed (P<.01).

Patients in both groups experienced similar rates of grade 3 and 4 toxicities, including alopecia, fatigue, headache, and nausea.

The investigators plan to evaluate the effect of memantine on overall survival and progression-free survival in these patients. Also, tissue specimens will be studied to identify biomarkers of cognitive decline as well as of response to memantine. u

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Stereotactic Body Radiation Therapy Is Effective, Cost Saving, and Convenient for Patients With Prostate Cancer Phoebe Starr

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n the United States right now, intensity-modulated radiation therapy (IMRT) has largely replaced 3-D conformal radiation therapy as the technique of choice for most patients with organ-confined prostate cancer treated with radiation as primary therapy. Other techniques in use include brachytherapy, and at some centers proton beam therapy is being studied.

Of all the radiation technologies, it appears that stereotactic body radiation therapy (SBRT) delivered via the CyberKnife may be the most cost-effective and convenient for patients, while achieving at least equivalent efficacy in disease control, according to 2 retrospective studies reported at the 54th Annual Meeting of ASTRO. Both studies have a median follow-up of about 3 years, and larger studies with longer follow-up are needed to verify these findings.

SBRT delivers precise, high doses of radiation to the prostate using converging, finely collimated beams, targeting prostate tissue and sparing healthy tissue. The CyberKnife is a robotic technology used to deliver SBRT, and a course of prostate radiation typically takes 5 sessions (or 1-2.5 weeks) compared with 40 to 45 sessions using IMRT. SBRT technology is now available at about 150 centers in the United States.

A pooled analysis of 1100 patients with organ-confined prostate cancer treated at 8 different centers from 2003 to 2010 with CyberKnife SBRT showed that actuarial 5-year biochemical control was 95% for low-risk patients, 90% for intermediate-risk patients, and 80% for high-risk patients. Similar results were found in 150 patients treated with androgen deprivation therapy and with different dose levels of SBRT, reported Alan J. Katz, MD, Flushing Radiation Oncology, Flushing, NY. “These results are 5% to 10% better than those with standard IMRT, which takes 40 to 45 days to deliver. At

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this point, the statistics should encourage men with organ-confined prostate cancer to seek SBRT as an alternative to IMRT, brachytherapy, or prostate surgery,” Katz stated.

SBRT can achieve huge cost savings, since Medicare reimbursement for SBRT is a median of $22,000 versus $40,000 to $45,000 for IMRT per patient. Also, because SBRT is delivered over 1 to 2.5 weeks instead of the 8 weeks needed for IMRT, there are cost savings in healthcare utilization and greater convenience for patients.

A second retrospective review, reported by Robert Meier, MD, Swedish Radiosurgery Center, Seattle, WA, focused on 129 patients with intermediate-risk, organconfined prostate cancer treated with CyberKnife SBRT at 21 different institutions from December 2007 to April 2010. Median follow-up of these patients was 3 years (range, 2.5-4 years).

Quality-of-life (QOL) Expanded Prostate Cancer Index Composite scores showed that both urinary and bowel side effects were greater early in the course of treatment but by 6 months tended to approach baseline levels. At 2 years following SBRT, QOL scores were similar to baseline. Most urinary and bowel side effects were grades 1 and 2.

Biochemical control was achieved in 99.2% of patients; only 1 of 129 patients experienced a rise in prostate-specific antigen following a nadir achieved by SBRT. Putting these preliminary results in context, Meier said that the typical rate of biochemical failure is 10% to 20% at 4 years with IMRT and proton beam therapy.

At a press conference, president-elect of ASTRO, Colleen Lawton, MD, Clinical Director of Radiation Oncology at the Medical College of Wisconsin, Milwaukee, said that these are exciting results, but longer follow-up is needed to establish SBRT as a standard of care. u

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• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma

July 26-28, 2013 Hyatt Regency La Jolla • San Diego, California

PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: • Epidemiology and genetic/environmental factors • Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies • Risk stratification based on patient and tumor characteristics • Principles of cancer prevention of melanoma and basal cell carcinoma • Current treatment guidelines • Emerging treatment options for personalized therapy • Future strategies in management based on translational data from current clinical trials and basic research

LEARNING OBJECTIVES Upon completion of this activity, the participant will be able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

TARGET AUDIENCE This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Advanced practice oncology or dermatololgy nurses, oncology pharmacists, and researchers interested in the molecular biology and management of cutaneous malignancies are also encouraged to participate.

DESIGNATION OF CREDIT STATEMENTS SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.0 contact hours.

REGISTERED PHARMACY DESIGNATION The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany

AGENDA* FRIDAY, JULY 26, 2013 3:00 pm – 7:00 pm

Registration

5:30 pm – 7:30 pm

Welcome Reception/Exhibits

SATURDAY, JULY 27, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Welcome to the Second Annual World Cutaneous Malignancies Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies • Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway • Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm

BREAK

1:15 pm – 4:30 pm

General Session II: Current Treatment Guidelines in Cutaneous Malignancies • Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expert’s Perspective on How I Treat My Patients • Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies • Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1

4:30 pm – 6:30 pm

Meet the Experts/Networking/Exhibits

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 12.0 AMA PRA Category 1 Credits ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Steven J. O’Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California

SUNDAY, JULY 28, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Review of Saturday’s Presentations and Preview of Today’s Sessions

8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician • Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies?

12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits

CONFERENCE REGISTRATION

1:00 pm – 1:15 pm

BREAK

1:15 pm – 2:45 pm

General Session V: “Hot Data” — What I Learned at Recent Meetings: Focus on Cutaneous Malignancies

2:45 pm – 3:00 pm

Closing Remarks - Steven J. O’Day, MD

EARLY BIRD REGISTRATION NOW OPEN! $175.00 UNTIL APRIL 30, 2013

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*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com

2012 San Antonio Breast Cancer Symposium

Activating HER2 Mutations Found in HER2-Negative Patients Phoebe Starr

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pproximately 4000 breast cancer patients in the United States harbor HER2 mutations amenable to treatment with anti-HER2 therapy but are not receiving it because they are not HER2positive on fluorescence in situ hybridization or immunohistochemical testing. However, genomic sequencing can identify patients with these mutations, who are likely to benefit from existing anti-HER2 therapies. These are the implications of a genomic sequencing study reported at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium.

“These patients are going to be missed by our routine testing for HER2-positive breast cancer, but the mutations can be identified by genomic sequencing,” said lead author Ron Bose, MD, PhD, assistant professor of medicine at Washington University School of Medicine in St. Louis, MO. “These mutations are not inherited,” he emphasized.

Bose and colleagues analyzed nearly 1500 patients who participated in 8 DNA sequencing studies; 25 patients were found to have HER2 mutations without HER2 gene amplification.

Bose explained that 1.5% to 2% of breast cancer patients will test negative for HER2 amplification (reflecting multiple copies of the gene) and have undetected HER2 mutations that drive tumor growth.

Bose and colleagues analyzed nearly 1500 patients who participated in 8 DNA sequencing studies; 25 patients were found to have HER2 mutations without HER2 gene amplification. These mutations clustered in 2 areas of the HER2 protein, he said: the tyrosine kinase area and the extracellular domain of the HER2 gene.

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Not all of the mutations were equally activating. Of 13 mutations that were analyzed, 7 were determined to drive cancer proliferation.

“The mutations stimulate the function of HER2, and we feel they are highly likely to drive the growth of cancers when they are present,” Bose continued.

Laboratory studies showed that activating HER2 mutations were sensitive to the drugs lapatinib and trastuzumab, with the exception of the L755S mutation and deletion of 755-759. Both mutations were resistant to lapatinib but sensitive to neratinib, a drug currently in phase 2 testing.

These findings led to the launching of a multi-institutional phase 2 trial in women with metastatic breast cancer who test negative for HER2 amplification and who harbor HER2 mutations found on genomic sequencing. The women will be treated with neratinib 240 mg/day and monitored every 2 weeks. Four institutions will participate in the phase 2 trial: Washington University, Dana-Farber Cancer Institute, Memorial Sloan-Kettering Cancer Center, and University of North Carolina.

The study was published online December 7, 2012, in Cancer Discovery, to coincide with the presentation of the data at the symposium.

“These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment, and gene sequencing is needed to identify these patients. If the phase 2 trial is successful, we estimate that 4000 women per year could benefit. This is the same size as the patient population with chronic myelogenous leukemia in the US,” Bose stated.

George Sledge, MD, Indiana University School of Medicine, Indianapolis, said that 1% to 2% of all breast cancer patients is comparable to the number of patients with lung cancer who are positive for the ALK gene. u

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Genetic Targets Identified in Triple-Negative Breast Cancer Alice Goodman

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riple-negative breast cancer carries a poor prognosis compared with other types of breast cancer because it lacks 3 treatment targets that occur in other types of breast cancer (estrogen receptor, progesterone receptor, and HER2). But triple-negative breast cancer has potential genetic targets of its own, according to a study presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

The study found that 90% of patients had mutations in 5 targetable biological pathways. These pathways have drugs on the market or in development that could be targeted in clinical trials, according to Justin Balko, PharmD, PhD, of the Breast Cancer Program at the Vanderbilt-Ingram Cancer Center in Nashville, TN. Currently, there are no approved targeted drugs for triple-negative breast cancer, which occurs in about 15% of all breast cancers, he continued. About 30% of patients with triple-negative breast cancer have a complete response to neoadjuvant chemotherapy and have good outcomes following surgery. But outcomes for patients with residual disease are typically poor.

Balko and colleagues analyzed samples of residual tumors to determine if any candidate genes for resistant cancers could be identified. They studied 114 samples from tumors of women with triple-negative breast cancer using 3 different methods, including gene expression profiling, deep sequencing, and immunohistochemistry.

They examined 182 oncogenes and tumor suppressors known to be altered in human cancers. Instead of finding similar genetic alterations among patients, they found alterations in a diverse set of genes. Median age of patients was 48 years, and the majority of cancers were stage III. “We already knew that triple-negative cancer is driven by a diverse group of alterations, so in one way, we fell further down this rabbit hole. But we also identified some genes that could be promising therapeuti-

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cally, such as frequent MYC, MCL1, and JAK2 amplifications, as well as alterations in the PI3K pathway.

Overall, with all 3 methods, dozens of genes were amplified, deleted, or mutated, with the most common gene being TP53, which was abnormal in 90% of tumor samples. MCL1 (56% abnormal) and MYC (33% abnormal) were the next most common genetic alterations. Amplified JAK2 was observed in 11% of tumors.

Alterations in the KI67 gene were not associated with relapse-free survival or overall survival in this triple-negative cohort.

“We arranged the genetic alterations into clinically targetable pathways,” he explained. These were the 5 pathways he discussed: • PI3K/mTOR pathway, involved in intracellular signaling and death • DNA repair genes (eg, BRCA1 and BRCA2) • RAS/MAPK pathway (involved in cell proliferation, differentiation, and death) • Cell cycle genes • Growth factor receptors, including epidermal growth factor receptor • The combination of MEK kinase genes and amplified MYC oncogene was potentially predictive of relapse Women who had only MEK kinase or MYC gene activation/amplification were significantly less likely to experience relapse compared with women who had both variants (P=.03).

“Ninety percent of patients had at least 1 genetic aberration in these pathways. We believe this has therapeutic implications and should be studied,” Balko said. “Targeted drugs exist for each of these 5 pathways.

We believe these data provide rationale for adjuvant studies of appropriate targeted therapeutics in triplenegative breast cancer patients who do not achieve pathological complete responses to neoadjuvant chemotherapy.” u

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Interview With the Innovators

Lynch Syndrome: An Interview With the Father of Hereditary Cancer Detection and Prevention, Henry T. Lynch, MD Henry T. Lynch, MD Creighton University School of Medicine Omaha, Nebraska

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ynch syndrome is a hereditary disorder caused by Lynch demonstrated Mendelian inheritance patterns for a mutation in a mismatch repair gene in which a previously unrecognized form of colon cancer (hereditary affected individuals have an increased risk of denonpolyposis colorectal cancer, now known as Lynch synveloping colorectal cancer, endometrial cancer, and vardrome), and for the hereditary breast-ovarian cancer synious other types of aggressive cancers. drome, which he subsequently helped The syndrome is named after its dislink to the BRCA1 and BRCA2 genes. coverer, Henry T. Lynch, MD, director In addition, he provided some of the of Creighton University’s Hereditary first findings of hereditary malignant Cancer Center. It is estimated that melanoma and prostate and pancreatic about 3 of every 100 colon cancers are cancers. The purpose of his work has caused by Lynch syndrome, making it been to enable physicians to more the most common inherited cause for quickly and accurately identify high-risk colon cancer. patients, leading to earlier and more efHereditary cancers were not acfective surveillance, management, and tively researched until the second half treatment. of the last century. There is documenToday, based on worldwide estiHenry T. Lynch, MD tation that physicians acknowledged mates, it is projected that over 600,000 family cancer clusters during the 1800s; individuals have the defective gene; however, it wasn’t until the late 1950s and early 1960s however, less than 5% of them have been diagnosed. that statistics were used in cancer research to establish Part of Dr Lynch’s vision is a network to serve those with the existence of hereditary cancers.

Lynch syndrome that includes genetic testing, a registry, Dr Lynch was a pioneer in the study of cancer and treatment centers, and ongoing surveillance for early genetics in the 1960s, when cancer incidence was largely prevention. To this end, he helped establish Lynch Synattributed to environmental causes. His use of statistics drome International, a nonprofit organization founded to prove genetic links to certain cancer types was unique in 2009 to raise public awareness and support for individuals afflicted with the syndrome. It was our great from other researchers at that time. His early cancer research significantly influenced how physicians and repleasure to interview Dr Lynch about his contributions to the field of oncology, particularly in genetics. searchers treat and study hereditary cancers today. Dr Dr Lynch is Professor of Medicine at the Creighton University School of Medicine and Director of the Creighton Cancer Center. His research involves clinical as well as laboratory investigations into a variety of hereditary cancer-prone disorders.

Dr Lynch was an Assistant Professor at the University of Texas MD Anderson Hospital and Tumor Institute in Houston prior to joining the Creighton University School of Medicine faculty in 1967. In 1984, he established Creighton University’s Hereditary Cancer Prevention Clinic, an interdisciplinary clinic that provides information and services related to hereditary cancers.

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PMO Thank you for speaking with us, Dr Lynch.

We’d like you to describe the process that led to the discovery of Lynch syndrome.

Dr Lynch I developed an interest in genetics early in my medical training, particularly as it related to cancer.

Many individuals with an extensive family history of colon cancer were diagnosed with familial adenomatous polyposis (FAP), a hereditary colon cancer that produces hundreds to thousands of polyps. However, some patients diagnosed with FAP did not have symptoms characteristic of the syndrome; the typical numerous polyps were not present in the first family I studied. I suspected another hereditary cancer might exist.

PMO Does the research of Lynch syndrome have implications for other research models/strategies?

Dr Lynch Yes, our research has extremely important implications for preventive as well as other clinical translational research models/strategies.

PMO Is there a research strategy specific to Lynch syndrome?

Dr Lynch The research strategy for the Lynch syndrome revolves around issues related to its diagnosis and ultimate management strategies. Its clinical importance relates to the fact that it is by far the most common hereditary colorectal cancer syndrome and extracolonic cancer syndrome problem. These often result in extremely important clinical/preventive cancer syndrome issues.

PMO Does Lynch syndrome resemble other disease states in terms of disease process, patient selectivity, or progression? In other words, is there any analog for gaining an understanding of it?

Dr Lynch Lynch syndrome, in fact, has strong similarities to disease processes relevant to patient selectivity and cancer progression. There are multiple clinical analogs revolving around the need for a comprehensive family history and ultimately genetic testing, when appropriate, in the search for cancer-causing mutations and design of preventive opportunities.

PMO What has been the greatest significance of the discovery and management of Lynch syndrome on cancer and/or personalized medicine research?

Dr Lynch The most significant issue, by far, in terms

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Dr Lynch (5th from left) has worked since the 1960s in the fields of oncology and genetics.

of its diagnosis and management pertains to the need for its personalized medical research contributing to a reduction in morbidity and mortality when compliance is adhered to.

PMO How has the discovery and clinical usage of diagnosis of Lynch syndrome changed morbidity and mortality outcomes of the various cancers it concerns?

Today, based on worldwide estimates, it is projected that over 600,000 individuals have the defective gene; however, less than 5% of them have been diagnosed.

Dr Lynch Discovery and clinical usage of diagnosis of Lynch syndrome has definitely changed morbidity and mortality outcomes. We have profound evidence of this in the study of countless families throughout the United States, South America, and Europe, where we have been highly privileged to have been involved clinically and genetically with physicians in multiple specialties; medical genetics, surgery – particularly surgical oncology and colorectal surgery – gastroenterology, and gynecologic oncology.

PMO How aware of and responsive to Lynch syndrome are practicing oncologists?

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Dr Lynch has identified patterns of genetic inheritance through generations of extended families.

Dr Lynch has been an invited speaker worldwide. Here he is pictured at a speaking engagement in Saudi Arabia.

Dr Lynch Well, it’s more fitting to ask if the patients are aware, and their response. We find that our patients have been partially responsive to the preventive implications of Lynch syndrome and the advice given by their family doctors as well as practicing oncologists. However, this only happens when the patients are adequately educated and have constant encouragement.

PMO Which factors tend to limit, and which increase, awareness and management of Lynch syndrome?

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Dr Lynch As part of our goals at the Hereditary Cancer Center, we strive to promote awareness and preventive management. Compliance is hopefully magnified through our genetic counselor and physician interventions. Awareness and management is based on many years of our intensive research, with attempts to come up with what is best for a particular patient.

Factors that limit increased awareness and management of Lynch syndrome revolve around physician interest and willingness to learn about the syndrome and provide its diagnostic and preventive implications to high-risk patients in their practices. Other factors that limit increased awareness and management revolve around limited interest on the part of the patient and willingness of insurance companies to help cover the cost, which can be very high in the case of the sine qua non for diagnosis, namely, the search for the cancercausing germline mutation.

PMO How would you describe awareness and management of the syndrome at Creighton?

Dr Lynch This has been done admirably well, in my opinion, in our academic setting. The preventive measures we use, particularly colonoscopy, with initiation at age 25 and repeated every other year to age 40 and then annually thereafter, have been successful. Implications for prophylactic hysterectomy and bilateral salpingooophorectomy, in collaboration with colleagues at the MD Anderson Cancer Center, in Houston, Texas, have been successful.

PMO Does any particular stakeholder group – practicing oncologists at the academic centers or community centers, payers, patients, etc – stand out as more, or less, cognizant of Lynch syndrome and its management? Put differently, where do healthcare disparities for Lynch syndrome tend to occur regarding patient risk stratification, diagnosis, treatment, patient management/follow-up, and payer coverage/reimbursement?

Dr Lynch The stakeholder groups, including practicing oncologists and academic centers, have worked very hard to get insurance companies’ support for its costly management. Healthcare disparities for Lynch syndrome enter the picture and may be a particular hazard for eth-

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nic and racial factors, particularly those involving African Americans and patients of Latino background.

These issues must be resolved.

PMO Are medical directors and pharmacy directors at health plans sufficiently informed about Lynch syndrome to provide proper coverage of its care?

Dr Lynch Our experience indicates that medical and pharmacy directors have, for the most part, not been sufficiently informed about Lynch syndrome to the extent that they can reasonably provide proper coverage of its diagnosis and management.

PMO While Lynch syndrome increases risk for some cancers, it does not for others. What accounts for the absence of risk for developing certain cancers?

Dr Lynch Lynch syndrome increases the risk for multiple primary cancers, particularly cancer of the colorectum, endometrium, ovary, among other extracolonic cancers. So far as we can determine, its risk for so-called environmental cancers, inclusive of head and neck and lung cancer, has not been an exceptionable problem.

However, we have no knowledge at this time about the absence of risk for developing certain cancers.

PMO How would you briefly describe the pathogenesis, pathophysiology, and clinical sequelae of Lynch syndrome in terms relevant to practicing oncologists?

Do clinicians understand the science behind Lynch syndrome, or just its impact on outcomes?

Dr Lynch Our pathology colleagues, among other specialists, have been working very hard at attempts to understand the pathogenesis, pathophysiology, and clinical sequelae of Lynch syndrome in terms that can be most useful to practicing oncologists. Understanding the science of the Lynch syndrome has been emerging, particularly at the molecular genetics level, but we have a long way to go in order to have its impact more fully explained on clinical outcomes.

PMO Where is Lynch syndrome trending in terms of clinician recognition, diagnosis, and management?

How has this progressed over the past 5 years?

Dr Lynch The Lynch syndrome has been increasing significantly in its clinical recognition, diagnosis, and management, and it has progressed favorably over the

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Dr Lynch attends genetic testing for a large, extended family of more than 70 people for a known mutation.

past 5 years in diagnosis. This is in contrast to my initial discovery of the Lynch syndrome in 1962, when I was a second-year medical resident at the University of Nebraska College of Medicine. Clearly, there was no editorial concern about what I was attempting to publish.

Attention to the syndrome throughout the world and

Understanding the science of the Lynch syndrome has been emerging, particularly at the molecular genetics level, but we have a long way to go... the lack of believability of my work was truly profound.

Over the years interest gradually increased, but at a slow pace. It began to emerge relevant to mounting evidence supporting the existence of Lynch syndrome. However, it wasnâ&#x20AC;&#x2122;t until the early 1990s that linkage analysis and other technology emerged in support of the diagnosis of Lynch syndrome. Substantial evidence emerged rapidly following the discovery of germline mutations giving evidence for its existence.

PMO Thank you so much for your time today, and our best to you in your continued pursuit of making a difference in the lives of those with Lynch syndrome. u

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KRAS and Colorectal Cancer: Shades of Gray Chloe E. Atreya, MD, PhD Helen Diller Family Comprehensive Cancer Center University of California, San Francisco San Francisco, California Jonathan M. Ostrem, BS, MD, PhD Candidate University of California, San Francisco San Francisco, California Robin K. Kelley, MD Helen Diller Family Comprehensive Cancer Center University of California, San Francisco San Francisco, California

Key Points • Although RAS mutations at glycine-12 and glycine-13 are adjacent, identical substitutions at these positions (eg, G12S vs G13S) lead to very different levels of RAS activation • The central clinical question remains unanswered: will a patient with metastatic colorectal cancer harboring a KRAS G13D mutation benefit from anti-EGFR therapy?

• If mutations in adjacent codons can have unequal effects, what level of “personalization” is required in oncology clinical research?

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux or Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux or Vectibix is not recommended for treatment of colorectal cancer with these mutations.

–FDA update to indications and usage of Erbitux (cetuximab) and Vectibix (panitumumab), July 2009.

T

he association between Kirsten-Ras (KRAS) mutations, present in approximately 40% of colorectal cancers (CRCs), and lack of benefit from epidermal growth factor receptor (EGFR)-targeted antibodies is well known to oncologists. It is standard

practice to test for KRAS codon 12 and 13 mutations in tumors of all patients with metastatic CRC (mCRC) because the results affect treatment decisions. Recently, however, 2 reports suggest that KRAS codon 12 and 13 mutations are nonequivalent, although they code for ad-

Dr Atreya is a gastrointestinal oncologist and scientist whose research focuses on the interplay between genotype and response to therapy in advanced colorectal cancer.

Dr Ostrem is in the Medical Scientist Training Program at the UCSF School of Medicine. His graduate thesis research in the laboratory of Dr Kevan Shokat focuses on targeting mutant RAS. Dr Kelley is a gastrointestinal oncologist with a research interest in developing biomarker-stratified clinical trials to identify new treatments, particularly for hepatocellular and bile duct cancers. She is also Executive Officer of the Alliance for Clinical Trials in Oncology Translational Research Program.

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jacent amino acids.1,2 In cetuximab-treated patients, the RAS signaling is almost invariably associated with dispresence of a glycine (G) to aspartic acid (D) change at ease. Hyperactivating somatic mutations in RAS are codon 13 of KRAS (c.38G>A, or p.G13D) was associamong the most common lesions found in human maated with intermediate survival, belignancies. Although mutation of any tween that of patients with KRAS of the 3 RAS isoforms (KRAS, NRAS, wild-type tumors and tumors harboring or HRAS) can lead to oncogenic a KRAS mutation at glycine-12. While transformation, KRAS mutations are the overall impact of KRAS mutations by far the most common.13-16 Hyperac3 on CRC prognosis remains unclear, tivation of the RAS pathway due to G13D mutations may be associated oncogenic mutations in other pathway with worse outcomes.1,2,4 The purpose members, including BRAF and EGFR, of this review is to place differences beaccounts for a significant proportion of tween KRAS mutations at codon 12 RAS wild-type cancers.17 and 13 in CRC into scientific and clinThree-dimensional structures of ical contexts, and to consider the poRAS isoforms have been well studied.

Chloe E. Atreya, MD, PhD tential implications of nonequivalent Indeed, over 100 crystal structures of mutations within the same gene for the RAS in various complexes have been pursuit of personalized medicine in oncology. solved. Nucleotide-dependent signaling relies on conformational changes in 2 regions that border the nuScientific Context cleotide-binding pocket, switch I (residues 30-38) and switch II (residues 60-76) (Figure 1).18 Threonine-35 The RAS guanine nucleotide-binding protein regulates cell survival, growth, and proliferation by acting as and glycine-60 make key hydrogen bonds with the Îła molecular switch in response to extracellular signals. phosphate of GTP, holding switch I and switch II in RAS regulates downstream pathways by cycling betheir active conformations. Upon hydrolysis of GTP and tween an inactive guanosine diphosphate (GDP)-bound release of phosphate, these regions relax into the inacstate and an active guanosine triphosphate (GTP)tive GDP-binding conformation. Only the GTP-bound 5,6 bound state. Posttranslational processing targets RAS conformation of the switch regions activates downto the membrane, where it resides in the OFF state, stream effector proteins. bound to GDP.7,8 Upon stimulation by growth factors such as insulin and EGF, RAS activators called guanine The RAS guanine nucleotide-binding nucleotide exchange factors localize to the membrane protein regulates cell survival, growth, and and stimulate the release of GDP from RAS, thus allowing GTP binding and activation.9,10 Once ON, RAS acproliferation by acting as a molecular tivates downstream signaling cascades, including the switch in response to extracellular signals.

RAF-MEK-ERK pathway.11 Inactivation of RAS signaling requires hydrolysis of the RAS-bound GTP back to The regions surrounding the nucleotide-binding GDP with release of phosphate. However, RAS is expocket contain the most common sites of RAS mutatremely slow at carrying out this reaction on its own. tion. Along with the switch regions, the borders of the Therefore, inactivation of RAS depends upon the acpocket include the phosphate-binding loop (P-loop, tion of GTPase-activating proteins (GAPs), which supresidues 10-17) and the base-binding loops (residues ply a critical arginine residue to the RAS active site to 116-120 and 145-147).19 The majority of oncogenic muassist in catalysis of GTP hydrolysis.5,12 Dysregulation of

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Figure 1. Location of Common Oncogenic Mutations Mapped Onto the 2- and 3-Dimensional Structures of KRAS

Colored spheres represent the sites of mutation and correspond to the colored labels on the 2-dimensional structure (G12, red; G13, orange; Q61, purple; A146, green). The switch I and switch II regions are shown in blue and cyan, respectively.

GTP indicates guanosine triphosphate.

tations occur at residues 12 or 13 in the P-loop, or residue 61 in switch II.17 Mutations activate RAS by 2 main mechanisms: decreasing GTP hydrolysis or increasing nucleotide exchange. Most oncogenic mutations follow the first mechanism. In wild-type RAS, residues 12 and 13 are both glycine, the smallest amino acid. Mutation of either of these residues to larger amino acids can occlude the critical arginine of the GAP, leading to decreased GAP binding and insensitivity to GAP-stimulated GTP hydrolysis.5,20,21 Glutamine-61 of RAS participates in catalysis, and therefore its mutation also affects GTP hydrolysis; however, GAP binding is generally normal or increased.12,21 Mutations near the base-binding region of RAS (eg, alanine-146 or phenyl-

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alanine-156) diminish nucleotide binding affinity and increase the intrinsic rate of exchange.22,23 The active form of RAS then predominates due to the higher concentration of GTP than GDP in the cell.

Biochemical and cellular assays demonstrate that although RAS mutations at glycine-12 and glycine-13 are adjacent, identical substitutions at these positions (eg, G12S vs G13S) lead to very different levels of RAS activation.21,24 Mutations at codon 12 are generally the most potent activators of RAS: the crystal structure of HRAS complexed with a GAP suggests that mutations at this position sterically clash with the arginine finger of the GAP, preventing both binding and catalysis.12 Indeed, mutation to any amino acid other than proline induces focus formation and anchorage-independent growth of rat fibroblasts, both measures of oncogenic transformation.24 Mutations at codon 13 are generally less activating in vitro. Three G13 mutations (G13S, G13V, and G13D) have been compared in GAP stimulation and focus formation assays. G13D completely blocks GAP activity and is the only codon 13 mutant that induces focus formation.

G13S is only slightly activating, having a small effect on GAP stimulation. G13V shows intermediate oncogenicity; this mutation completely blocks GAP activity, without inducing focus formation.20,21 G12 mutations may confer greater resistance to apoptosis and increase the proportion of GTP-bound RAS well above the level achieved by G13 mutations.1,25-27 Glutamine-61 mutations decrease RAS GTPase activity but vary widely in transformation efficiency.28 Unlike G12 and G13 mutants, some Q61 mutants unexpectedly increase binding to GAP, which could hyperactivate wild-type RAS.21 The most potent mutant, Q61L, increases nucleotide exchange in addition to diminishing GTPase activity.22,29 Substitutions at alanine146 are less activating than G12 mutations and may be comparable to G13 mutations in transforming efficiency.30 These base-binding mutations increase the intrinsic rate of nucleotide exchange,22 thus increasing RAS-GTP without affecting GAP stimulation. Despite lower oncogenicity, one would expect KRAS A146 mutants to be growth factor independent due to their

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capacity for autonomous nucleotide exchange Figure 2. Mutational Frequency of RAS Pathway Genes (left) and Distribution of KRAS Mutations (right) in A, Colorectal and activation.31 The spectrum of RAS pathway mutations Adenocarcinoma; B, Pancreatic Adenocarcinoma; C, Lung differs markedly by cancer type (Figure 2).17 Adenocarcinoma; and D, Melanoma Pancreatic cancer exhibits the highest freA. Colorectal adenocarcinoma quency of KRAS mutations: 72% in the Sanger Catalogue of Somatic Mutations in Cancer and >90% in other series (Figure 2 B).17 By contrast, breast cancer (not shown) has a low frequency of RAS pathway mutations: 4% KRAS, 3% BRAF, 2% NRAS, and <1% HRAS mutations.17 Melanoma has a high frequency of RAS pathway mutations, but KRAS mutations are rare (Figure 2 D). In CRC, half of tumors exhibit a mutation in the RAS pathway (mutually exclusive), most often a missense mutation in KRAS itself (Figure 2 A). Unlike in lung cancer, EGFR mutations are rare in CRC. Differences by cancer type are also observed in the distribution of KRAS single-base substitution mutations (Figure 2). Across cancers, mutations at codon 12 predominate: G12D and G12V are the first and second most common KRAS mutations. In lung cancer, however, the most frequent KRAS substitution is glycine to cysteine (G12C). Of all cancer types, CRC exhibits the greatest proportion of G13D mutations: ~20% of KRAS mutations and 8% overall. Of note, clinical testing for KRAS mutations is typically performed using polymerase chain reactionâ&#x20AC;&#x201C;based assays with probes specific for mutations in codons 12 and 13. Consequently, KRAS mutations at other codons, including Q61 and A146, may be underrepresented.32,33 Despite decades of RAS research, 5 years passed beity to cetuximab in CRC cell lines.34 This experience tween FDA approval of cetuximab for treatment of underscores the necessity of evaluating annotated human tumor specimens for associations between speEGFR-expressing mCRC and the label change to excific mutations, survival, and response to therapies, clude patients with tumors harboring KRAS mutations. thereby enabling the clinical findings to guide further A major reason for the delay was that no correlation was mechanistic investigations. observed between KRAS mutational status and sensitiv-

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Table. Survival by Treatment Type and KRAS Allele KRAS G13D

Other KRAS (codon 12)

KRAS Wild-Type

(n=45)

(n=265)

(n=464)

Best supportive care, No. Median OS, mo (95% CI)

13 3.6 (2.2-4.8)

69 4.7 (3.6-3.51)

113 5.0 (4.2-5.5)

Any cetuximab-based therapy, No. Median OS, mo (95% CI)

32 7.6 (5.7-20.5)

195 5.7 (4.9-6.8)

325 10.1 (9.4-11.3)

Cetuximab monotherapy, No. Median OS, mo (95% CI)

10 6.7 (3.3-20.5)

91 4.8 (4.0-5.9)

146 9.4 (7.7-10.3)

Cetuximab + chemotherapy, No. Median OS, mo (95% CI)

22 10.6 (5.7-24.6)

104 7.4 (5.5-9.0)

199 11.3 (9.9-13.6)

De Roock et al1

Tejpar et al2

(n=83)

(n=325)*

(n=845)

Chemotherapy only, No. Median OS, mo (95% CI)

41 14.7 (12.4-19.4)

148 17.7 (15.3-20.5)

447 19.5 (17.8-21.1)

Cetuximab + chemotherapy, No. Median OS, mo (95% CI)

42 15.4 (12.4-20.4)

177 15.4 (13.5-17.5)

398 23.5 (20.7-25.7)

*Excludes KRAS G12V. Abbreviations: mo indicates months; OS, overall survival.

Clinical Context A landmark study linking KRAS G13D mutations with clinical outcomes was a retrospective, pooled analysis of 774 patients with chemotherapy-refractory mCRC treated with cetuximab-based therapy from 3 data sets (the National Cancer Institute of Canada/Australasian Gastrointestinal Trials Group and a Leuven and an Italian data set) encompassing 7 clinical trials (CO.17, EVEREST, BOND, SAVAGE, BABEL, MABEL, and EMER202600).1 Three hundred ten patients (40%) had a KRAS mutation at codon 12 or 13, 45 of which were G13D (14.5% of KRAS mutations; 6% overall). Thirteen patients with KRAS G13D-mutated tumors received best supportive care on the CO.17 trial and experienced significantly worse overall survival (OS) compared with patients with other KRAS-mutated or KRAS wild-type tumors in a univariate analysis. After adjustment for potential prognostic factors (eg, age, sex, performance status, prior chemotherapy, and primary site) in the multivariate analysis, however, there were no survival differences by KRAS status (Table). Patients with G13D-mutated tumors who received any cetuximab-based therapy (monotherapy or cetuximab plus

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chemotherapy) experienced longer survival than patients with other KRAS mutations, with OS 7.6 versus 5.7 months and progression-free survival (PFS) 4.0 versus 1.9 months (Cox regression P=.005 and .004, respectively) (Table). But because G13D did not portend a worse prognosis in multivariate analysis, the significance of improved survival end points for cetuximab-treated patients with G13D-mutated tumors compared with other KRAS mutations is unclear. Moreover, all of the benefit occurred in patients treated with cetuximab plus chemotherapy, raising the possibility that outcomes could have been more affected by the chemotherapy. In the presence of a G13D mutation, cetuximab monotherapy (pooled data) did predict significantly better OS compared with no cetuximab (CO.17 trial) (P=.02 by log-rank test), and there was a trend toward significance in the CO.17 trial only. There was no significant difference in response rates between G13D and other KRAS mutants treated with cetuximab-based therapy. Overall, the results of De Roock et al1 provide greater support for G13D as a predictive rather than a prognostic marker.

Following these findings in the refractory setting, the association of KRAS G13D with outcomes in patients

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with mCRC treated with first-line chemotherapy with or without cetuximab was investigated by Tejpar et al in a retrospective analysis of 1378 patients from the randomized CRYSTAL and OPUS trials.2 Here, 533 patients (39%) had a KRAS mutation at codon 12 or 13, 83 of which were G13D (16% of KRAS mutations; 8% overall). Median OS was longer than in De Roock et al,1 consistent with first-line therapy, compared with the chemotherapy-refractory setting (Table). When treated with chemotherapy alone, patients with G13D mutant tumors had a worse outcome compared with patients with other KRAS mutant or KRAS wild-type tumors.

When cetuximab was added to chemotherapy, significant improvements in PFS (median 7.4 vs 6.0 months, hazard ratio [HR] 0.47; P=.039) and tumor response (40.5% vs 22.0%; odds ratio 3.38; P=.042) were observed among patients with G13D mutations, although the OS benefit did not reach significance (Table). The cetuximab treatment effect in the G13D subset was comparable to that in patients with KRAS wild-type tumors, but OS and PFS were considerably lower. By contrast, survival worsened with the addition of cetuximab to chemotherapy among patients with other KRAS mutations (6.7 vs 8.1 months; HR 1.37).

To summarize, both of these large, pooled retrospective studies found that patients with KRAS G13D mutant mCRC may have a poor prognosis when treated with best supportive care or standard chemotherapy in the chemotherapy-refractory1 or first-line setting,2 respectively. In both studies, patients with G13D mutations appeared to derive modest benefit from the addition of cetuximab.

Smaller, single-arm studies have yielded complex results with respect to the prognostic significance of KRAS G13D mutations, a confounding factor that clouds interpretation of predictive impact.4,35 Evaluation of 229 Japanese CRC patients found a nonsignificant trend toward worse OS of patients with G13D mutations compared with patients with KRAS wild-type tumors (HR 1.67; 95% CI, 0.93-3.02; P=.086 on univariate analysis).4 Survival of patients with G12 mutant tumors was similar to KRAS wild-type, whereas patients with BRAF

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V600E mutant tumors had the worst OS (HR 3.78; 95% CI, 1.89-7.54; P≤.001).4 On the other hand, 2 reports suggest a link between KRAS G13D and microsatellite instability (MSI) associated with favorable outcome.35,36 An analysis of mutation frequency in 158 hereditary nonpolyposis CRC (HNPCC) and 864 sporadic CRC cases identified a significantly higher rate of G13D mutations in HNPCC tumors (microsatellite unstable) compared with sporadic microsatellite-stable tumors (51% vs 12% of KRAS mutations).36 G13D mutations were also overrepresented in sporadic MSI-high tumors without hMLH1 methylation (27% of KRAS mutations).36 In a study of 94 hereditary and 404 sporadic CRC cases, KRAS G13D mutations were associated with a better prognosis in HNPCC and sporadic MSIhigh subsets.35 A growing number of small studies are examining the predictive value of KRAS G13D with respect to cetuximab treatment.37-39 These studies, limited by size and clinical heterogeneity, highlight the importance of access to tissue from large groups of similarly treated patients for subset analyses.

Treated with chemotherapy alone, patients with G13D mutant tumors had a worse outcome compared to patients with other KRAS mutant or KRAS wild-type tumors.

Peeters et al40 presented an important counterpoint to the findings in De Roock et al1 and Tejpar et al2 at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting. Evaluation of 1083 patients treated with secondline FOLFIRI plus panitumumab (NCT00339183), 1096 patients treated with first-line FOLFOX4 plus panitumumab (PRIME, NCT00364013), and 184 patients who received panitumumab monotherapy (NCT00113776) yielded inconsistent associations between specific KRAS mutations and survival.40 Tejpar et al2 pooled data from the CRYSTAL (FOLFIRI ± cetuximab) and OPUS (FOLFOX4 ± cetuximab) studies because they found that

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irinotecan- and oxaliplatin-containing chemotherapy regimens produced similar treatment effects in patients stratified by KRAS mutation status. Conversely, Peeters et al40 reported a trend toward better OS among patients with G13D-mutated tumors treated with FOLFIRI plus panitumumab (N=39; P=.07), whereas G13D was significantly associated with worse OS among patients treated with FOLFOX4 plus panitumumab (N=46; P=.003), and G13D was not predictive or prognostic of outcome when the panitumumab studies were pooled. The possibility that different anti-EGFR agents, in addition to lines of therapy and chemotherapy backbones, may contribute to unequal outcomes in association with KRAS mutation status further complicates the G13D story.

If “shades of gray” exist among KRAS mutations, might the same be true for other oncogenes and tumor suppressor genes?

The answer is, of course, yes.

More Questions Than Answers Following these analyses of over 3000 patients, evidence to support KRAS G13D as an independent predictive and/or prognostic biomarker in CRC still has not matured. Returning to the question of biologic mechanism, is there a plausible explanation for intermediate effects of KRAS G13D with respect to both response to cetuximab and survival? Intermediate response to cetuximab is easier to explain because KRAS mutations at codon 13 are less oncogenic than mutations at codon 12.1,20,21,24 A less activating KRAS mutation may mean that the tumor is partially growth factor dependent and thereby somewhat responsive to EGFR inhibition. It is difficult to directly attribute worse survival to G13D mutations. More likely, G13D mutations could signify a different biological signature that portends worse prognosis.

Different carcinogenic triggers produce distinct patterns of mutations: depending on the chemical used, KRAS codon 12 or 61 mutant lung cancers can be induced in mice.41 In human lung cancers, KRAS muta-

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tions are common in smokers, whereas EGFR and ALK mutations are more frequent in never-smokers.42 In CRC, rather than being a driver, KRAS G13D mutations may develop secondary to another oncologic process and propagate because they confer a modest survival advantage for tumor cells. This hypothesis is supported by findings in cultured cells subjected to continuous cetuximab: KRAS G13D mutations accompanied emergence of resistance, and deep sequencing subsequently detected preexisting G13D mutations in a minority of parental cells.43 KRAS G13D is also a nontumor-initiating mutation in HNPCC, caused by defects in DNA mismatch repair genes that lead to a myriad of somatic mutations.36,44 A poor prognosis, BRAF-mutated–like gene expression signature was identified in 30% of KRAS mutant CRCs.45 Follow-up work presented at the 2012 ASCO Annual Meeting showed additional evidence for heterogeneity among KRAS mutant colon tumors but no significant division by specific KRAS mutation.46 A moderately aggressive CRC subgroup marked by KRAS G13D mutations has not been described.

If “shades of gray” exist among KRAS mutations, might the same be true for other oncogenes and tumor suppressor genes? The answer is, of course, yes. For example, phosphoinositide-3-kinase (PI3K, coded by the PIK3CA gene) is mutated in ~15% of CRCs. PIK3CA has 2 mutational hot-spot clusters located approximately 1500 nucleotides apart, corresponding to the helical domain (eg, E545K) and the kinase domain (eg, H1047R). Helical and kinase domain mutations induce gain of function by different mechanisms. Helical domain mutations are dependent on RAS binding for transformation; kinase domain activation is mediated by interaction with the p85 regulatory subunit.47 In CRC, helical domain mutations associate with KRAS mutations, methylation of the MGMT DNA repair gene, and CpG island methylator phenotype–low status, while kinase domain mutations correlate with serrated pathway features including BRAF mutation and MSI.48 As with KRAS, the distribution of PIK3CA helical and kinase domain mutations varies by tissue of origin. In

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CRC, the distribution is roughly two-thirds helical to one-third kinase domain mutations. Breast cancer has the highest rate of PI3K mutations (25%), and the ratio of helical to kinase domain mutations is opposite that in CRC.17 Even identical mutations can have differing effects by cancer type, as highlighted by dissimilar responses to BRAF inhibitors among patients with BRAF V600E CRC or melanoma.49 A final example of the potential for disparate impact of mutant alleles within a single gene involves the tumor suppressor protein p53. Mutation of p53 is the most common genetic lesion in human malignancies, including nearly half of CRCs. Whereas a limited number of mutations activate oncogenes, a greater variety of lesions can inactivate tumor suppressors. One study assessed effects of 2314 point mutations in the p53 DNA-binding domain.50 We ascertained p53 status in 604 tumors from the CALGB 89803 trial of adjuvant therapy for stage III colon cancer. Tumors were classified as p53 wild-type or mutation present in the zinc-binding (ZB) or the non–zinc-binding (NZB) regions of the DNA-binding domain. Overall, p53 mutational status was not associated with survival.51 However, among women, survival was superior with NZB mutations compared with wild-type p53 and worst with ZB mutations.51 A larger sample would be required to determine whether these differences could be attributed to specific p53 hotspot mutations.

Implications for Personalized Medicine The central clinical question remains unanswered: will a patient with mCRC harboring a KRAS G13D mutation benefit from anti-EGFR therapy? Based on the modest efficacy of anti-EGFR therapy even among patients with KRAS wild-type tumors, the sample size required for a prospective randomized study in the KRAS G13D subset would be prohibitive and perhaps inappropriate in light of the priority to identify new targets and more active agents. Additional large retrospective analyses of cohorts of CRC patients with matched clinicopathologic and treatment characteristics may provide greater precision in estimating the prognostic and pre-

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dictive value of G13D, although there remains a distinct possibility that the impact is unsatisfyingly contextdependent and marginal. Are the differences meaningful, or are we trying to distinguish gray from grey?

KRAS G13D heralds an approaching onslaught of new questions as next-generation sequencing and other technologies reach the clinical arena. If mutations in adjacent codons can have unequal effects, what level of “personalization” is required in oncology clinical research? Even synonymous mutations (resulting in the same amino acid sequence) can produce differences in RNA processing that significantly alter protein levels or functions.52 We submit that validation of novel “personalized medicine” biomarkers should involve an iterative

KRAS G13D heralds an approaching onslaught of new questions as nextgeneration sequencing and other technologies reach the clinical arena. approach whereby hypothesis-generating data from clinical samples – such as the observations reviewed here suggesting a differential impact of KRAS G13D versus other KRAS mutations – should trigger a return to preclinical mechanistic studies in parallel with additional retrospective analyses of independent clinical data sets.

Across these endeavors, tumor genotyping should be specific to the nucleotide level and compiled to identify broad signals of high-impact genetic events. As our understanding of CRC biology becomes more nuanced, we must steadfastly search for therapies with unequivocal benefit for molecularly defined subsets of patients. u

Acknowledgments CEA is supported in part by Postdoctoral Fellowship 11-183-01-TBG from the American Cancer Society and also acknowledges the support Millennium provided through the Alliance for Clinical Trials in Oncology Foundation. JMO is supported by the UCSF Medical Scientist Training Program NIH-NIGMS-MSTP

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(#GMO7618). We thank David Donner, PhD, for editorial assistance.

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2. Tejpar S, Celik I, Schlichting M, et al. Association of KRAS G13D tumor mutations with outcomes in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab [published online ahead of print June 25, 2012]. J Clin Oncology.

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5. Trahey M, McCormick F. A cytoplasmic protein stimulates normal Nras p21 GTPase, but does not affect oncogenic mutants. Science. 1987; 238:542-545.

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Mol Cell Biol. 1987;7:2128-2133.

7. Gutierrez L, Magee AI, Marshall CJ, et al. Post-translational processing of p21ras is two-step and involves carboxyl-methylation and carboxy-terminal proteolysis. EMBO J. 1989;8:1093-1098.

8. Casey PJ, Solski PA, Der CJ, et al. p21ras is modified by a farnesyl isoprenoid. Proc Natl Acad Sci U S A. 1989;86:8323-8327.

9. Medema RH, de Vries-Smits AM, van der Zon GC, et al. Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21ras. Mol Cell Biol. 1993;13:155-162.

10. Buday L, Downward J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell. 1993;73:611-620.

11. Moodie SA, Willumsen BM, Weber MJ, et al. Complexes of Ras. GTP with Raf-1 and mitogen-activated protein kinase kinase. Science. 1993;260: 1658-1661.

12. Scheffzek K, Ahmadian MR, Kabsch W, et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science. 1997;277:333-338.

13. Parada LF, Tabin CJ, Shih C, et al. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature. 1982;297:474-478.

14. Santos E, Tronick SR, Aaronson SA, et al. T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes. Nature. 1982;298:343-347.

15. Der CJ, Krontiris TG, Cooper GM. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc Natl Acad Sci U S A. 1982;79:3637-3640.

16. Shimizu K, Goldfarb M, Suard Y, et al. Three human transforming genes are related to the viral ras oncogenes. Proc Natl Acad Sci U S A. 1983;80:2112-2116.

17. Wellcome Trust Sanger Institute. www.sanger.ac.uk/genetics/CGP/cosmic.

18. Milburn MV, Tong L, deVos AM, et al. Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science. 1990;247:939-945.

19. Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science. 2001;294:1299-1304.

20. Fasano O, Aldrich T, Tamanoi F, et al. Analysis of the transforming potential of the human H-ras gene by random mutagenesis. Proc Natl Acad Sci U S A. 1984;81:4008-4012.

21. Gideon P, John J, Frech M, et al. Mutational and kinetic analyses of the GTPase-activating protein (GAP)-p21 interaction: the C-terminal domain of GAP is not sufficient for full activity. Mol Cell Biol. 1992;12:20502056.

22. Feig LA, Cooper GM. Relationship among guanine nucleotide exchange, GTP hydrolysis, and transforming potential of mutated ras proteins. Mol Cell Biol. 1988;8:2472-2478.

23. Quilliam LA, Zhong S, Rabun KM, et al. Biological and structural

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characterization of a Ras transforming mutation at the phenylalanine-156 residue, which is conserved in all members of the Ras superfamily. Proc Natl Acad Sci U S A. 1995;92:1272-1276.

24. Seeburg PH, Colby WW, Capon DJ, et al. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature. 1984;312:71-75.

25. Recktenwald CV, Mendler S, Lichtenfels R, et al. Influence of Ki-rasdriven oncogenic transformation on the protein network of murine fibroblasts. Proteomics. 2007;7:385-398.

26. Horsch M, Recktenwald CV, Schadler S, et al. Overexpressed vs mutated Kras in murine fibroblasts: a molecular phenotyping study. Br J Cancer. 2009;100:656-662.

27. Guerrero S, Casanova I, Farré L, et al. K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression. Cancer Res. 2000;60:6750-6756.

28. Der CJ, Finkel T, Cooper GM. Biological and biochemical properties of human rasH genes mutated at codon 61. Cell. 1986;44:167-176.

29. Lacal JC, Aaronson SA. Activation of ras p21 transforming properties associated with an increase in the release rate of bound guanine nucleotide.

Mol Cell Biol. 1986;6:4214-4220.

30. Sloan SR, Newcomb EW, Pellicer A. Neutron radiation can activate Kras via a point mutation in codon 146 and induces a different spectrum of ras mutations than does gamma radiation. Mol Cell Biol. 1990;10:405-408.

31. Feig LA, Cooper GM. Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol Cell Biol.

1988;8:3235-3243.

32. Smith G, Bounds R, Wolf H, et al. Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine. Br J Cancer. 2010;102:693-703.

33. Edkins S, O’Meara S, Parker A, et al. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther. 2006;5:928-932.

34. Jhawer M, Goel S, Wilson AJ, et al. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 2008;68:1953-1961.

35. Zlobec I, Kovac M, Erzberger P, et al. Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer. Int J Cancer.

2010;127:2569-2575.

36. Oliveira C, Westra JL, Arango D, et al. Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status. Hum Mol Gen. 2004;13:2303-2311.

37. Gajate P, Sastre J, Bando I, et al. Influence of KRAS p.G13D mutation in patients with metastatic colorectal cancer treated with cetuximab [published online ahead of print April 24, 2012]. Clin Colorectal Cancer.

38. Modest DP, Reinacher-Schick A, Stintzing S, et al. Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13Dmutated metastatic colorectal cancer: a pooled analysis. Anticancer Drugs.

2012;23:666-673.

39. Modest DP, Jung A, Moosmann N, et al. The influence of KRAS and BRAF mutations on the efficacy of cetuximab-based first-line therapy of metastatic colorectal cancer: an analysis of the AIO KRK-0104-trial. Int J Cancer. 2012;131:980-986.

40. Peeters M, Douillard J, Van Cutsem E, et al. Mutant (MT) KRAS codon 12 and 13 alleles in patients (pts) with metastatic colorectal cancer (mCRC): assessment as prognostic and predictive biomarkers of response to panitumumab (pmab). J Clin Oncol. 2012;30(suppl). Abstract 3581.

41. You M, Candrian U, Maronpot RR, et al. Activation of the Ki-ras protooncogene in spontaneously occurring and chemically induced lung tumors of the strain A mouse. Proc Natl Acad Sci U S A. 1989;86:3070-3074.

42. Paik PK, Johnson ML, D’Angelo SP, et al. Driver mutations determine survival in smokers and never-smokers with stage IIIB/IV lung adenocarcinomas [published online ahead of print May 17, 2012]. Cancer.

43. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature.

2012;486:532-536.

44. Boland CR, Goel A. Microsatellite instability in colorectal cancer.

Gastroenterology. 2010;138:2073-2087.

45. Popovici V, Budinska E, Tejpar S, et al. Identification of a poor-prognosis BRAF-mutant-like population of patients with colon cancer. J Clin Oncol. 2012;30:1288-1295.

46. Popovici VC, Budinska E, Tejpar S, et al. Molecular and clinicopatho-

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logic evidence of heterogeneity in KRAS-mutant colon cancers. J Clin Oncol. 2012;30(suppl). Abstract 3575.

47. Zhao L, Vogt PK. Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS. Cell Cycle. 2010;9:596-600.

48. Whitehall VL, Rickman C, Bond CE, et al. Oncogenic PIK3CA mutations in colorectal cancers and polyps. Int J Cancer. 2012;131:813-820.

49. Kopetz S, Desai J, Chan E, et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol. 2010;28(suppl):15s.

Abstract 3534.

50. Kato S, Han SY, Liu W, et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A. 2003;100:8424-8429.

51. Warren RS, Atreya CE, Niedzwiecki D, et al. A novel interaction of genotype, gender, and adjuvant treatment in survival after resection of stage III colon cancer: results of CALGB 89803. J Clin Oncol.

2012;30(suppl). Abstract 3517.

52. Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet. 2011;12:683-691.

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Deborah Dunsire, MD President and Chief Executive Officer Millennium: The Takeda Oncology Company

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K. Peter Hirth, PhD Chief Executive Officer Plexxikon, Inc.

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Healthcare Economics

Institute of Medicine Report: Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Highlights for the Cancer Community James Conway Harvard School of Public Health Boston, Massachusetts

O

adox. The past 50 years have seen an explosion in bion September 6, 2012, the Institute of Medimedical knowledge, dramatic innovation in therapies cine (IOM) released the report Best Care at and surgical procedures, and management of conditions Lower Cost: The Path to Continuously Learning 1 that previously were fatal, with ever more exciting clinHealth Care in America. The aim of this report, authored by the Committee on the Learning ical capabilities on the horizon. Yet, the IOM report Best Care at Lower Health Care System in America, was to Cost finds that America’s healthcare identify how the effectiveness and effisystem has become too complex and ciency of the current healthcare system costly to continue business as usucan be transformed, and to develop recal. Inefficiencies, an overwhelming ommendations for actions that can be amount of data, and other economic taken to achieve that end. This study and quality barriers hinder progress in builds on earlier IOM studies of various aspects of the healthcare system, from improving health and threaten the naTo Err Is Human: Building a Safer Health tion’s economic stability and global System,2 on patient safety; to Crossing competitiveness. At the same time, the report notes there is significant evthe Quality Chasm: A New Health Sys3 James Conway idence that the knowledge and tools tem for the 21st Century, on healthcare exist now to put the health system on quality; to Unequal Treatment: Con4 the right course to achieve continuous improvement fronting Racial and Ethnic Disparities in Health Care, on and better quality care at lower cost. healthcare disparities. The study process was also facilIn the area of costs, including both financial and itated and informed by the 6 years of published summaries of workshops conducted under the auspices of the harm, the system’s current inefficiency underscores the urgent need for a system-wide transformation. HealthIOM Roundtable on Value & Science-Driven Health care costs have risen at an unsustainable rate – increasCare. Sponsors of the report included Blue Shield of ing at a greater rate than the economy as a whole for 31 California Foundation, Charina Endowment Fund, and of the past 40 years. Yet, the report found that a substanthe Robert Wood Johnson Foundation. tial amount of this investment was wasted. It calculated that about 30% of health spending in 2009 – roughly Overall Findings and $750 billion – was wasted on unnecessary services, exRecommendations cessive administrative costs, fraud, and other problems.

Healthcare in America presents a fundamental parJames Conway is a member of the Institute of Medicine committee for this report, the faculty of Harvard School of Public Health, and a board member of the American Cancer Society New England Region. He previously served as Executive Vice President and COO of the Dana-Farber Cancer Institute, Boston.

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Part of the reason for this waste comes from the way that healthcare is paid for and reimbursed. Most payment systems emphasize volume over quality and value by reimbursing providers for individual procedures and tests rather than paying a flat rate or reimbursing based on patients’ outcomes, the report notes. Regardless of the cause, these inefficiencies cause needless suffering. By one estimate, roughly 75,000 deaths might have been averted in 2005 if every state had delivered care at the quality level of the best performing state.

The report says better use of data is a critical element of a continuously improving health system. About 75 million Americans have more than 1 chronic condition, requiring coordination among multiple specialists and therapies, which can increase the potential for miscommunication, misdiagnosis, potentially conflicting interventions, and dangerous drug interactions. Health professionals and patients frequently lack relevant and useful information at the point of care where decisions are made. And it can take years for new breakthroughs to gain widespread adoption; for example, it took 13 years for the use of beta-blockers to become standard practice after they were shown to improve survival rates for heart attack victims.

The committee found that engaging patients and their families in care decisions and management of their conditions leads to better outcomes and can reduce costs. Yet, such participation remains limited. Increased transparency about the costs and outcomes of care also boosts opportunities to learn and improve and should be a hallmark of institutions’ organizational cultures, the committee said. Linking providers’ performance to patient outcomes and measuring performance against internal and external benchmarks allow organizations to enhance their quality and become better stewards of limited resources, the report says.

In framing the plan for moving forward, the report finds that incremental upgrades and changes by individual hospitals or providers will not suffice. Achieving higher quality care at lower cost will require an acrossthe-board commitment to transform the US health system into a “learning” system that continuously improves

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by systematically capturing and broadly disseminating lessons from every care experience and new research discovery. It will necessitate embracing new technologies to collect and tap clinical data at the point of care, engaging patients and their families as partners, and establishing greater teamwork and transparency within healthcare organizations. Also, incentives and payment systems should emphasize the value and outcomes of care. The ways that healthcare providers currently train, practice, and learn new information cannot keep pace with the flood of research discoveries and technological advances. How healthcare organizations approach care delivery and how providers are paid for their services also often lead to inefficiencies and lower effectiveness and may hinder improvement.

Engaging patients and their families in care decisions and management of their conditions leads to better outcomes and can reduce costs.

The report outlines the characteristics of a continuously learning healthcare system – science and informatics, patient-clinician partnerships, incentives, and culture – and offers 10 foundational, care improvement, and supportive policy environment recommendations (Table).

Implications for the Cancer Community Cancer is frequently cited in the report for its successes, such as the improvements cancer care has achieved in 5-year survival rates, for its experience in developing and using evidence-based practice guidelines, and for often generating evidence from routine cancer care. The cancer professional considering the recommendations will be struck with their resonance not only in successes but also challenges and gaps. No doubt they will also be energized with the possibilities and power of a learning healthcare system for cancer.

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Table. Categories of the Committeeâ&#x20AC;&#x2122;s Recommendations Foundational Elements Recommendation 1: The digital infrastructure. Improve the capacity to capture clinical, care delivery process, and financial data for better care, system improvement, and the generation of new knowledge.

Recommendation 2: The data utility. Streamline and revise research regulations to improve care, promote the capture of clinical data, and generate knowledge.

Care Improvement Targets Recommendation 3: Clinical decision support. Accelerate integration of the best clinical knowledge into care decisions.

Recommendation 4: Patient-centered care. Involve patients and families in decisions regarding health and healthcare, tailored to fit their preferences.

Recommendation 5: Community links. Promote community-clinical partnerships and services aimed at managing and improving health at the community level.

Recommendation 6: Care continuity. Improve coordination and communication within and across organizations.

Recommendation 7: Optimized operations. Continuously improve healthcare operations to reduce waste, streamline care delivery, and focus on activities that improve patient health.

Supportive Policy Environment Recommendation 8: Financial incentives. Structure payment to reward continuous learning and improvement in the provision of best care at lower cost.

Recommendation 9: Performance transparency. Increase transparency on healthcare system performance.

Recommendation 10: Broad leadership. Expand commitment to the goals of a continuously learning health care system.

Reprinted with permission, Institute of Medicine. Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. 2012 by the National Academy of Sciences, Courtesy of the National Academies Press, Washington, DC. www.nap.edu/catalog.php?record_id=13444.

Familiar to cancer care are the struggles in the translation from science to evidence to care to improved patient and family experience. There are challenges in performing high-quality, coordinated care in the existing disaggregated environment. Cancer care is delivered by many, and often unconnected, players â&#x20AC;&#x201C; in the home,

Familiar to cancer care are the struggles in the translation from science to evidence to care to improved patient and family experience.

office, local hospital, regional academic setting, and hospice by patient and family, healthcare providers, notfor-profit associations, and others. Furthermore, clinicians must confront the complexity of different

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treatment options and understand the variations of the patient populations in their treatment responses. To overcome these challenges, cancer providers are enhancing, and will need to accelerate, evidence-based practice; implement shared decision making in all aspects of clinical care and research; and improve access and optimize the flow of their patients.

Drawing from leading-edge practices in cancer, the authoring committee emphasizes the power and privilege of patient- and family-centered care. The committee makes special note of the increasing role that communities must play in care, with care designed across the continuum. At the moment, patients and families are shuffled from place to place. In the future, the system must be integrated, designed to manage care across the continuum and facilitate outcomes through access, care, flow, and the reduction of waste and inequity. Note is frequently made of the growing emphasis

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in cancer on health and prevention as well as healthcare. Stakeholder organizations in communities must come together in support of health and healthcare.

The role of the policy environment clearly resonates in cancer. In pondering the role of financial incentives, the need for, and current lack of, reimbursement for palliative care quickly come to mind. With the growing emphasis on waste and value, the question is increasingly being asked on how we can assure the right cancer care in the right place at the right time; nothing more, nothing less. Efforts such as the ABIM-led Choosing Wisely campaign are consistent with recommendations in the report and inform our journey to answer these questions in partnership with the patient and family.

Cancer care providers are already seeing the growing focus on outcomes and calls for greater transparency, particularly around financial outcomes. While financial outcomes are essential, they must be considered in the context of transparency of all outcomes: clinical, financial, service, and experience (staff and patient). This will require an accelerated emphasis in the cancer community; in the absence of other outcomes, finance will trump. Finally, leadership driven by a culture of teamwork, collaboration, and adaptability must deepen not only in organizations but, even more crucially, across them. Cancer care providers must continue to seize the power of communities of learning – in research, care, prevention, operations – and become master collaborators and continuous improvers across all organizations in the cancer space.

Closing Since its release, the IOM report Best Care at Lower Cost: The Path to Continuously Learning Health Care in America has garnered considerable attention. At one end people are struck at the potential power of the recommendations to transform, the clarity of the path forward, the strength of the evidence, and the centrality of

Leadership driven by a culture of teamwork, collaboration, and adaptability must deepen not only in organizations but, even more crucially, across them. patient, family, and community in partnership with their care team. They are sobered, if not stunned, by the extent of the missed opportunities, waste, and harm when presented in the aggregate. Most already know them in their own experience or that of someone they love. It is now time the cancer community rapidly accelerates efforts to take, inform, and improve the Path to Continuously Learning Health Care in America. u

References 1. Institute of Medicine. Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Washington, DC: National Academies Press; 2012. www.iom.edu/bestcare.

2. Institute of Medicine. To Err Is Human: Building a Safer Health System.

Washington, DC: National Academies Press; 1999.

3. Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academies Press; 2001.

4. Institute of Medicine. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. Washington, DC: National Academies Press; 2002.

SECOND ANNUAL CONFERENCE #

Clinical Approaches to Targeted Technologies# October 4-6, 2013

The Seaport Boston Hotel • 1 Seaport Lane • Boston, MA 02210

✓REGISTER TODAY AT www.globalbiomarkersconsortium.com Volume 1 • No 6

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Melanoma

The New Therapeutic Paradigm for Personalized Therapy of Melanoma At the 2012 conference of the Global Biomarkers Consortium, which took place March 9-11, 2012, in Orlando, Florida, Sanjiv Agarwala, MD, from Temple University School of Medicine and St. Luke’s Cancer Center in Bethlehem, Pennsylvania, discussed the use of personalized therapy in the management of melanoma.

T

he incidence of melanoma in The prognosis is excellent for patients the United States is increasing who present with localized disease and at an alarming rate (Figure 1).1 primary tumors ≤1.0 mm in thickness, In men, melanoma is increasing more with 5-year survival achieved in >90% rapidly than in any other cancer; in of patients. However, survival rates women, it is increasing more rapidly range from 50% to 90% when the lothan any other cancer except lung cancalized melanomas are >1.0 mm in cer.2 In 2012, an estimated 76,250 new thickness. When regional nodes are incases of melanoma (44,250 in men and volved, survival rates are roughly 32,000 in women) are expected in the halved. However, within stage III, 5United States, and 9180 people are exyear survival rates range from 20% to pected to die of this cancer.3 70%, depending primarily on the nodal Sanjiv Agarwala, MD More than 80% of melanoma patumor burden. Long-term survival in tients present with localized disease, 10% to 13% with patients with stage IV disease is <10%.2 2 regional disease, and 2% to 5% with distant metastases.

Systemic therapy is the primary treatment option for most patients with stage IV disease.2 For the past 30 years, there were no major advances in treatment for Case 1 metastatic melanoma, and until recently people with • 47-year-old male with a history of melanoma 6 years ago; the disease had few options.2 However, the therapeutic no adjuvant therapy given landscape for metastatic melanoma is rapidly changing • Routine follow-up shows “spots on chest x-ray” with the recent development of novel agents that have • CT scan confirms 4 lesions, 2 in each lung; biopsy confirms demonstrated better efficacy than traditional chemometastatic melanoma therapy2 (Figure 2). Importantly, melanomas can now • Lactate dehydrogenase (LDH) within normal limits; no be classified according to the underlying molecular aberother metastases; performance status 0 rations that drive tumor progression, and these biomark• Tumor is BRAF V600E positive ers are now being used in therapeutic practice.2

Case 2 • 56-year-old male with history of melanoma on left upper back; T4b N2a M0 in 2008 • Received high-dose interferon for 1 year, tolerated with 33% dose reduction • Now presents with multiple cutaneous metastases, lung metastases • Biopsy positive for metastatic melanoma; LDH normal • BRAF wild-type; NRAS positive

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Chemotherapy DTIC (dacarbazine) (Table 1) is the only FDA-approved chemotherapy agent for the treatment of stage IV melanoma. It is administered as an IV infusion.4-6 Temozolomide is an oral chemotherapy agent that is considered an oral form of DTIC, but it is not approved by the FDA for the treatment of melanoma.4,6 A number of combination therapies, including the Dartmouth regimen (DTIC, cisplatin, carmustine, and

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Interferon alpha-2b is the FDA-approved standard treatment for patients with metastatic melanoma, but interferon therapy is associated with significant adverse reactions in most patients. Interleukin-2 (IL-2) has been used for the treatment of melanoma with modest success for several decades, but many acute toxicities are associated with interleukin therapy, and extremely close monitoring is essential for safe administration.8-10 Ipilimumab, a monoclonal antibody that binds to CTLA-4, was approved by the FDA on March 25, 2011, making it the first drug in 13 years to be approved for the treatment of melanoma. Approval was based on a randomized phase 3 trial of 676 patients with unresectable metastatic disease that progressed during sys-

Volume 1 â&#x20AC;˘ No 6

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IL-2 has been used for the treatment of melanoma with modest success for several decades, but many acute toxicities are associated with interleukin therapy. gp100 alone (6.4 months). The best objective response rates were 5.7% for ipilimumab plus gp100, 10.9% for ipilimumab alone, and 1.5% for gp100 alone. Ipilimumab stimulates T cells and is associated with a substantial risk of immune-related reactions. Grade 3 or 4 immune-related adverse events occurred in 10% to 15% of patients treated with ipilimumab and in 3% of those

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Melanoma "

Figure 2. Metastatic Melanoma Treatment Landscape

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Ipilimumab is the first immunotherapy to show an OS advantage for patients with metastatic melanoma. An OS benefit was seen as a single agent compared with a vaccine and in combination with DTIC compared with DTIC alone, and the drug is effective for both frontline and second-line therapy. As yet, however, there is no confirmed biomarker to predict response to ipilimumab.

Biochemotherapy

Biochemotherapy is the combination of chemotherapy IJKA!!4:4!4" >+")*&''" " " and biological agents. Recent " " " " " " " " studies have shown that outCVD indicates cisplatin-vinblastine-DTIC; Dartmouth, DTIC-cisplatin-carmustine-tamoxifen; DTIC, dacarbazine; IFN, interferon; IL-2, interleukin-2; TMZ, temozolomide. Figure courtesy of Sanjiv Agarwala, MD. comes in patients treated with biochemotherapy are no better than outcomes in patients treated with combination treated with gp100 alone. There were 14 deaths related chemotherapy. In a phase 3 randomized study, to the study drugs (2.1%), and 7 were associated with biochemotherapy (cisplatin, vinblastine, DTIC, IL-2, immune-related adverse events.11 and interferon alpha-2b) produced a slightly higher response rate and progression-free survival (PFS) than cisMelanoma is not 1 disease. Evidence platin, vinblastine, and dacarbazine (CVD) alone, but increasingly shows that melanoma is not 1 it was not associated with either improved quality of response or OS, and biochemotherapy was substantially malignant disorder but rather a family of more toxic than CVD.13 Other studies that attempted distinct molecular diseases. to decrease the toxicity of biochemotherapy by administering subcutaneous outpatient IL-2 did not show a A second phase 3 study was conducted in 502 pasubstantial benefit of biochemotherapy versus chemotherapy alone.14-16 A meta-analysis also showed that altients with previously untreated metastatic melanoma.12 OS was significantly longer in the group receiving ipithough biochemotherapy improved overall response limumab plus DTIC than in the group receiving DTIC rates, there was no survival benefit for patients with metastatic melanoma.17 plus placebo (11.2 months vs 9.1 months), and survival rates were higher for the group receiving ipilimumabTargeted Therapy DTIC at 1-, 2-, and 3-year time points (Table 2). Grade Melanoma is not 1 disease. Evidence increasingly 3 or 4 adverse events occurred in 56.3% of patients shows that melanoma is not 1 malignant disorder but treated with ipilimumab plus DTIC versus 27.5% of rather a family of distinct molecular diseases.1 Exposure those treated with DTIC and placebo (P<.001).

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Table 1. Therapies for Metastatic Melanoma Chemotherapy

• Single agents: DTIC, temozolomide • Combination therapies: Dartmouth regimen, CVD

Immunotherapy

• IL-2 • Ipilimumab

Biochemotherapy

• Example: Cisplatin, vinblastine, DTIC, IL-2, and interferon alpha-2b

Targeted (personalized) therapy

• Vemurafenib for patients with a documented V600E mutation of the BRAF gene • Imatinib for melanoma with c-KIT mutation

CVD indicates cisplatin-vinblastine-DTIC; Dartmouth, DTIC-cisplatin-carmustine-tamoxifen; DTIC, dacarbazine; IL-2, interleukin-2.

Proportion Surviving

to the sun is generally accepted as a major Figure 3. Survival: Single-Agent DTIC vs 4-Drug Dartmouth causative factor of melanoma; however, Regimen the role of exposure to ultraviolet light is complex. For example, in light-skinned 1.0 people, the group that is predominantly affected by melanoma, tumors are most 0.8 common on areas that are intermittently exposed to the sun, such as the trunk, arms, and legs, rather than on areas that 0.6 are chronically exposed to the sun, such as the face. A small proportion of melanomas arise without obvious expo0.4 sure to ultraviolet light, because they affect sites that are relatively or absolutely protected, such as the palms and soles 0.2 (acral melanoma), and mucosal membranes.18 Curtin and colleagues examined 102 0.0 0 12 24 36 48 60 72 84 melanomas from 4 groups in which the Months degree of exposure to ultraviolet light difDartmouth indicates DTIC-cisplatin-carmustine-tamoxifen; DTIC, dacarbazine. fered: 18 melanomas from skin with Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartchronic sun-induced damage and 18 mouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17:2745melanomas from skin without such dam2751. Reprinted with permission. © 1999 American Society of Clinical Oncology. All rights reserved. age; 28 melanomas from palms, soles, and subungual (acral) sites; and 18 mucosal melanomas,19 was approved by the FDA in August 2011 melanomas, and genetic analysis showed significant diffor both first- and second-line treatment of unresectable ferences in the distribution of genetic mutations in 18 or metastatic melanoma with a V600E mutation in the BRAF, NRAS, and KIT among the 4 groups (Figure 4).

BRAF gene, as detected by an FDA-approved test. The Vemurafenib, a selective inhibitor of the activated cobas 4800 BRAF V600 Mutation Test, a companion BRAF V600E gene, a gene found in 70% of malignant

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Table 2. Survival Rates With Ipilimumab Plus DTIC vs DTIC Plus Placebo12

randomized to receive either vemurafenib orally twice daily or DTIC IV on day 1 every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, Ipilimumab Plus DTIC DTIC Plus Placebo and/or consent withdrawal. The major efficacy outcome 1-Year Survival 47.3% 36.3% measures were OS and investigator-assessed PFS. The 28.5% 17.9% 2-Year Survival overall response rate was 48% in the vemurafenib arm 3-Year Survival 20.8% 12.2% versus 5% in the DTIC arm. There were 2 complete reDTIC indicates dacarbazine. sponses and 104 partial responses in the vemurafenib arm, and all 12 responses in the DTIC Figure 4. Distribution of Genetic Alterations in BRAF, NRAS, and KIT arm were partial responses. The Among the 4 Groups of Melanomas median PFS was 5.3 months in the vemurafenib arm versus 1.6 months in the DTIC arm. Skin complications were frequently associated with the agent: 18% of vemurafenib-treated patients developed cutaneous squamous cell carcinoma or keratoacanthoma that required simple excision, while 12% experienced grade 2 or 3 photosensitivity skin reactions. Arthralgia was the most common (21%) noncutaneous side effect.

The FDA approval of vemurafenib in patients who received prior systemic therapy was based on a single-arm, multicenter phase 2 study in 132 patients.21 The confirmed best overall response rate was 53%; 6% with a complete response and 47% with a partial response. The meCSD indicates chronic sun-induced damage. dian time to response was 1.4 Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol.

2006;24:4340-4346. Reprinted with permission. Š 2006 American Society of Clinical Oncology. All rights months, with 75% of responses reserved. occurring by month 1.6 of treatment. The median duration of diagnostic test to determine the tumor mutational response was 6.5 months. Median survival was 15.9 months. Secondary skin lesions were detected in 26% status, received approval along with the agent. of patients.

The FDA approval of vemurafenib in previously unImatinib, a tyrosine kinase inhibitor that is FDA treated patients was based on an international, random20 approved as therapy for gastrointestinal stromal tumors ized, open-label trial in 675 subjects. Patients were

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and chronic myeloid leukemia, is under investigation as a treatment for patients with metastatic melanomas with c-KIT aberrations.22-24 In a phase 2 study of 43 patients with a median follow-up time of 12 months, the median PFS was 3.5 months, and the 6-month PFS rate was 36.6%. Ten patients (23.3%) achieved partial responses, and 13 patients (30.2%) achieved stable disease. The 1-year OS rate was 51.0%.24

The New Therapeutic Paradigm for Personalized Therapy of Melanoma The most important first step in treating a patient with metastatic melanoma today is to test the tumor, at least for BRAF status, and then choose a therapy based on BRAF status (Figure 5). If the tumor is BRAF positive (ie, mutant), vemurafenib is probably the best choice. If it is BRAF positive, and vemurafenib therapy has failed, then ipilimumab or IL-2 can be tried. If the tumor is BRAF negative (ie, wild-type), choices include ipilimumab, IL-2, or a clinical trial. It is important to always consider clinical trials.

Because not every patient is a candidate for immunotherapy, and not all patients are BRAF positive, chemotherapy will still play a role in the new therapeutic paradigm, but probably as a single agent in secondor third-line therapy.

Based on these new considerations, a good first-line choice for treating Case 1 would be vemurafenib, with ipilimumab as second-line treatment. A good first-line choice for treating Case 2 would be ipilimumab, with high-dose IL-2 as second-line treatment.

According to the National Comprehensive Cancer Network guidelines, “Although approval of ipilimumab and vemurafenib has significantly altered the initial management of patients with stage IV melanoma, each agent has unique limitations. For ipilimumab, there is the potential for serious autoimmune toxicity, clinical responses may take months to become apparent, and the overall response rate is less than 20%. However, when responses are seen, they can be quite durable. Vemurafenib, on the other hand, is associated with a 40% to 50% response rate in patients with a V600 mutated

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Figure 5. The New Therapeutic Paradigm for Personalized Therapy of Melanoma • Test the tumor: BRAF – c-KIT, NRAS for clinical trials • Pick therapy based on BRAF status – BRAF positive (mutant) • Vemurafenib • Immunotherapy with ipilimumab or IL-2 for selected patients – BRAF negative (wild-type) – ipilimumab, IL-2 – BRAF positive, fails BRAF therapy • Ipilimumab/IL-2 • Chemotherapy –ALWAYS consider clinical trials IL-2 indicates interleukin-2.

BRAF gene, and responses may be seen in days to weeks after starting the drug. Unfortunately, the median duration of response is only 5 to 6 months. The success of these 2 agents has prompted a new wave of questions regarding their use in the adjuvant setting, augmenting response by combining them with cytotoxic chemotherapy, and defining mechanisms of drug resistance. The pace of change underscores the importance of participating in a clinical trial whenever possible.”2 u

References 1. Romano E, Schwartz GK, Chapman PB, et al. Treatment implications of the emerging molecular classification system for melanoma. Lancet Oncol. 2011;12:913-922.

2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Melanoma. Version 2.2013. www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed November 16, 2012.

3. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. www.cancer.org/acs/groups/content/@epi demiologysurveilance/documents/document/acspc-031941.pdf. Accessed November 16, 2012.

4. Melanoma Research Foundation. Melanoma Treatment. www.me lanoma.org/learn-more/melanoma-101/melanoma-treatment. Accessed November 9, 2012.

5. Serrone L, Zeuli M, Sega FM, et al. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. 2000;19:21-34.

6. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18:158-166.

7. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17:2745-2751.

8. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using highdose bolus interleukin 2. JAMA. 1994;271:907-913.

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9. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105-2116.

10. Atkins MB, Kunkel L, Sznol M, et al. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(suppl 1):S11-S14.

11. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363: 711-723.

12. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364: 2517-2526.

13. Atkins M, Hsu J, Lee S, et al. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol.

2008;26:5748-5754.

14. Bajetta E, Del Vecchio M, Nova P, et al. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon alpha2b in metastatic melanoma. Ann Oncol. 2006;17:571-577.

15. Keilholz U, Punt CJ, Gore M, et al. Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for Research

and Treatment of Cancer Melanoma Group. J Clin Oncol. 2005;23:6747-6755.

16. Ridolfi R, Chiarion-Sileni V, Guida M, et al. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002;20:1600-1607.

17. Ives NJ, Stowe RL, Lorigan P, et al. Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol. 2007;25:5426-5434.

18. Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340-4346.

19. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809-819.

20. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.

21. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707-714.

22. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:2327-2334.

23. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29:2904-2909.

24. Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26:2046-2051.

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The Last Word

Companion Diagnostics and the Paradoxical Return of the Blockbuster Drug

I

n my article in the inaugural issue of Personalized which augurs well for a robust pipeline of quality drugs Medicine in Oncology, I got a bit dogmatic in prosupportive of the PM cancer care revolution. It may turn claiming that personalized medicine (PM) drug the blockbuster drug model on its head, but it achieves treatment selectivity spelled the end of the same results: stabilization of the population-based medicine, and with healthcare system and affordable canit, the blockbuster drug. This is true cer treatment. only insofar as we define blockbuster The old blockbuster rules of engagedrug from within the population-based ment entailed expanding utilization to drug utilization process that PM is rethe furthest limits of credibility, courtplacing. As PM establishes itself, a new ing off-label usage, and blindly searchkind of blockbuster drug is emerging ing to bring the drug to the right with a criterion that supersedes its patient through a massive process of predecessor. Since blockbusters have elimination. The process was tolerated sustained the pharmaceutical industry because companion diagnostics techfor decades, concern about the demise nology did not exist. Now that it does, Robert E. Henry of the blockbuster drug has been drug utilization can be limited to an strong: if PM and its reliance on bioenriched patient population based on logicals in cancer care is incompatible with blockbuster individual patient chemistry. Last year the FDA got raddrugs, could this spell the collapse of the pharmaceutiical and simultaneously approved 2 drugs with compancal/biologicals industry? The question is worth answerion diagnostics. One was Roche’s vemurafenib, for ing. PM, after all, must be more than a Pandora’s box of patients with metastatic or inoperable melanoma with unintended consequences. tumors testing positive for the BRAF V600E mutation, The new blockbuster drug model is form-fitted to PM with its companion diagnostic, the Roche cobas 4800 dynamics. The old blockbuster model required massive, BRAF V600 Mutation Test. The other was Pfizer’s crizopopulation-based drug utilization. If randomized continib, approved for late-stage non–small cell lung cancer, trolled trials showed positive results, the drug would find and Abbott’s Vysis ALK Break Apart FISH Probe Kit, indiscriminate use in practice and payer coverage just as for detecting abnormal anaplastic lymphoma kinase indiscriminate – almost an urge to “put it in the tap (ALK) gene expression. water,” especially when it went generic. PM alters that, These simultaneous approvals signal the dawn of this of course, aligning drugs to patients based on body new era of the minibuster, increasing drug effectiveness chemistry, not empirical averages. This is an enriched while facilitating payer coverage. Now pharma can go population, and it is guided, even empowered, by comwith the flow of PM’s smaller patient populations and panion diagnostics, to shrink patient populations to boustill end up with a blockbuster, only now its financial tique levels. This only redefines, not eliminates, success is based on value, not volume. Never has “less is more” meant more to every stakeholder in the process blockbuster drugs, by achieving targeted value proposiof care. Results, not waste usage, now form the basis for tions. Blockbuster drugs provide the profits needed for blockbuster drug status. This can allow for a rational the technologically ambitious research for biologicals. pricing and utilization strategy, helping cancer care stay The new targeted model accommodates this need,

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on the high road where it belongs. Diagnostics pave the way for drug utilization based on clinical merit, not dubious patient selection methods. It allows pharma to achieve its financial goals while remaining true to its clinical mission.

The selectivity of biologicals usage will see high unit costs, but it is attractive to payers who recoil at the prospect of an onslaught of aging baby boomers receiving unsustainable levels of biologics. This is making diagnostics as valued as the drugs they measure, since they keep biologics affordable by cutting waste – and not just in clinical treatment, but also in research. The average cost of a new drug launch hovers near $2 billion, a problem aggravated by research failures. Companion diagnostics not only lessen payer worries over waste drug usage, they also help fast-failure research, which will allow biologicals to be priced more affordably.

Dan Theodorescu, MD, PhD, Paul Bunn Professor of Cancer Research, professor of urology and pharmacology, and director of the University of Colorado Comprehensive Cancer Center, described the process: “Developing drugs is so expensive that the industry can’t afford any longer to take a drug to phase 1 or 2 clinical trials and find out that it’s not working like they hoped. It’s clear that the biomarker or markers should be embedded in the process very early. In my opinion, even phase 1 trials should be biomarker-driven for patient selection and prediction of response.” He predicts that pharma will pursue

the companion diagnostics approach, relying on this fastfail approach to identify winning products worth taking to phase 2 and beyond. Pharma can afford the small patient populations it previously could not afford to attend to because payers will tolerate a higher price tag for a drug with a higher likelihood of clinical success.

The role of companion diagnostics in the new blockbuster model demonstrates the intricacy of PM and the interlocking stakeholder relationships that sustain it.

The blockbuster drug has been retooled in boutique proportions to fulfill the PM quest for targeted, predictable, low-waste usage. This will attract investors, whose funding has never been more critically needed, at this young stage of research into biomarkers and other methods for predicting biologicals’ clinical utility. Pharma will have to master this transition, titrating the price-to-treatment ratio to balance their financial needs with those of patients and payers. Breakthrough biologicals usage is now being sustained by equally remarkable companion diagnostics. Together they make possible a flourishing of value: the elusive balance of cost, quality, and access that brings the process of care from theory into practice.

To Our Health,

Robert E. Henry

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PM O

Annual Index

2012

Biomarkers

Immunotherapy

Clinical Trial Designs for Biomarker Evaluation.

Mandrekar SJ, Sargent DJ....................................1:26

The Cancer Immunotherapy Trials Network: A National Strategy for the Development and Implementation of Immunotherapy for the Treatment of Cancer. Kohrt HE, Kaufman HL, Disis ML...............................................................5:46

Precision Medicine: Applying Predictive and Prognostic Indices to Risk-Adapted Treatment Selection. Kurtin S...............................................1:50 Implementing the Promise of Personalized Cancer Care: Highlights From the Inaugural Conference of the Global Biomarkers Consortium. Hehlmann R, Rugo HS...............................................................2:22 Clinical Approaches to Targeted Technologies: Implementing the Promise of Prognostic Precision Into Personalized Cancer Care............................5:26

Interview With the Innovators Accelerating Personalized Medicine Approaches in Multiple Myeloma: An Interview With Kathy Giusti and Deborah Dunsire, MD...................................1:38 Personalized Medicine Advances in Melanoma: An Interview With K. Peter Hirth, PhD...................2:15 Incorporating Genomics Into Practice: An Interview With Kimberly J. Popovits...................................3:18

Breast Cancer Which Breast Cancer Patients Should Receive Adjuvant Chemotherapy? Moreno-Aspita A......3:52

Novel Approaches to Delivering Personalized Medicine: An Interview With Thomas C. Reynolds, MD, PhD..............................................................4:30

Clinical Trial Design

Cultivating Personalized Medicine Clinical Acumen in the Management of Breast Cancer: An Interview With Edith Perez, MD.........................................5:17

Adaptive Clinical Trial Design: From Simple DoseFinding Trials to Large-Scale Personalized Medicine Trials. Ye F, Shyr Y................................................4:36

Lynch Syndrome: An Interview With the Father of Hereditary Cancer Detection and Prevention, Henry T. Lynch, MD ........................................ 6:18.

Colorectal Cancer KRAS and Colorectal Cancer: Shades of Gray. Atreya CE, Ostrem JM, Kelley RK.................................6:22.

Lung Cancer Crizotinib Miracle: A Nursing Perspective.

Rich TL................................................................2:54

Cutaneous Malignancies Cutaneous Malignancies: Highlights From the 2012 World Cutaneous Malignancies Congress. Petrella T, Margolin KA........................................................3:26

Melanoma

Editorial

The New Therapeutic Paradigm for Personalized Therapy of Melanoma. Agarwala S....................6:36.

Personalized Medicine in Oncology: The Landscape of the Next Generation of Cancer Care.

Henry RE..............................................................1:12

Myelodysplastic Syndrome

A Personal Introduction and Invitation to Join My Journey Through the World of Personalized Medicine. Henry RE............................................5:56

Personalized Therapy in the Management of Myelodysplastic Syndrome. Borthakur G............4:49

Companion Diagnostics and the Paradoxical Return of the Blockbuster Drug. Henry RE....................6:44.

Multiple Myeloma

Institute of Medicine Report: Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Highlights for the Cancer Community.

Conway J.............................................................6:32.

46

Management of Ipilimumab-Related Toxicities.

Ott PA, Kaufman HL, Hodi FS...........................2:43

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The Role of Personalized Therapy in the Management of Multiple Myeloma: Case Study of a Patient With a Cytogenetic Abnormality. Lonial S..................5:41

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Annual Index

2012

PM O

Pharmacogenomics

Regulatory Issues

Pharmacogenomics in Cancer Care: Adding Some Science to the Art of Medicine.

Pinto N, Ratain MJ..............................................4:56

Rapid Changes in Reimbursement Protocols for Molecular Tests. Quinn B....................................2:36

Author Index

Mandrekar SJ..........................................................1:26 Margolin KA ..........................................................3:26 Moreno-Aspita A...................................................3:52 Ostrem JM..............................................................6:22 Ott PA ....................................................................2:43 Perez E ....................................................................5:17 Petrella T................................................................3:26 Pinto N....................................................................4:56 Popovits KJ.............................................................3:18 Quinn B..................................................................2:36 Ratain MJ...............................................................4:56 Reynolds TC ..........................................................4:30 Rich TL ..................................................................2:54 Rugo HS ................................................................2:22 Sargent DJ ..............................................................1:26 Shyr Y......................................................................4:36 Walcoff SD..............................................................3:43 Ye F..........................................................................4:36

Agarwala S ............................................................6:36 Atreya CE...............................................................6:22 Borthakur G............................................................4:49 Conway J.................................................................6:32 Disis ML..................................................................5:46 Dunsire D................................................................1:38 Giusti K...................................................................1:38 Hehlmann R...........................................................2:22 Henry RE..............................................1:12, 5:56, 6:44 Hirth KP..................................................................2:15 Hodi FS...................................................................2:43 Kaufman HL..................................................2:43, 5:46 Kelley RK ..............................................................6:22 Kohrt HE ................................................................5:46 Kurtin S ..................................................................1:50 Lonial S ..................................................................5:41 Lynch HT ..............................................................6:18

Facilitating the Next Generation of Precision Medicine in Oncology. Walcoff SD.....................3:43

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