December 2012 Volume 1, Number 6

Institute of Medicine Report: Best Care at Lower Cost: The Path to Continuously LearningHealth Care in America. Highlights for the CancerCommunity................................................... Page 32

The New Therapeutic Paradigm for PersonalizedTherapy of Melanoma....................................Page 36

Lynch Syndrome: An Interview With the Father of Hereditary Cancer Detection and Prevention,Henry T. Lynch, MD.......................................8

December 2012

Volume 1 • Number 6

A Peer-Reviewed Journal

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

IMPLEMENTING THE PROMISE OFPROGNOSTIC PRECISION INTO PERSONALIZED CANCER CARETM

HEALTHCARE ECONOMICS

MELANOMA

INTERVIEW WITH THE INNOVATORS

The official publication of

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

COLORECTAL CANCER

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

In partnership with

PERSONALIZEDMEDICINE INONCOLOGYM

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WWW.PERSONALIZEDMEDONC.COM 3Volume 1 • No 6 December 2012

December 2012

Volume 1 • Number 6

MOP

News from ASH, ASTRO, and the San Antonio Breast Cancer Symposium PAGE 10

Ibrutinib: Proof of Concept Pays Off

Two Studies Show That Radiation Extends Survival in

Elderly Women With Early-Stage Breast Cancer

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

Genetic Targets Identified in Triple-Negative Breast Cancer

CONFERENCE NEWS

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

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.

PERSONALIZEDMEDICINE INONCOLOGY™

Professional Experienceof GBC Attendees INTERVIEW WITH THE INNOVATORS

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1-3 years

3-5 years

5-10 years

10-20 years

>20 years

56.7%

6.7%

26.7%

6.7%

3.3%

KRAS and Colorectal Cancer: Shades of Gray 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.

COLORECTAL CANCER

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

The Global Biomarkers Consortium™

(GBC) is a community of world-

renowned healthcare professionals who

will convene in multiple educational fo-

rums in order to better understand the

clinical application of predictive molec-

ular biomarkers and advanced personal-

ized care for patients.

Save the date for the Second Annual Conference,

October 4-6, 2013

Visit www.globalbiomarkersconsortium.com

to register

SENIOR VICE PRESIDENT, SALES AND MARKETINGPhilip Pawelko

[email protected]

PUBLISHERSJohn W. Hennessy

[email protected]

Russell [email protected]

DIRECTOR, CLIENT SERVICESLou Lesperance Jr

[email protected]

MANAGING DIRECTORPam Rattananont Ferris

EDITORIAL DIRECTORKristin Siyahian

[email protected]

STRATEGIC EDITORRobert E. Henry

SENIOR COPY EDITORBJ Hansen

PRODUCTION MANAGERMarie RS Borrelli

QUALITY CONTROL DIRECTORBarbara Marino

BUSINESS MANAGERBlanche Marchitto

CIRCULATION [email protected]

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN ap-plied for (online) is published 6 times a year by Green Hill HealthcareCommunications, LLC, 1249 South River Road, Suite 202A, Cran-bury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy -right ©2012 by Green Hill Health care Com muni cations, LLC. Allrights reserved. Personalized Medicine in Oncology logo is a trademarkof Green Hill Healthcare Communications, LLC. No part of thispublication may be reproduced or transmitted in any form or by anymeans now or hereafter known, electronic or mechanical, includingphotocopy, recording, or any informational storage and retrieval sys-tem, without written permission from the publisher. Printed in theUnited States of America.

EDITORIAL CORRESPONDENCE should be ad dressed to ED-ITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO),1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLYSUBSCRIPTION RATES: United States and possessions: individ-uals, $50.00; institutions, $90.00; single issues, $5.00. Orders will bebilled at individual rate until proof of status is confirmed. Prices aresubject to change without notice. Correspondence regarding permis-sion to reprint all or part of any article published in this journal shouldbe addressed to REPRINT PERMISSIONS DEPART MENT,Green Hill Healthcare Communications, LLC, 1249 South RiverRoad, Suite 202A, Cranbury, NJ 08512. The ideas and opinions ex-pressed in PMO do not necessarily reflect those of the editorial board,the editorial director, or the publishers. Publication of an advertise-ment or other product mention in PMO should not be construed asan endorsement of the product or the manufacturer’s claims. Readersare encouraged to contact the manufacturer with questions about thefeatures or limitations of the products mentioned. Neither the edito-rial board nor the publishers assume any responsibility for any injuryand/or damage to persons or property arising out of or related to anyuse of the material contained in this periodical. The reader is advisedto check the appropriate medical literature and the product informa-tion currently provided by the manufacturer of each drug to be ad-ministered to verify the dosage, the method and duration ofadministration, or contraindications. It is the responsibility of thetreating physician or other healthcare professional, relying on inde-pendent experience and knowledge of the patient, to determine drugdosages and the best treatment for the patient. Every effort has beenmade to check generic and trade names, and to verify dosages. Theultimate responsibility, however, lies with the prescribing physician.Please convey any errors to the editorial director.

PUBLISHING STAFF

MOP PERSONALIZED

MEDICINE INONCOLOGY™

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

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 PAGE 36

A report from the 2012 conference of the Global

Biomarkers Consortium.

Sanjiv Agarwala, MD

OUR MISSIONThe mission of Personalized Medicine in Oncology is to deliver practice-changing informationto clinicians about customizing healthcare based on molecular profiling technologies, eachpatient’s unique genetic blueprint, and their specific, individual psychosocial profile, prefer-ences, 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, wheredecisions and practices are tailored for the individual – beginning with an incremental integrationof personalized techniques into the conventional practice paradigm currently in place.

Volume 1 • No 6 December 20124 PERSONALIZED MEDICINE IN ONCOLOGY

THE LAST WORD

Companion Diagnostics and the Paradoxical Return of the Blockbuster Drug PAGE 44

If personalized medicine in cancer care is incompatible

with blockbuster drugs, could this spell the collapse of

the pharmaceutical/biologicals industry?

Robert E. Henry

James Conway

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PERSONALIZED MEDICINE IN ONCOLOGY6 Volume 1 • No 6 December 2012

Editor in ChiefAL B. BENSON III, MDNorthwestern UniversityChicago, Illinois

Editorial Board

Breast CancerEDITH PEREZ, MD Mayo ClinicJacksonville, Florida

Hematologic MalignanciesGAUTAM BORTHAKUR, MDThe University of Texas MD Anderson Cancer CenterHouston, Texas

PathologyDAVID L. RIMM, MD, PHDYale Pathology Tissue Services Yale University School of MedicineNew Haven, Connecticut

Drug DevelopmentIGOR PUZANOV, MDVanderbilt UniversityVanderbilt-Ingram Cancer CenterNashville, Tennessee

Lung CancerVINCENT A. MILLER, MDFoundation MedicineCambridge, Massachusetts

Predictive ModelingMICHAEL KATTAN, PHD Case Western Reserve UniversityCleveland, Ohio

Gastrointestinal CancerEUNICE KWAK, MD Massachusetts General Hospital Cancer CenterHarvard Medical School Boston, Massachusetts

MelanomaDOUG SCHWARTZENTRUBER, MD Indiana University Simon Cancer CenterIndianapolis, Indiana

Prostate CancerOLIVER SARTOR, MD Tulane UniversityNew Orleans, Louisiana

SECTION EDITORS

SANJIV S. AGARWALA, MDSt. Luke’s HospitalBethlehem, Pennsylvania

GREGORY D. AYERS, MS Vanderbilt University School of MedicineNashville, Tennessee

LYUDMILA BAZHENOVA, MDUniversity of California, San DiegoSan Diego, California

LEIF BERGSAGEL, MDMayo ClinicScottsdale, Arizona

KENNETH BLOOM, MDClarient Inc.Aliso Viejo, California

MARK S. BOGUSKI, MD, PHDHarvard Medical SchoolBoston, Massachusetts

GILBERTO CASTRO, MDInstituto do Câncer do Estado de São Paulo São Paulo, Brazil

MADELEINE DUVIC, MD The University of TexasMD Anderson Cancer CenterHouston, Texas

BETH FAIMAN, PHD(C), MSN, APRN-BC, AOCNCleveland Clinic Taussig Cancer CenterCleveland, Ohio

STEPHEN GATELY, MDTGen Drug Development (TD2)Scottsdale, Arizona

STEVEN D. GORE, MDThe Johns Hopkins University School of MedicineBaltimore, Maryland

K. PETER HIRTH, PHDPlexxikon, Inc.Berkeley, California

HOWARD L. KAUFMAN, MDRush UniversityChicago, Illinois

KATIE KELLEY, MDUCSF School of MedicineSan Francisco, California

MINETTA LIU, MD Georgetown University HospitalWashington, DC

KIM MARGOLIN, MDUniversity of WashingtonFred Hutchinson Cancer Research CenterSeattle, Washington

GENE MORSE, PHARMDUniversity at BuffaloBuffalo, New York

AFSANEH MOTAMED-KHORASANI, PHDRadient PharmaceuticalsTustin, California

NIKHIL C. MUNSHI, MD Dana-Farber Cancer InstituteBoston, Massachusetts

STEVEN O’DAY, MDJohn Wayne Cancer Institute Santa Monica, California

DAVID A. PROIA, PHDSynta PharmaceuticalsLexington, Massachusetts

RAFAEL ROSELL, MD, PHDCatalan Institute of OncologyBarcelona, Spain

STEVEN T. ROSEN, MD, FACP Northwestern UniversityChicago, Illinois

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

DANIELLE SCELFO, MHSAGenomic HealthRedwood City, California

LEE SCHWARTZBERG, MD The West ClinicMemphis, Tennessee

JOHN SHAUGHNESSY, PHDUniversity of Arkansas for Medical SciencesLittle Rock, Arkansas

LAWRENCE N. SHULMAN, MDDana-Farber Cancer Institute Boston, Massachusetts

JAMIE SHUTTER, MDSouth Beach Medical Consultants, LLCMiami Beach, Florida

DARREN SIGAL, MDScripps Clinic Medical GroupSan Diego, California

DAVID SPIGEL, MDSarah Cannon Research InstituteNashville, Tennessee

MOSHE TALPAZ, MDUniversity of Michigan Medical CenterAnn Arbor, Michigan

SHEILA D. WALCOFF, JDGoldbug Strategies, LLCRockville, Maryland

ANAS YOUNES, MDThe University of Texas MD Anderson Cancer CenterHouston, Texas

EDITORIAL BOARD

Tumor Invasion and MetastasisCo-Chairpersons: Zena Werb and Bruce R. ZetterJanuary 20-23, 2013 • San Diego, CA

Ninth AACR-Japanese Cancer Association JointConference: Breakthroughs in Basic andTranslational Cancer ResearchCo-Chairpersons: Tyler Jacks and Kohei MiyazonoFebruary 21-25, 2013 • Maui, HI

Joint AACR-Society of Nuclear Medicine andMolecular Imaging Conference: State-of-the-ArtMolecular Imaging in Cancer Biology and TherapyCo-Chairpersons: Carolyn J. Anderson and David Piwnica-WormsFebruary 27-March 2, 2013 • San Diego, CA

AACR Annual Meeting 2013Chairperson: José BaselgaApril 6-10, 2013 • Washington, DC

Synthetic Lethal Approaches to Cancer VulnerabilitiesCo-Chairpersons: William C. Hahn, Sebastian Nijman, and Louis M. Staudt May 17-20, 2013 • Bellevue, WA

Chromatin and Epigenetics in CancerCo-Chairpersons: Suzanne J. Baker, Charles W.M.Roberts, and Gerald R. CrabtreeJune 19-22, 2013 • Atlanta, GA

Frontiers in Basic Cancer ResearchChairperson: Scott W. LoweCo-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 ClinicCo-Chairpersons: David G. Huntsman, Douglas A. Levine, and Sandra Orsulic September 18-21, 2013 • Miami, FL

Advances in Breast Cancer ResearchCo-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 onMolecular Targets and Cancer TherapeuticsCo-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 ResearchChairperson: Paul J. LimburgOctober 27-30, 2013 • National Harbor, MD

Pediatric Cancer at the Crossroads:Translating Discovery into Improved OutcomesCo-Chairpersons: John M. Maris, Stella M. Davies, James R. Downing, Lee J. Helman, andMichael B. Kastan November 3-6, 2013 • San Diego, CA

The Translational Impact of Model Organisms in CancerCo-Chairpersons: Cory Abate-Shen, A. Thomas Look, and Terry A. Van DykeNovember 5-8, 2013 • San Diego, CA

CTRC-AACR San Antonio Breast Cancer SymposiumCo-Directors: Carlos L. Arteaga, C. Kent Osborne, and Peter M. RavdinDecember 10-14, 2013 • San Antonio, TX

AACR EDUCATIONAL WORKSHOPSAccelerating AnticancerAgent Development and ValidationCo-Chairpersons: H. Kim Lyerly andRichard PazdurMay 8-10, 2013Bethesda, MD

NEW! IntegrativeMolecular CancerEpidemiologyDirector: Thomas A.Sellers; Co-Directors: Peter L. Kraft and Margaret R. SpitzJuly 15-20, 2013Boston, MA

Molecular Biology in Clinical OncologyCo-Directors: William G. Kaelin Jr., Mark Geraci, andSuzanne TopalianJuly 21-28, 2013Snowmass, CO

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

Translational Research for Basic ScientistsCo-Directors: Tom Curran, George D. Demetri, and Pasi A. JänneFall 2013Boston, MA

www.aacr.org/Workshops2013


Letter From the Board

Dear Colleague,

In the new era of personalizing cancer care, a vital issue is raised: the assumptionthat personalized medicine will be too costly to be part of the healthcare land-scape. The content of Personalized Medicine in Oncology (PMO) explores per-

sonalized medicine as a frontier – one that, with resourceful exploration andproblem solving, can deliver value and not just quality, placing therapeutics withinthe economic reach of a cost-strained healthcare system. But personalized medi-cine does not run itself. It is a strategy in perpetual search of new tactics that sup-port its quality with value: healthcare’s “Iron Triangle” of cost, quality, and access. Payers fear that cancer therapies will pose an unsustainable cost burden. This

is based in part on a long history of cancer drug usage based solely on population-based evidence. PMO exists to help oncologists cultivate tactical, value-based approaches to cancer treat-ments and to integrate them into the full constellation of personalized medicine techniques. We arededicated to the proposition that new life-saving technologies need not be prohibitively expensive, pro-vided they are used skillfully. Conversely, misuse or overuse of cancer therapies would ensure their extinc-tion. Techniques appropriate to the pretargeted drug era must be supplanted with new ones, for targetedtherapies are not just novel: they are game-changing interventions altering the very culture of cancer carewhose rules of engagement must be learned, and quickly.Chemotherapy regimens relied on population-based research suggesting only potential effectiveness, mak-

ing aggressive but uninformed usage customary and even appropriate in the absence of anything better tooffer a dying patient. But such a “frontal attack” strategy is ill suited to targeted therapies and diagnostics andinvites payer obstruction, placing unlucky patients in the middle of stakeholder stalemate. Payers are keenlyaware that treatment may turn an acute condition into a chronic one, incurring care measured in years ratherthan weeks or months. Such care must be accurate to justify its expense. We help achieve this goal by bringingthe knowledge that replaces frontal-attack drug usage with a sensitive process of patient selection that healswhile 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 intovalue. It empowers the iterative process of personalized medicine with techniques that reduce chance andensure that appropriate treatments reach patients capable of responding to them. This will deliver thevalue 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

PMO: Exploring the New Frontier ofPersonalizing Cancer Care

Doug Schwartzentruber, MD

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CONFERENCE CO-CHAIRS

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida

Craig K. Deligdish, MDHematologist/OncologistOncology Resource Networks

Gary M. Owens, MDPresidentGary Owens Associates

Burt Zweigenhaft, BSPresident and CEOOncoMed

THURSDAY, MAY 2, 20138:00 am - 5:00 pm Registration

FRIDAY, MAY 3, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am Session 1: Welcome, Introductions, and Opening RemarksConference 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 CollaborationsRoy 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

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 CareF. 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 CareJayson Slotnick, JD, MPH

5:15 pm - 5:45 pm Summary/Wrap-Up of Day 1

6:00 pm - 8:00 pm Cocktail Reception in the Exhibit Hall

SATURDAY, MAY 4, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 8: Advanced Care Directives: Palliative Care, Hospice, EthicsJ. Russell Hoverman, MD, PhDThomas J. Smith, MD, FACP, FASCO

9:15 am - 10:00 am Session 9: Medicaid: A Healthcare Delivery System ReviewMatthew Brow

10:00 am - 10:15 am Break

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 IssuesPat 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 PropositionMark 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

SUNDAY, MAY 5, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship CareJulie Silver, MD

9:15 am - 10:00 am Session 15: Current and Future Considerations for the Oncology Practice ManagerDawn 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, BiosimilarsDouglas 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

*Agenda is subject to change.

PROGRAM OVERVIEWFollowing on the success of our Second Annual Conference, AVBCC will be comingto Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise ofleaders in these fields providing at tendees with a thorough understanding of the evo-lution of the value equation as it relates to cancer therapies. Our goal is to be able toassist them in implementing, improving, and sustaining their organizations and institu-tions, while improving access for patients and ultimately quality patient care.

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

SPONSORSThis activity is jointly sponsored by Medical Learning Institute Inc, the Association forValue-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core PrincipleSolutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

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

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Comple-tion 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 activityis (To be determined).

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

DESIGNATION OF CREDIT STATEMENTS

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

• Define the barriers associated with cost, quality, and access as they relate to health-care 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.

CONFERENCE REGISTRATIONDiscounted Pricing Available!

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

Influencing the Patient-Impact Factor

THIRD ANNUALAssociation for Value-Based Cancer Care Conference

www.regonline.com/avbcc2013REGISTER TODAY AT

AGENDA*

� � ��


2012 ASH Annual Meeting

Ibrutinib as a single agent and in combination with ri -tuximab achieved unprecedented response rates instudies of chronic lymphocytic leukemia (CLL) and

mantle cell lymphoma (MCL) presented at the 54th An-nual Meeting of the American Society of Hematology(ASH). The drug is being studied in several B-cell ma-lignancies, including CLL/small lymphocytic leukemia(SLL), relapsed/refractory MCL, diffuse large B-cell lym-phoma (DLBCL), follicular lymphoma, and multiplemyeloma. The drug is under development by Pharma-cyclics and Janssen Biotech, Inc.Ibrutinib is an investigational Bruton’s tyrosine kinase

(BTK) inhibitor. BTK is a key mediator of at least 3 criticalB-cell prosurvival mechanisms: regulating B-cell apoptosis,cell adhesion, and lymphocyte migration and homing. “Ibrutinib is the molecule of the year. This agent repre-

sents a revolution in the treatment of lymphomas,” statedMartin Dreyling, professor at the University of Munich inGermany and a lymphoma expert. He cited 2 studies ofibrutinib at ASH as potentially practice changing. One wasa study in relapsed/refractory MCL (Abstract 904), and theother 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 re-lapsed/refractory MCL. Median number of previous treat-ments was 3. In these difficult-to-treat patients, ibrutinibachieved an overall response rate (ORR) of 70% and acomplete response rate of 20%, which increased to 50% at14 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 followingbortezomib treatment has been initiated. At next year’sASH, Wang is expected to present results of a study of ibru-tinib as first-line therapy for MCL.Moving on to the study of 70 patients with relapsed

DLBCL presented by Wyndham Wilson, MD, NationalCancer Institute in Bethesda, MD, treatment with ibru-tinib achieved an ORR of about 28%. However, when

patients were stratified according to genetic expression,response rates in activated B-cell–like (ABC) DLBCLwere 40% (this group has the worst prognosis), and in ger-minal center B-cell–like DLBCL, 5.3%.These results in the ABC subgroup of relapsed DLBCL

patients are considered unprecedented. Wilson and col-leagues concluded that future clinical trials of ibrutinibin DLBCL should be confined to the ABC subtype.

CLL/SLL Phase 2 StudiesTwo phase 2 trials were reported with ibrutinib in

CLL/SLL. The first was with single-agent ibrutinib (Ab-stract 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. Ibrutinibmonotherapy achieved excellent progression-free survival(PFS) at 26 months for both elderly, treatment-naive pa-tients (estimated PFS, 96%) and relapsed/refractory high-risk CLL/SLL patients (estimated PFS, 75%).“These results with ibrutinib continue to support the

possibility that we can address some of the criticalunmet needs in CLL/SLL. Rarely does a drug comealong that helps patients this much. This drug is highlyeffective and very well tolerated,” said lead author JohnR. Byrd, MD, D. Warren Brown Chair of Leukemia Re-search and director of the Division of Hematology atOhio State University Comprehensive Cancer Centerin Columbus.ORRs were 68% in the treatment-naive, relapsed/re-

fractory patients at a median follow-up of 20.3 monthsand 71% in the high-risk relapsed/refractory group at amedian follow-up of 15.7 months. At 26 months, esti-mated 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 withhigh-risk CLL, and 38 of the 40 patients have no evidence

Ibrutinib: Proof of Concept Pays OffPhoebe Starr


2012 ASTRO Annual Meeting

Radiation therapy extends life in older womenwith early-stage breast cancer, according to 2studies 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 ascause-specific survival (CSS) in women aged 70 or older.The study population included 29,949 women iden-

tified in a SEER Medicare database who were diagnosedwith stage I, estrogen receptor–positive (ER+) breastcancer. All women underwent lumpectomy with orwithout adjuvant radiation and survived at least 1 yearafter the initial diagnosis. Seventy-six percent receivedadjuvant radiation therapy.Median survival was 13.1 years for women treated

with surgery plus radiation and 11.1 years for thosetreated with surgery alone. Five-year CSS was 98.3% forthe adjuvant radiation group versus 97.6% for the sur-gery-alone group. Ten-year CSS was 95.4% versus93.3%, respectively; 15-year CSS was 91.4% versus89.5%, respectively.At all time points, the use of adjuvant radiation im-

proved OS. At 5 years, OS was 88.6% for those who re-ceived radiation versus 73.1% for the surgery-alone arm

(P<.0001); at 10 years, OS was 65% versus 41.7%, re-spectively (P<.0001); at 15 years, OS was 39.6% versus20%, respectively.A related study based on 27,559 patients from a

SEER Medicare database found that older women withearly-stage, low-risk breast cancer treated with radiationafter breast-conserving surgery (BCS) had superior CSSand OS rates compared with women who did not un-dergo radiation after BCS. The study showed a 6% de-cline in use of radiation after 2004, coinciding withrevised National Comprehensive Cancer Networkguidelines allowing omission of radiation therapy as areasonable option for women over age 70 with smallER+ tumors treated with adjuvant tamoxifen.CSS favored radiotherapy. At 5 years, CSS was 97%

for those who received radiotherapy versus 95% forthose who did not, an absolute difference of 2%; by 10years, the absolute difference was doubled to 4%, favor-ing radiation: 95% and 91%, respectively.OS also favored the addition of radiotherapy to sur-

gery. 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 anabsolute difference of 23% favoring radiation. u

Two Studies Show That Radiation Extends Survival inElderly Women With Early-Stage Breast CancerPhoebe Starr

of disease progression and are continuing on treatment.“High-risk CLL patients typically have inferior out-

comes compared with low- and intermediate-risk pa-tients. This study shows profound activity for thiscombination in high-risk patients with CLL. The overallresponse rate is favorable compared with standard treat-ment, and the toxicity compares favorably to other treat-ment options,” stated Jan Burger, MD, lead author of thisphase 2 trial. Burger is associate professor at the Univer-sity of Texas MD Anderson Cancer Center.High risk was defined as having 1 of the following

characteristics: deletion of 17p, TP53mutation, deletionof 11q, or <3 years of remission after first-line chemo -immunotherapy.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 lymphnodes and spleen; 84% experienced >50% decrease inlymph node size.In both phase 2 trials in CLL, treatment was well toler-

ated, with transient and infrequent grade 3 and 4 toxicitiesassociated with ibrutinib. u


Patterns of use of radiotherapy have changed overtime in elderly patients with stage I breast cancer,and these changes have financial implications for

the healthcare system. In elderly patients with favor-able-risk breast cancer, use of intensity-modulated radi-ation therapy (IMRT) and brachytherapy steadilyincreased from 2001 to 2007, while use of standard ex-ternal beam radiation therapy (EBRT) decreased. Dataare lacking on whether the newer technologies improveoutcomes in this group of patients. These patterns of uti-lization led to an increase of 63% per treated patient,according to a study of Medicare patients enrolled in theSEER Medicare database reported at the 54th AnnualMeeting of ASTRO.In 2007, 52% of favorable-risk breast cancer patients

received EBRT, and 24% received a newer form of ther-apy. The median cost of EBRT was $6000 per patient,while the costs of IMRT and brachytherapy were twiceas high: $12,469 and $13,981, respectively.“The incremental cost to our nation for new radia-

tion therapy modalities in 2007 was $31 billion. Weneed to determine if the benefit is commensurate withthe increased cost,” stated Kenneth Roberts, MD, YaleUniversity School of Medicine in New Haven, CT.“Further study is needed to explore radiation modalitiesin this low-risk population.”The CALGB C9343 trial, published in 2004, in-

cluded women aged 70 and older with clinical stage T1N0 treated with lumpectomy with negative margins.Ten-year follow-up showed that the local recurrencerate 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 favorable-risk patients. “Radiation use remained stable even

in patients with low life expectancy,” he said.Over the past decade new treatments have been

adopted, including accelerated partial breast irradiationand brachytherapy, without much evidence to support theiruse, he said. The present study was conducted to determinetemporal trends in usage of technology and the associatedcost 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 can-cer undergoing lumpectomy. Tumor size was <2 cm, andall cancers were estrogen receptor positive. Seventy-six 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 increasein brachytherapy (11.2%) and IMRT (12.4%) was seen.Use of standard EBRT decreased from 76% in 2001 to52% in 2007.Fewer women aged 85 and older received radiation

therapy, but even in this group there were temporalchanges as follows: in 2008, 8.8% were treated withbrachytherapy, 5.3% with IMRT, and 21.2% with stan-dard 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 studyshowed the utilization of EBRT has decreased in olderwomen, yet they are opting for costly newer technolo-gies with no data to show improved outcomes.The real question, she indicated, is how to define el -

derly. Also, it is not clear that radiation should be omit-ted in elderly patients with favorable-risk breast cancer.“The decision should encompass tumor characteristics,patient anxiety, and patient goals,” she stated. u


Newer More Costly Radiation Technologies Adoptedin the ElderlyPhoebe Starr


Memantine delayed cognitive decline in pa-tients treated with whole-brain radiationtherapy (WBRT) for brain metastases, ac-

cording to results of a randomized phase 3 trial presentedat the 54th Annual Meeting of ASTRO.Cognitive decline is common with WBRT, occurring

in 50% to 60% of patients 4 months following radiationtreatment. Since the mechanism of radiation-inducedcognitive decline appears to be similar to that of vascu-lar or Alzheimer’s dementia, the researchers postulatedthat memantine, a drug used to treat Alzheimer’s dis-ease, 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 preservetheir cognitive function after whole-brain radiotherapyeven 6 months after treatment. Our findings suggest thatmemantine may prevent the changes that occur in thebrain following radiation therapy, impacting futuretreatment practices for these patients, and suggest a rolefor further study in patients receiving radiation to thebrain,” said lead author Nadia N. Laack, MD, radiationoncologist at the Mayo Clinic in Rochester, MN.Formal discussant of this trial, Vinai Gondi, MD, Asso-

ciate Director of the CDH Proton Center in Warrenville,IL, called this study “a good first step” in understanding thecognitive changes resulting from brain radiation and therole of memantine in preventing or delaying them. He saidthat the effect of memantine was modest in this trial, andthat other strategies to improve cognitive effects of radia-tion are being pursued by researchers.The study included 508 patients with brain metastases

who received WBRT between March 2008 and June2010. WBRT was delivered as 37.5 Gy in 15 daily frac-tions. Patients were randomized to memantine 20 mg/dayor placebo within 3 days of the start of radiation therapy.Six domains of cognitive function (memory, processingspeed, executive function, global function, self-reported

cognitive function, and quality of life) were assessed bydifferent instruments at baseline and weeks 8, 16, 24, and52. The primary end point was memory as assessed by theHopkins Verbal Learning Test-Revised (HVLT-R).Compliance with the cognitive testing protocol was

suboptimal, with 32% of patients completing drug ther-apy and cognitive assessments. The reasons for noncom-pliance appeared to be death, disease progression, anddifficulty in getting patients to stay longer during aclinic visit or in physicians scheduling the extra 20 min-utes to 1 hour required for cognitive testing. Of the 508patients randomized to the 2 arms, only 149 were avail-able for analysis at 24 weeks.

For the primary end point, memantine reduced thedecline in HVLT-R delayed recall, with a median de-cline of 0 versus –2 for placebo at 24 weeks, with a sta-tistical significance of P=.059, “teetering on the edge ofsignificance,” according to Laack.At 24 weeks, memantine reduced the relative risk of

cognitive decline by 17% versus placebo (P=.01) andreduced the rate of decline in cognitive, executive, andglobal 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 me-

mantine on overall survival and progression-free sur-vival in these patients. Also, tissue specimens will bestudied to identify biomarkers of cognitive decline aswell as of response to memantine. u


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

Memantine Delays Cognitive Decline in Patients WithBrain Metastases Treated With Whole-Brain RadiationPhoebe Starr



In the United States right now, intensity-modulatedradiation therapy (IMRT) has largely replaced 3-Dconformal radiation therapy as the technique of

choice for most patients with organ-confined prostatecancer treated with radiation as primary therapy. Othertechniques in use include brachytherapy, and at somecenters proton beam therapy is being studied.Of all the radiation technologies, it appears that

stereotactic body radiation therapy (SBRT) deliveredvia the CyberKnife may be the most cost-effective andconvenient for patients, while achieving at least equiv-alent efficacy in disease control, according to 2 retro-spective studies reported at the 54th Annual Meetingof ASTRO. Both studies have a median follow-up ofabout 3 years, and larger studies with longer follow-upare needed to verify these findings.SBRT delivers precise, high doses of radiation to the

prostate using converging, finely collimated beams, tar-geting prostate tissue and sparing healthy tissue. TheCyberKnife is a robotic technology used to deliverSBRT, and a course of prostate radiation typically takes5 sessions (or 1-2.5 weeks) compared with 40 to 45 ses-sions using IMRT. SBRT technology is now available atabout 150 centers in the United States.A pooled analysis of 1100 patients with organ-con-

fined prostate cancer treated at 8 different centers from2003 to 2010 with CyberKnife SBRT showed that ac-tuarial 5-year biochemical control was 95% for low-riskpatients, 90% for intermediate-risk patients, and 80%for high-risk patients. Similar results were found in 150patients treated with androgen deprivation therapy andwith 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

this point, the statistics should encourage men withorgan-confined prostate cancer to seek SBRT as an al-ternative 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, becauseSBRT is delivered over 1 to 2.5 weeks instead of the 8weeks needed for IMRT, there are cost savings in health-care 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, organ-confined prostate cancer treated with CyberKnife SBRTat 21 different institutions from December 2007 to April2010. 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 andbowel side effects were greater early in the course oftreatment but by 6 months tended to approach baselinelevels. At 2 years following SBRT, QOL scores were sim-ilar to baseline. Most urinary and bowel side effects weregrades 1 and 2.Biochemical control was achieved in 99.2% of patients;

only 1 of 129 patients experienced a rise in prostate-specificantigen following a nadir achieved by SBRT.Putting these preliminary results in context, Meier

said that the typical rate of biochemical failure is 10% to20% at 4 years with IMRT and proton beam therapy.At a press conference, president-elect of ASTRO,

Colleen Lawton, MD, Clinical Director of Radiation On-cology at the Medical College of Wisconsin, Milwaukee,said that these are exciting results, but longer follow-upis needed to establish SBRT as a standard of care. u

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

AGENDA*

FRIDAY, JULY 26, 20133:00 pm – 7:00 pm Registration5:30 pm – 7:30 pm Welcome Reception/Exhibits

SATURDAY, JULY 27, 20137:00 am – 8:00 am Breakfast Symposium/Product Theater/Exhibits8:00 am – 8:15 am BREAK8:15 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/Exhibits1:00 pm – 1:15 pm BREAK1:15 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 AcceptedGuidelines 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

SUNDAY, JULY 28, 20137:00 am – 8:00 am Breakfast Symposium/Product Theater/Exhibits8:00 am – 8:15 am BREAK8:15 am – 8:30 am Review of Saturday’s Presentations and Preview of Today’s Sessions8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for

Cutaneous MalignanciesGeneral 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/Exhibits1:00 pm – 1:15 pm BREAK1:15 pm – 2:45 pm General Session V: “Hot Data” — What I Learned at Recent Meetings:

Focus on Cutaneous Malignancies2:45 pm – 3:00 pm Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

A 2-day congress dedicated to informing, educating, and fostering the exchangeof clinically relevant information in the field of cutaneous malignancies on topics inmelanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carci-noma, and Merkel cell carcinoma, including:

• Epidemiology and genetic/environmental factors

• Molecular biology and cytogenetics related to the pathogenesis of cutaneousmalignancies

• 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 clinicaltrials and basic research

PROGRAM OVERVIEW

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

TARGET AUDIENCE

Upon completion of this activity, the participant will be able to:

• Review the molecular biology and pathogenesis of cutaneous malignancies asthey relate to the treatment of cutaneous T-cell lymphoma, basal cell carci-noma, Merkel cell tumors, and malignant melanoma

• Compare risk stratification of patients with cutaneous malignancies, and how totailor treatment based on patient and tumor characteristics

• Summarize a personalized treatment strategy that incorporates current stan-dards of care and emerging treatment options for therapy of patients with cu-taneous malignancies

LEARNING OBJECTIVES

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DESIGNATION OF CREDIT STATEMENTS

PHYSICIAN CREDIT DESIGNATION

SPONSORS

REGISTERED NURSE DESIGNATION

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

This activity is jointly sponsored by Medical Learning Institute Inc, Center of ExcellenceMedia, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

Medical Learning Institute IncProvider approved by the California Board of Registered Nursing, Provider Number15106, for 12.0 contact hours.

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

Steven J. O’Day, MDHematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer CenterClinical Associate Professor of MedicineUSC Keck School of MedicineLos Angeles, California

Professor Dr. Med. AxelHauschildProfessor, Department of DermatologyUniversity of KielKiel, Germany

CONFERENCE CO-CHAIRS

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

• Melanoma

• Basal Cell Carcinoma

• Cutaneous T-Cell Lymphoma

• Squamous Cell Carcinoma

• Merkel Cell Carcinoma

CONFERENCE REGISTRATION

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

www.CutaneousMalignancies.com

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the AccreditationCouncil for Pharmacy Education as a provider of continuing pharmacyeducation. Completion of this knowledge-based activity provides for 12.0contact hours (1.2 CEUs) of continuing pharmacy education credit. The

Universal Activity Number for this activity is (To be determined).

For complete agenda please visit www.CutaneousMalignancies.com

� � ��


2012 San Antonio Breast Cancer Symposium

Approximately 4000 breast cancer patients inthe United States harbor HER2 mutationsamenable to treatment with anti-HER2 ther-

apy but are not receiving it because they are not HER2-positive on fluorescence in situ hybridization orimmunohistochemical testing. However, genomic se-quencing can identify patients with these mutations,who are likely to benefit from existing anti-HER2 ther-apies. These are the implications of a genomic sequenc-ing study reported at the 2012 CTRC-AACR SanAntonio Breast Cancer Symposium.“These patients are going to be missed by our routine

testing for HER2-positive breast cancer, but the muta-tions can be identified by genomic sequencing,” saidlead author Ron Bose, MD, PhD, assistant professor ofmedicine at Washington University School of Medicinein St. Louis, MO. “These mutations are not inherited,”he emphasized.

Bose explained that 1.5% to 2% of breast cancer pa-tients will test negative for HER2 amplification (reflect-ing multiple copies of the gene) and have undetectedHER2 mutations that drive tumor growth.Bose and colleagues analyzed nearly 1500 patients

who participated in 8 DNA sequencing studies; 25 pa-tients were found to have HER2 mutations withoutHER2 gene amplification. These mutations clustered in2 areas of the HER2 protein, he said: the tyrosine kinasearea and the extracellular domain of the HER2 gene.

Not all of the mutations were equally activating. Of 13mutations that were analyzed, 7 were determined todrive cancer proliferation.“The mutations stimulate the function of HER2, and

we feel they are highly likely to drive the growth of can-cers when they are present,” Bose continued.Laboratory studies showed that activating HER2

mutations were sensitive to the drugs lapatinib andtrastuzumab, with the exception of the L755S mutationand deletion of 755-759. Both mutations were resistantto lapatinib but sensitive to neratinib, a drug currentlyin phase 2 testing.These findings led to the launching of a multi-insti-

tutional phase 2 trial in women with metastatic breastcancer who test negative for HER2 amplification andwho harbor HER2 mutations found on genomic se-quencing. The women will be treated with neratinib240 mg/day and monitored every 2 weeks. Four institu-tions will participate in the phase 2 trial: WashingtonUniversity, Dana-Farber Cancer Institute, MemorialSloan-Kettering Cancer Center, and University ofNorth Carolina.The study was published online December 7, 2012,

in Cancer Discovery, to coincide with the presentationof the data at the symposium.“These results show how cancer genome sequencing

can be directly applied to guide individual patient treat-ment. HER2 mutations are a target for breast cancertreatment, and gene sequencing is needed to identifythese patients. If the phase 2 trial is successful, we esti-mate that 4000 women per year could benefit. This isthe same size as the patient population with chronicmyelogenous leukemia in the US,” Bose stated.George Sledge, MD, Indiana University School of

Medicine, Indianapolis, said that 1% to 2% of all breastcancer patients is comparable to the number of patientswith lung cancer who are positive for the ALK gene. u

Activating HER2 Mutations Found in HER2-NegativePatientsPhoebe Starr

Bose and colleagues analyzed nearly 1500patients who participated in 8 DNAsequencing studies; 25 patients werefound to have HER2 mutations withoutHER2 gene amplification.


2012 San Antonio Breast Cancer Symposium

Triple-negative breast cancer carries a poor prog-nosis compared with other types of breast can-cer because it lacks 3 treatment targets that

occur in other types of breast cancer (estrogen receptor,progesterone receptor, and HER2). But triple-negativebreast cancer has potential genetic targets of its own, ac-cording to a study presented at the CTRC-AACR SanAntonio Breast Cancer Symposium.The study found that 90% of patients had mutations

in 5 targetable biological pathways. These pathwayshave drugs on the market or in development that couldbe targeted in clinical trials, according to Justin Balko,PharmD, PhD, of the Breast Cancer Program at theVanderbilt-Ingram Cancer Center in Nashville, TN. Currently, there are no approved targeted drugs for

triple-negative breast cancer, which occurs in about15% of all breast cancers, he continued. About 30% ofpatients with triple-negative breast cancer have a com-plete response to neoadjuvant chemotherapy and havegood outcomes following surgery. But outcomes for pa-tients with residual disease are typically poor.Balko and colleagues analyzed samples of residual tu-

mors to determine if any candidate genes for resistantcancers could be identified. They studied 114 samplesfrom tumors of women with triple-negative breast can-cer using 3 different methods, including gene expressionprofiling, deep sequencing, and immunohistochemistry.They examined 182 oncogenes and tumor suppressorsknown to be altered in human cancers. Instead of find-ing similar genetic alterations among patients, theyfound alterations in a diverse set of genes. Median ageof patients was 48 years, and the majority of cancerswere 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 iden-tified some genes that could be promising therapeuti-

cally, such as frequent MYC, MCL1, and JAK2 amplifi-cations, as well as alterations in the PI3K pathway.Overall, with all 3 methods, dozens of genes were am-

plified, deleted, or mutated, with the most commongene being TP53, which was abnormal in 90% of tumorsamples. MCL1 (56% abnormal) and MYC (33% ab-normal) were the next most common genetic alter-ations. Amplified JAK2 was observed in 11% of tumors.Alterations in the KI67 gene were not associated withrelapse-free survival or overall survival in this triple-neg-ative cohort.“We arranged the genetic alterations into clinically

targetable pathways,” he explained. These were the 5pathways he discussed:• PI3K/mTOR pathway, involved in intracellular sig-naling 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 growthfactor receptor

• The combination of MEK kinase genes and amplifiedMYC oncogene was potentially predictive of relapseWomen who had only MEK kinase or MYC gene ac-

tivation/amplification were significantly less likely toexperience relapse compared with women who had bothvariants (P=.03).“Ninety percent of patients had at least 1 genetic

aberration in these pathways. We believe this has ther-apeutic implications and should be studied,” Balkosaid. “Targeted drugs exist for each of these 5 pathways.We believe these data provide rationale for adjuvantstudies of appropriate targeted therapeutics in triple-negative breast cancer patients who do not achievepathological complete responses to neoadjuvantchemotherapy.” u

Genetic Targets Identified in Triple-Negative BreastCancerAlice Goodman


Lynch syndrome is a hereditary disorder caused bya mutation in a mismatch repair gene in whichaffected individuals have an increased risk of de-

veloping colorectal cancer, endometrial cancer, and var-ious other types of aggressive cancers.The syndrome is named after its dis-coverer, Henry T. Lynch, MD, directorof Creighton University’s HereditaryCancer Center. It is estimated thatabout 3 of every 100 colon cancers arecaused by Lynch syndrome, making itthe most common inherited cause forcolon cancer.Hereditary cancers were not ac-

tively researched until the second halfof the last century. There is documen-tation that physicians acknowledgedfamily cancer clusters during the 1800s;however, it wasn’t until the late 1950s and early 1960sthat statistics were used in cancer research to establishthe existence of hereditary cancers.Dr Lynch was a pioneer in the study of cancer and

genetics in the 1960s, when cancer incidence was largelyattributed to environmental causes. His use of statistics to prove genetic links to certain cancer types was uniquefrom other researchers at that time. His early cancer re-search significantly influenced how physicians and re-searchers treat and study hereditary cancers today. Dr

Lynch demonstrated Mendelian inheritance patterns fora previously unrecognized form of colon cancer (hereditarynonpolyposis colorectal cancer, now known as Lynch syn-drome), and for the hereditary breast-ovarian cancer syn-

drome, which he subsequently helpedlink to the BRCA1 and BRCA2 genes.In addition, he provided some of the first findings of hereditary malignantmelanoma and prostate and pancreaticcancers. The purpose of his work hasbeen to enable physicians to morequickly and accurately identify high-riskpatients, leading to earlier and more ef-fective surveillance, management, andtreatment.Today, based on worldwide esti-

mates, it is projected that over 600,000individuals have the defective gene;

however, less than 5% of them have been diagnosed.Part of Dr Lynch’s vision is a network to serve those withLynch syndrome that includes genetic testing, a registry,treatment centers, and ongoing surveillance for earlyprevention. To this end, he helped establish Lynch Syn-drome International, a nonprofit organization foundedin 2009 to raise public awareness and support for indi-viduals afflicted with the syndrome. It was our greatpleasure to interview Dr Lynch about his contributionsto the field of oncology, particularly in genetics.

Interview With the Innovators

Lynch Syndrome: An Interview With the Father ofHereditary Cancer Detection and Prevention, Henry T. Lynch, MDHenry T. Lynch, MDCreighton University School of MedicineOmaha, Nebraska

Dr Lynch is Professor of Medicine at the Creighton University School of Medicine and Director of the Creighton CancerCenter. 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 priorto joining the Creighton University School of Medicine faculty in 1967. In 1984, he established Creighton University’s Hered-itary Cancer Prevention Clinic, an interdisciplinary clinic that provides information and services related to hereditary cancers.

Henry T. Lynch, MD


PMO Thank you for speaking with us, Dr Lynch.We’d like you to describe the process that led to the dis-covery of Lynch syndrome.

Dr Lynch I developed an interest in genetics early inmy medical training, particularly as it related to cancer.Many individuals with an extensive family history ofcolon cancer were diagnosed with familial adenomatouspolyposis (FAP), a hereditary colon cancer that pro-duces hundreds to thousands of polyps. However, somepatients diagnosed with FAP did not have symptomscharacteristic of the syndrome; the typical numerouspolyps were not present in the first family I studied. Isuspected another hereditary cancer might exist.

PMODoes the research of Lynch syndrome have im-plications for other research models/strategies?

Dr Lynch Yes, our research has extremely importantimplications for preventive as well as other clinical trans-lational research models/strategies.

PMO Is there a research strategy specific to Lynchsyndrome?

Dr Lynch The research strategy for the Lynch syn-drome revolves around issues related to its diagnosis andultimate management strategies. Its clinical importance re-lates to the fact that it is by far the most common heredi-tary colorectal cancer syndrome and extracolonic cancersyndrome problem. These often result in extremely im-portant clinical/preventive cancer syndrome issues.

PMO Does Lynch syndrome resemble other diseasestates in terms of disease process, patient selectivity, orprogression? In other words, is there any analog for gain-ing an understanding of it?

Dr Lynch Lynch syndrome, in fact, has strong simi-larities to disease processes relevant to patient selectivityand cancer progression. There are multiple clinicalanalogs revolving around the need for a comprehensivefamily history and ultimately genetic testing, when ap-propriate, in the search for cancer-causing mutationsand design of preventive opportunities.

PMOWhat has been the greatest significance of thediscovery and management of Lynch syndrome on can-cer and/or personalized medicine research?

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

of its diagnosis and management pertains to the needfor its personalized medical research contributing to areduction in morbidity and mortality when compliance isadhered to.

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

Dr Lynch Discovery and clinical usage of diagnosisof Lynch syndrome has definitely changed morbidityand mortality outcomes. We have profound evidence ofthis in the study of countless families throughout theUnited States, South America, and Europe, where wehave been highly privileged to have been involved clin-ically and genetically with physicians in multiple spe-cialties; medical genetics, surgery – particularly surgicaloncology and colorectal surgery – gastroenterology, andgynecologic oncology.

PMO How aware of and responsive to Lynch syn-drome are practicing oncologists?


Today, based on worldwide estimates, it isprojected that over 600,000 individualshave the defective gene; however, lessthan 5% of them have been diagnosed.

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


Dr LynchWell, it’s more fitting to ask if the patientsare aware, and their response. We find that our patientshave been partially responsive to the preventive impli-cations of Lynch syndrome and the advice given by theirfamily doctors as well as practicing oncologists. How-ever, this only happens when the patients are adequatelyeducated and have constant encouragement.

PMO Which factors tend to limit, and which in-crease, awareness and management of Lynch syndrome?

Dr LynchAs part of our goals at the Hereditary Can-cer Center, we strive to promote awareness and preven-tive management. Compliance is hopefully magnifiedthrough our genetic counselor and physician interven-tions. Awareness and management is based on manyyears of our intensive research, with attempts to comeup with what is best for a particular patient.Factors that limit increased awareness and manage-

ment of Lynch syndrome revolve around physician in-terest and willingness to learn about the syndrome andprovide its diagnostic and preventive implications tohigh-risk patients in their practices. Other factors thatlimit increased awareness and management revolvearound limited interest on the part of the patient andwillingness of insurance companies to help cover thecost, which can be very high in the case of the sine quanon for diagnosis, namely, the search for the cancer-causing germline mutation.

PMO How would you describe awareness and man-agement of the syndrome at Creighton?

Dr Lynch This has been done admirably well, in myopinion, in our academic setting. The preventive mea -sures we use, particularly colonoscopy, with initiation atage 25 and repeated every other year to age 40 and thenannually thereafter, have been successful. Implicationsfor prophylactic hysterectomy and bilateral salpingo-oophorectomy, in collaboration with colleagues at theMD Anderson Cancer Center, in Houston, Texas, havebeen successful.

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

Dr Lynch The stakeholder groups, including practic-ing oncologists and academic centers, have worked veryhard to get insurance companies’ support for its costlymanagement. Healthcare disparities for Lynch syndromeenter the picture and may be a particular hazard for eth-


Dr Lynch has identified patterns of genetic inheritance throughgenerations of extended families.

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


nic and racial factors, particularly those involvingAfrican Americans and patients of Latino background.These issues must be resolved.

PMO Are medical directors and pharmacy directorsat health plans sufficiently informed about Lynch syn-drome to provide proper coverage of its care?

Dr LynchOur experience indicates that medical andpharmacy directors have, for the most part, not been suf-ficiently informed about Lynch syndrome to the extentthat they can reasonably provide proper coverage of itsdiagnosis and management.

PMOWhile Lynch syndrome increases risk for somecancers, it does not for others. What accounts for theabsence of risk for developing certain cancers?

Dr Lynch Lynch syndrome increases the risk for mul-tiple primary cancers, particularly cancer of the colorec-tum, endometrium, ovary, among other extracoloniccancers. So far as we can determine, its risk for so-calledenvironmental cancers, inclusive of head and neck andlung cancer, has not been an exceptionable problem.However, we have no knowledge at this time about theabsence of risk for developing certain cancers.

PMOHow would you briefly describe the pathogen-esis, pathophysiology, and clinical sequelae of Lynchsyndrome in terms relevant to practicing oncologists?Do clinicians understand the science behind Lynch syn-drome, or just its impact on outcomes?

Dr Lynch Our pathology colleagues, among otherspecialists, have been working very hard at attempts tounderstand the pathogenesis, pathophysiology, and clin-ical sequelae of Lynch syndrome in terms that can bemost useful to practicing oncologists. Understanding thescience of the Lynch syndrome has been emerging, par-ticularly at the molecular genetics level, but we have along way to go in order to have its impact more fully ex-plained on clinical outcomes.

PMO Where is Lynch syndrome trending in termsof clinician recognition, diagnosis, and management?How has this progressed over the past 5 years?

Dr Lynch The Lynch syndrome has been increasingsignificantly in its clinical recognition, diagnosis, andmanagement, and it has progressed favorably over the

past 5 years in diagnosis. This is in contrast to my initialdiscovery of the Lynch syndrome in 1962, when I was asecond-year medical resident at the University of Ne-braska College of Medicine. Clearly, there was no edi-torial concern about what I was attempting to publish.Attention to the syndrome throughout the world and

the lack of believability of my work was truly profound.Over the years interest gradually increased, but at a slowpace. It began to emerge relevant to mounting evidencesupporting the existence of Lynch syndrome. However,it wasn’t until the early 1990s that linkage analysis andother technology emerged in support of the diagnosis ofLynch syndrome. Substantial evidence emerged rapidlyfollowing the discovery of germline mutations giving evidence for its existence.

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


Understanding the science of the Lynchsyndrome has been emerging, particularlyat the molecular genetics level, but wehave a long way to go...

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


Colorectal Cancer

The association between Kirsten-Ras (KRAS)mutations, present in approximately 40% ofcolorectal cancers (CRCs), and lack of benefit

from epidermal growth factor receptor (EGFR)-targetedantibodies is well known to oncologists. It is standard

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

KRAS and Colorectal Cancer: Shades of GrayChloe E. Atreya, MD, PhDHelen Diller Family Comprehensive Cancer CenterUniversity of California, San FranciscoSan Francisco, California

Jonathan M. Ostrem, BS, MD, PhD CandidateUniversity of California, San FranciscoSan Francisco, California

Robin K. Kelley, MDHelen Diller Family Comprehensive Cancer CenterUniversity of California, San FranciscoSan Francisco, California

Dr Atreya is a gastrointestinal oncologist and scientist whose research focuses on the interplay between genotype and responseto 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 thelaboratory 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 newtreatments, particularly for hepatocellular and bile duct cancers. She is also Executive Officer of the Alliance for Clinical Trialsin Oncology Translational Research Program.

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 aKRAS G13D mutation benefit from anti-EGFR therapy?

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

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

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


jacent amino acids.1,2 In cetuximab-treated patients, thepresence of a glycine (G) to aspartic acid (D) change atcodon 13 of KRAS (c.38G>A, or p.G13D) was associ-ated with intermediate survival, be-tween that of patients with KRASwild-type tumors and tumors harboringa KRASmutation at glycine-12. Whilethe overall impact of KRAS mutationson CRC prognosis remains unclear,3

G13D mutations may be associatedwith worse outcomes.1,2,4 The purposeof this review is to place differences be-tween KRAS mutations at codon 12and 13 in CRC into scientific and clin-ical contexts, and to consider the po-tential implications of nonequivalentmutations within the same gene for thepursuit of personalized medicine in oncology.

Scientific Context The RAS guanine nucleotide-binding protein regu-

lates cell survival, growth, and proliferation by acting asa molecular switch in response to extracellular signals.RAS regulates downstream pathways by cycling be-tween an inactive guanosine diphosphate (GDP)-boundstate and an active guanosine triphosphate (GTP)-bound state.5,6 Posttranslational processing targets RASto the membrane, where it resides in the OFF state,bound to GDP.7,8 Upon stimulation by growth factorssuch as insulin and EGF, RAS activators called guaninenucleotide exchange factors localize to the membraneand stimulate the release of GDP from RAS, thus allow-ing GTP binding and activation.9,10 Once ON, RAS ac-tivates downstream signaling cascades, including theRAF-MEK-ERK pathway.11 Inactivation of RAS signal-ing requires hydrolysis of the RAS-bound GTP back toGDP with release of phosphate. However, RAS is ex-tremely slow at carrying out this reaction on its own.Therefore, inactivation of RAS depends upon the ac-tion of GTPase-activating proteins (GAPs), which sup-ply a critical arginine residue to the RAS active site toassist in catalysis of GTP hydrolysis.5,12 Dysregulation of

RAS signaling is almost invariably associated with dis-ease. Hyperactivating somatic mutations in RAS areamong the most common lesions found in human ma-

lignancies. Although mutation of anyof the 3 RAS isoforms (KRAS, NRAS,or HRAS) can lead to oncogenictransformation, KRAS mutations areby far the most common.13-16 Hyperac-tivation of the RAS pathway due tooncogenic mutations in other pathwaymembers, including BRAF and EGFR,accounts for a significant proportion ofRAS wild-type cancers.17

Three-dimensional structures ofRAS isoforms have been well studied.Indeed, over 100 crystal structures ofRAS in various complexes have been

solved. Nucleotide-dependent signaling relies on con-formational changes in 2 regions that border the nu-cleotide-binding pocket, switch I (residues 30-38) andswitch II (residues 60-76) (Figure 1).18 Threonine-35and glycine-60 make key hydrogen bonds with the γ-phosphate of GTP, holding switch I and switch II intheir active conformations. Upon hydrolysis of GTP andrelease of phosphate, these regions relax into the inac-tive GDP-binding conformation. Only the GTP-boundconformation of the switch regions activates down-stream effector proteins.

The regions surrounding the nucleotide-bindingpocket contain the most common sites of RAS muta-tion. Along with the switch regions, the borders of thepocket include the phosphate-binding loop (P-loop,residues 10-17) and the base-binding loops (residues116-120 and 145-147).19 The majority of oncogenic mu-

Colorectal Cancer

Chloe E. Atreya, MD, PhD

The RAS guanine nucleotide-bindingprotein regulates cell survival, growth, andproliferation by acting as a molecularswitch in response to extracellular signals.


tations occur at residues 12 or 13 in the P-loop, orresidue 61 in switch II.17 Mutations activate RAS by 2main mechanisms: decreasing GTP hydrolysis or in-creasing nucleotide exchange. Most oncogenic muta-tions follow the first mechanism. In wild-type RAS,residues 12 and 13 are both glycine, the smallest aminoacid. Mutation of either of these residues to larger aminoacids can occlude the critical arginine of the GAP, lead-ing to decreased GAP binding and insensitivity toGAP-stimulated GTP hydrolysis.5,20,21 Glutamine-61 ofRAS participates in catalysis, and therefore its mutationalso affects GTP hydrolysis; however, GAP binding isgenerally normal or increased.12,21 Mutations near thebase-binding region of RAS (eg, alanine-146 or phenyl -

alanine-156) diminish nucleotide binding affinity andincrease the intrinsic rate of exchange.22,23 The activeform of RAS then predominates due to the higher con-centration of GTP than GDP in the cell.Biochemical and cellular assays demonstrate that al-

though RAS mutations at glycine-12 and glycine-13 areadjacent, identical substitutions at these positions (eg,G12S vs G13S) lead to very different levels of RAS acti-vation.21,24 Mutations at codon 12 are generally the mostpotent activators of RAS: the crystal structure of HRAScomplexed with a GAP suggests that mutations at thisposition sterically clash with the arginine finger of theGAP, preventing both binding and catalysis.12 Indeed,mutation to any amino acid other than proline inducesfocus formation and anchorage-independent growth ofrat fibroblasts, both measures of oncogenic transforma-tion.24 Mutations at codon 13 are generally less activatingin vitro. Three G13 mutations (G13S, G13V, and G13D)have been compared in GAP stimulation and focus for-mation assays. G13D completely blocks GAP activity andis the only codon 13 mutant that induces focus formation.G13S is only slightly activating, having a small effect onGAP stimulation. G13V shows intermediate oncogenic-ity; this mutation completely blocks GAP activity, with-out inducing focus formation.20,21 G12 mutations mayconfer greater resistance to apoptosis and increase theproportion of GTP-bound RAS well above the levelachieved 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 hy-peractivate wild-type RAS.21 The most potent mutant,Q61L, increases nucleotide exchange in addition to di-minishing GTPase activity.22,29 Substitutions at alanine-146 are less activating than G12 mutations and may becomparable to G13 mutations in transforming effi-ciency.30 These base-binding mutations increase the in-trinsic rate of nucleotide exchange,22 thus increasingRAS-GTP without affecting GAP stimulation. Despitelower oncogenicity, one would expect KRASA146 mu-tants to be growth factor independent due to their

Colorectal Cancer

Figure 1. Location of Common Oncogenic MutationsMapped Onto the 2- and 3-Dimensional Structuresof KRAS

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


capacity for autonomous nucleotide exchangeand activation.31

The spectrum of RAS pathway mutationsdiffers markedly by cancer type (Figure 2).17

Pancreatic cancer exhibits the highest fre-quency of KRAS mutations: 72% in theSanger Catalogue of Somatic Mutations inCancer and >90% in other series (Figure 2B).17 By contrast, breast cancer (not shown)has a low frequency of RAS pathway muta-tions: 4% KRAS, 3% BRAF, 2% NRAS, and<1% HRAS mutations.17 Melanoma has ahigh frequency of RAS pathway mutations,but KRAS mutations are rare (Figure 2 D). InCRC, half of tumors exhibit a mutation in theRAS pathway (mutually exclusive), mostoften a missense mutation in KRAS itself (Fig-ure 2 A). Unlike in lung cancer, EGFRmuta-tions are rare in CRC.Differences by cancer type are also ob-

served in the distribution of KRAS single-basesubstitution mutations (Figure 2). Across can-cers, mutations at codon 12 predominate:G12D and G12V are the first and second mostcommon KRAS mutations. In lung cancer,however, the most frequent KRAS substitu-tion is glycine to cysteine (G12C). Of all cancer types, CRC exhibits the greatest proportion of G13D mutations: ~20% ofKRAS mutations and 8% overall. Of note,clinical testing for KRAS mutations is typi-cally performed using polymerase chain reac-tion–based assays with probes specific formutations in codons 12 and 13. Consequently,KRAS mutations at other codons, includingQ61 and A146, may be underrepresented.32,33

Despite decades of RAS research, 5 years passed be-tween FDA approval of cetuximab for treatment ofEGFR-expressing mCRC and the label change to ex-clude patients with tumors harboring KRAS mutations.A major reason for the delay was that no correlation wasobserved between KRAS mutational status and sensitiv-

ity to cetuximab in CRC cell lines.34 This experienceunderscores the necessity of evaluating annotatedhuman tumor specimens for associations between spe-cific mutations, survival, and response to therapies,thereby enabling the clinical findings to guide furthermechanistic investigations.

Colorectal Cancer

Figure 2. Mutational Frequency of RAS Pathway Genes (left)and Distribution of KRAS Mutations (right) in A, ColorectalAdenocarcinoma; B, Pancreatic Adenocarcinoma; C, LungAdenocarcinoma; and D, Melanoma

A. Colorectal adenocarcinoma


Clinical ContextA landmark study linking KRAS G13D mutations

with clinical outcomes was a retrospective, pooled analy-sis of 774 patients with chemotherapy-refractory mCRCtreated with cetuximab-based therapy from 3 data sets(the National Cancer Institute of Canada/AustralasianGastrointestinal Trials Group and a Leuven and an Ital-ian data set) encompassing 7 clinical trials (CO.17,EVEREST, BOND, SAVAGE, BABEL, MABEL, andEMER202600).1 Three hundred ten patients (40%) hada KRAS mutation at codon 12 or 13, 45 of which wereG13D (14.5% of KRAS mutations; 6% overall). Thir-teen patients with KRAS G13D-mutated tumors re-ceived best supportive care on the CO.17 trial andexperienced significantly worse overall survival (OS)compared with patients with other KRAS-mutated orKRAS wild-type tumors in a univariate analysis. Afteradjustment for potential prognostic factors (eg, age, sex,performance status, prior chemotherapy, and primarysite) in the multivariate analysis, however, there were nosurvival differences by KRAS status (Table). Patientswith G13D-mutated tumors who received any cetux-imab-based therapy (monotherapy or cetuximab plus

chemotherapy) experienced longer survival than pa-tients with other KRAS mutations, with OS 7.6 versus5.7 months and progression-free survival (PFS) 4.0 versus1.9 months (Cox regression P=.005 and .004, respec-tively) (Table). But because G13D did not portend aworse prognosis in multivariate analysis, the significanceof improved survival end points for cetuximab-treatedpatients with G13D-mutated tumors compared withother KRAS mutations is unclear. Moreover, all of thebenefit occurred in patients treated with cetuximab pluschemotherapy, raising the possibility that outcomescould have been more affected by the chemotherapy. Inthe presence of a G13D mutation, cetuximab monother-apy (pooled data) did predict significantly better OScompared with no cetuximab (CO.17 trial) (P=.02 bylog-rank test), and there was a trend toward significancein the CO.17 trial only. There was no significant differ-ence in response rates between G13D and other KRASmutants treated with cetuximab-based therapy. Overall,the results of De Roock et al1 provide greater support forG13D as a predictive rather than a prognostic marker.Following these findings in the refractory setting, the

association of KRAS G13D with outcomes in patients

Colorectal Cancer

Other KRASKRAS G13D (codon 12) KRASWild-Type

De Roock et al1 (n=45) (n=265) (n=464)

Best supportive care, No. 13 69 113Median OS, mo (95% CI) 3.6 (2.2-4.8) 4.7 (3.6-3.51) 5.0 (4.2-5.5)

Any cetuximab-based therapy, No. 32 195 325Median OS, mo (95% CI) 7.6 (5.7-20.5) 5.7 (4.9-6.8) 10.1 (9.4-11.3)

Cetuximab monotherapy, No. 10 91 146Median OS, mo (95% CI) 6.7 (3.3-20.5) 4.8 (4.0-5.9) 9.4 (7.7-10.3)

Cetuximab + chemotherapy, No. 22 104 199Median OS, mo (95% CI) 10.6 (5.7-24.6) 7.4 (5.5-9.0) 11.3 (9.9-13.6)

Tejpar et al2 (n=83) (n=325)* (n=845)

Chemotherapy only, No. 41 148 447Median OS, mo (95% CI) 14.7 (12.4-19.4) 17.7 (15.3-20.5) 19.5 (17.8-21.1)

Cetuximab + chemotherapy, No. 42 177 398Median OS, mo (95% CI) 15.4 (12.4-20.4) 15.4 (13.5-17.5) 23.5 (20.7-25.7)

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

Table. Survival by Treatment Type and KRAS Allele


with mCRC treated with first-line chemotherapy withor without cetuximab was investigated by Tejpar et alin a retrospective analysis of 1378 patients from the ran-domized CRYSTAL and OPUS trials.2 Here, 533 pa-tients (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 etal,1 consistent with first-line therapy, compared with thechemotherapy-refractory setting (Table). When treatedwith chemotherapy alone, patients with G13D mutanttumors had a worse outcome compared with patientswith other KRAS mutant or KRAS wild-type tumors.When cetuximab was added to chemotherapy, signifi-cant 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 ob-served among patients with G13D mutations, althoughthe OS benefit did not reach significance (Table). Thecetuximab treatment effect in the G13D subset wascomparable to that in patients with KRAS wild-type tu-mors, but OS and PFS were considerably lower. By con-trast, survival worsened with the addition of cetuximabto chemotherapy among patients with other KRASmu-tations (6.7 vs 8.1 months; HR 1.37).To summarize, both of these large, pooled retrospec-

tive studies found that patients with KRAS G13D mu-tant mCRC may have a poor prognosis when treatedwith best supportive care or standard chemotherapy inthe chemotherapy-refractory1 or first-line setting,2 re-spectively. In both studies, patients with G13D muta-tions appeared to derive modest benefit from theaddition of cetuximab.Smaller, single-arm studies have yielded complex re-

sults with respect to the prognostic significance of KRASG13D mutations, a confounding factor that clouds in-terpretation of predictive impact.4,35 Evaluation of 229Japanese CRC patients found a nonsignificant trend to-ward worse OS of patients with G13D mutations com-pared with patients with KRAS wild-type tumors (HR1.67; 95% CI, 0.93-3.02; P=.086 on univariate analy-sis).4 Survival of patients with G12 mutant tumors wassimilar to KRAS wild-type, whereas patients with BRAF

V600E mutant tumors had the worst OS (HR 3.78; 95%CI, 1.89-7.54; P≤.001).4 On the other hand, 2 reportssuggest a link between KRAS G13D and microsatelliteinstability (MSI) associated with favorable outcome.35,36

An analysis of mutation frequency in 158 hereditarynonpolyposis CRC (HNPCC) and 864 sporadic CRCcases identified a significantly higher rate of G13D mu-tations in HNPCC tumors (microsatellite unstable)compared with sporadic microsatellite-stable tumors(51% vs 12% of KRAS mutations).36 G13D mutationswere also overrepresented in sporadic MSI-high tumorswithout hMLH1 methylation (27% of KRAS muta-tions).36 In a study of 94 hereditary and 404 sporadicCRC cases, KRAS G13D mutations were associatedwith a better prognosis in HNPCC and sporadic MSI-high subsets.35

A growing number of small studies are examining thepredictive value of KRAS G13D with respect to cetux-imab treatment.37-39 These studies, limited by size andclinical heterogeneity, highlight the importance of ac-cess to tissue from large groups of similarly treated pa-tients for subset analyses.

Peeters et al40 presented an important counterpoint tothe findings in De Roock et al1 and Tejpar et al2 at the 2012American Society of Clinical Oncology (ASCO) AnnualMeeting. Evaluation of 1083 patients treated with second-line FOLFIRI plus panitumumab (NCT00339183), 1096patients treated with first-line FOLFOX4 plus panitu-mumab (PRIME, NCT00364013), and 184 patients whoreceived panitumumab monotherapy (NCT00113776)yielded inconsistent associations between specific KRASmutations and survival.40 Tejpar et al2 pooled data from theCRYSTAL (FOLFIRI ± cetuximab) and OPUS (FOL-FOX4 ± cetuximab) studies because they found that

Colorectal Cancer

Treated with chemotherapy alone,patients with G13D mutant tumors had aworse outcome compared to patientswith other KRAS mutant or KRASwild-type tumors.


irinotecan- and oxaliplatin-containing chemotherapyregimens produced similar treatment effects in patientsstratified by KRAS mutation status. Conversely, Peeterset al40 reported a trend toward better OS among patientswith G13D-mutated tumors treated with FOLFIRI pluspanitumumab (N=39; P=.07), whereas G13D was signif-icantly associated with worse OS among patients treatedwith FOLFOX4 plus panitumumab (N=46; P=.003), andG13D was not predictive or prognostic of outcome whenthe panitumumab studies were pooled. The possibilitythat different anti-EGFR agents, in addition to lines oftherapy and chemotherapy backbones, may contribute tounequal outcomes in association with KRAS mutationstatus further complicates the G13D story.

More Questions Than AnswersFollowing these analyses of over 3000 patients, evi-

dence to support KRASG13D as an independent predic-tive and/or prognostic biomarker in CRC still has notmatured. Returning to the question of biologic mecha-nism, is there a plausible explanation for intermediate ef-fects of KRAS G13D with respect to both response tocetuximab and survival? Intermediate response to cetux-imab is easier to explain because KRAS mutations atcodon 13 are less oncogenic than mutations at codon12.1,20,21,24 A less activating KRAS mutation may meanthat the tumor is partially growth factor dependent andthereby somewhat responsive to EGFR inhibition. It isdifficult to directly attribute worse survival to G13D mu-tations. More likely, G13D mutations could signify a dif-ferent biological signature that portends worse prognosis.Different carcinogenic triggers produce distinct pat-

terns of mutations: depending on the chemical used,KRAS codon 12 or 61 mutant lung cancers can be in-duced in mice.41 In human lung cancers, KRAS muta-

tions are common in smokers, whereas EGFR and ALKmutations are more frequent in never-smokers.42 InCRC, rather than being a driver, KRAS G13D muta-tions may develop secondary to another oncologicprocess and propagate because they confer a modest sur-vival advantage for tumor cells. This hypothesis is sup-ported by findings in cultured cells subjected tocontinuous cetuximab: KRAS G13D mutations accom-panied emergence of resistance, and deep sequencingsubsequently detected preexisting G13D mutations in aminority of parental cells.43 KRAS G13D is also a non-tumor-initiating mutation in HNPCC, caused by defectsin DNA mismatch repair genes that lead to a myriad ofsomatic mutations.36,44 A poor prognosis, BRAF-mu-tated–like gene expression signature was identified in30% of KRAS mutant CRCs.45 Follow-up work pre-sented at the 2012 ASCO Annual Meeting showed ad-ditional evidence for heterogeneity among KRASmutant colon tumors but no significant division by spe-cific KRAS mutation.46 A moderately aggressive CRCsubgroup marked by KRAS G13D mutations has notbeen described.If “shades of gray” exist among KRAS mutations,

might the same be true for other oncogenes and tumorsuppressor genes? The answer is, of course, yes. For ex-ample, phosphoinositide-3-kinase (PI3K, coded by thePIK3CA gene) is mutated in ~15% of CRCs. PIK3CAhas 2 mutational hot-spot clusters located approxi-mately 1500 nucleotides apart, corresponding to the hel-ical domain (eg, E545K) and the kinase domain (eg,H1047R). Helical and kinase domain mutations inducegain of function by different mechanisms. Helical do-main mutations are dependent on RAS binding fortransformation; kinase domain activation is mediatedby interaction with the p85 regulatory subunit.47 InCRC, helical domain mutations associate with KRASmutations, methylation of the MGMT DNA repairgene, and CpG island methylator phenotype–low status,while kinase domain mutations correlate with serratedpathway features including BRAF mutation and MSI.48

As with KRAS, the distribution of PIK3CA helical andkinase domain mutations varies by tissue of origin. In

Colorectal Cancer

If “shades of gray” exist among KRASmutations, might the same be true for otheroncogenes and tumor suppressor genes?The answer is, of course, yes.


CRC, the distribution is roughly two-thirds helical toone-third kinase domain mutations. Breast cancer hasthe highest rate of PI3K mutations (25%), and the ratioof helical to kinase domain mutations is opposite thatin CRC.17 Even identical mutations can have differingeffects by cancer type, as highlighted by dissimilar re-sponses to BRAF inhibitors among patients with BRAFV600E CRC or melanoma.49

A final example of the potential for disparate impactof mutant alleles within a single gene involves the tumorsuppressor protein p53. Mutation of p53 is the mostcommon genetic lesion in human malignancies, includ-ing nearly half of CRCs. Whereas a limited number ofmutations activate oncogenes, a greater variety of le-sions can inactivate tumor suppressors. One study as-sessed effects of 2314 point mutations in the p53DNA-binding domain.50 We ascertained p53 status in604 tumors from the CALGB 89803 trial of adjuvanttherapy for stage III colon cancer. Tumors were classifiedas p53 wild-type or mutation present in the zinc-binding(ZB) or the non–zinc-binding (NZB) regions of theDNA-binding domain. Overall, p53 mutational statuswas not associated with survival.51 However, amongwomen, survival was superior with NZB mutations com-pared with wild-type p53 and worst with ZB mutations.51

A larger sample would be required to determine whetherthese differences could be attributed to specific p53 hot-spot mutations.

Implications for Personalized MedicineThe central clinical question remains unanswered:

will a patient with mCRC harboring a KRASG13D mu-tation benefit from anti-EGFR therapy? Based on themodest efficacy of anti-EGFR therapy even among pa-tients with KRAS wild-type tumors, the sample size re-quired for a prospective randomized study in the KRASG13D subset would be prohibitive and perhaps inappro-priate in light of the priority to identify new targets andmore active agents. Additional large retrospectiveanalyses of cohorts of CRC patients with matched clin-icopathologic and treatment characteristics may providegreater precision in estimating the prognostic and pre-

dictive value of G13D, although there remains a distinctpossibility that the impact is unsatisfyingly context-dependent and marginal. Are the differences meaning-ful, or are we trying to distinguish gray from grey?KRAS G13D heralds an approaching onslaught of

new questions as next-generation sequencing and othertechnologies reach the clinical arena. If mutations inadjacent codons can have unequal effects, what level of“personalization” is required in oncology clinical re-search? Even synonymous mutations (resulting in thesame amino acid sequence) can produce differences inRNA processing that significantly alter protein levels orfunctions.52 We submit that validation of novel “person-alized medicine” biomarkers should involve an iterative

approach whereby hypothesis-generating data from clin-ical samples – such as the observations reviewed heresuggesting a differential impact of KRAS G13D versusother KRAS mutations – should trigger a return to pre-clinical mechanistic studies in parallel with additionalretrospective analyses of independent clinical data sets.Across these endeavors, tumor genotyping should bespecific to the nucleotide level and compiled to identifybroad signals of high-impact genetic events. As our un-derstanding of CRC biology becomes more nuanced, wemust steadfastly search for therapies with unequivocalbenefit for molecularly defined subsets of patients. u

AcknowledgmentsCEA is supported in part by Postdoctoral Fellowship

11-183-01-TBG from the American Cancer Society andalso acknowledges the support Millennium providedthrough the Alliance for Clinical Trials in OncologyFoundation. JMO is supported by the UCSF MedicalScientist Training Program NIH-NIGMS-MSTP

Colorectal Cancer

KRAS G13D heralds an approachingonslaught of new questions as next-generation sequencing and othertechnologies reach the clinical arena.


(#GMO7618). We thank David Donner, PhD, for edi-torial assistance.

References1. De Roock W, Jonker DJ, Di Nicolantonio F, et al. Association of KRASp.G13D mutation with outcome in patients with chemotherapy-refractorymetastatic colorectal cancer treated with cetuximab. JAMA. 2010;304:1812-1820.2. Tejpar S, Celik I, Schlichting M, et al. Association of KRAS G13Dtumor mutations with outcomes in patients with metastatic colorectal can-cer treated with first-line chemotherapy with or without cetuximab [pub-lished online ahead of print June 25, 2012]. J Clin Oncology.3. Yokota T. Are KRAS/BRAF mutations potent prognostic and/or pre-dictive biomarkers in colorectal cancers? Anticancer Agents Med Chem.2012;12:163-171.4. Yokota T, Ura T, Shibata N, et al. BRAF mutation is a powerful prog-nostic factor in advanced and recurrent colorectal cancer. Br J Cancer.2011;104:856-862.5. Trahey M, McCormick F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science. 1987;238:542-545.6. Field J, Broek D, Kataoka T, et al. Guanine nucleotide activation of,and competition between, RAS proteins from Saccharomyces cerevisiae.Mol Cell Biol. 1987;7:2128-2133.7. Gutierrez L, Magee AI, Marshall CJ, et al. Post-translational processingof p21ras is two-step and involves carboxyl-methylation and carboxy-ter-minal proteolysis. EMBO J. 1989;8:1093-1098.8. Casey PJ, Solski PA, Der CJ, et al. p21ras is modified by a farnesyl iso-prenoid. 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 activationby 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 p21rasthrough the formation of a complex of receptor, Grb2 adapter protein, andSos nucleotide exchange factor. Cell. 1993;73:611-620.11. Moodie SA, Willumsen BM, Weber MJ, et al. Complexes of Ras. GTPwith 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 com-plex: structural basis for GTPase activation and its loss in oncogenic Rasmutants. Science. 1997;277:333-338.13. Parada LF, Tabin CJ, Shih C, et al. Human EJ bladder carcinoma oncogeneis homologue of Harvey sarcoma virus ras gene. Nature. 1982;297:474-478.14. Santos E, Tronick SR, Aaronson SA, et al. T24 human bladder carci-noma oncogene is an activated form of the normal human homologue ofBALB- and Harvey-MSV transforming genes. Nature. 1982;298:343-347.15. Der CJ, Krontiris TG, Cooper GM. Transforming genes of human blad-der and lung carcinoma cell lines are homologous to the ras genes of Harveyand 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 transforminggenes 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 signaltransduction: structural differences between active and inactive forms ofprotooncogenic ras proteins. Science. 1990;247:939-945.19. Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch inthree dimensions. Science. 2001;294:1299-1304.20. Fasano O, Aldrich T, Tamanoi F, et al. Analysis of the transformingpotential of the human H-ras gene by random mutagenesis. Proc Natl AcadSci U S A. 1984;81:4008-4012.21. Gideon P, John J, Frech M, et al. Mutational and kinetic analyses ofthe GTPase-activating protein (GAP)-p21 interaction: the C-terminal do-main of GAP is not sufficient for full activity. Mol Cell Biol. 1992;12:2050-2056.22. Feig LA, Cooper GM. Relationship among guanine nucleotide ex-change, GTP hydrolysis, and transforming potential of mutated ras pro-teins. Mol Cell Biol. 1988;8:2472-2478.23. Quilliam LA, Zhong S, Rabun KM, et al. Biological and structural

characterization of a Ras transforming mutation at the phenylalanine-156residue, which is conserved in all members of the Ras superfamily. ProcNatl Acad Sci U S A. 1995;92:1272-1276.24. Seeburg PH, Colby WW, Capon DJ, et al. Biological properties ofhuman 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-ras-driven oncogenic transformation on the protein network of murine fibro -blasts. 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 JCancer. 2009;100:656-662.27. Guerrero S, Casanova I, Farré L, et al. K-ras codon 12 mutation in-duces higher level of resistance to apoptosis and predisposition to anchor-age-independent growth than codon 13 mutation or proto-oncogeneoverexpression. Cancer Res. 2000;60:6750-6756.28. Der CJ, Finkel T, Cooper GM. Biological and biochemical propertiesof human rasH genes mutated at codon 61. Cell. 1986;44:167-176.29. Lacal JC, Aaronson SA. Activation of ras p21 transforming propertiesassociated 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 K-ras via a point mutation in codon 146 and induces a different spectrum ofras mutations than does gamma radiation. Mol Cell Biol. 1990;10:405-408.31. Feig LA, Cooper GM. Inhibition of NIH 3T3 cell proliferation by amutant 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 out-with ‘hotspot’ codons in sporadic colorectal tumours – implications for per-sonalised cancer medicine. Br J Cancer. 2010;102:693-703.33. Edkins S, O’Meara S, Parker A, et al. Recurrent KRAS codon 146 mu-tations in human colorectal cancer. Cancer Biol Ther. 2006;5:928-932.34. Jhawer M, Goel S, Wilson AJ, et al. PIK3CA mutation/PTEN expres-sion status predicts response of colon cancer cells to the epidermal growthfactor receptor inhibitor cetuximab. Cancer Res. 2008;68:1953-1961.35. Zlobec I, Kovac M, Erzberger P, et al. Combined analysis of specificKRAS mutation, BRAF and microsatellite instability identifies prognosticsubgroups 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 mu-tations in colorectal carcinomas according to germline mismatch repair de-fects 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 mutationin 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-basedor bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated 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 andBRAF mutations on the efficacy of cetuximab-based first-line therapy ofmetastatic colorectal cancer: an analysis of the AIO KRK-0104-trial. Int JCancer. 2012;131:980-986.40. Peeters M, Douillard J, Van Cutsem E, et al. Mutant (MT) KRAScodon 12 and 13 alleles in patients (pts) with metastatic colorectal cancer(mCRC): assessment as prognostic and predictive biomarkers of responseto panitumumab (pmab). J Clin Oncol. 2012;30(suppl). Abstract 3581.41. You M, Candrian U, Maronpot RR, et al. Activation of the Ki-ras pro-tooncogene in spontaneously occurring and chemically induced lung tu-mors 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 determinesurvival in smokers and never-smokers with stage IIIB/IV lung adenocar-cinomas [published online ahead of print May 17, 2012]. Cancer.43. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutationsand 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-prog-nosis BRAF-mutant-like population of patients with colon cancer. J ClinOncol. 2012;30:1288-1295.46. Popovici VC, Budinska E, Tejpar S, et al. Molecular and clinicopatho-

Colorectal Cancer


logic evidence of heterogeneity in KRAS-mutant colon cancers. J ClinOncol. 2012;30(suppl). Abstract 3575.47. Zhao L, Vogt PK. Hot-spot mutations in p110alpha of phosphatidyl -inositol 3-kinase (pI3K): differential interactions with the regulatory sub-unit p85 and with RAS. Cell Cycle. 2010;9:596-600.48. Whitehall VL, Rickman C, Bond CE, et al. Oncogenic PIK3CA mu-tations 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 can-cer 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-structureand function-mutation relationships of p53 tumor suppressor protein byhigh-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 ofgenotype, gender, and adjuvant treatment in survival after resection ofstage 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 syn-onymous mutations to human disease. Nat Rev Genet. 2011;12:683-691.

Colorectal Cancer

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Thomas C.Reynolds, MD, PhDChief Medical OfficerSeattle Genetics

Edith Perez, MDDeputy DirectorMayo Clinic Cancer Center Florida

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On September 6, 2012, the Institute of Medi-cine (IOM) released the report Best Care atLower Cost: The Path to Continuously Learning

Health Care in America.1 The aim of this report, authoredby the Committee on the LearningHealth Care System in America, was toidentify how the effectiveness and effi-ciency of the current healthcare systemcan be transformed, and to develop rec-ommendations for actions that can betaken to achieve that end. This studybuilds on earlier IOM studies of variousaspects of the healthcare system, fromTo Err Is Human: Building a Safer HealthSystem,2 on patient safety; to Crossingthe Quality Chasm: A New Health Sys-tem for the 21st Century,3 on healthcarequality; to Unequal Treatment: Con-fronting Racial and Ethnic Disparities in Health Care,4 onhealthcare disparities. The study process was also facil-itated and informed by the 6 years of published sum-maries of workshops conducted under the auspices of theIOM Roundtable on Value & Science-Driven HealthCare. Sponsors of the report included Blue Shield ofCalifornia Foundation, Charina Endowment Fund, andthe Robert Wood Johnson Foundation.

Overall Findings andRecommendationsHealthcare in America presents a fundamental par-

adox. The past 50 years have seen an explosion in bio-medical knowledge, dramatic innovation in therapiesand surgical procedures, and management of conditionsthat previously were fatal, with ever more exciting clin-

ical capabilities on the horizon. Yet,the IOM report Best Care at LowerCost finds that America’s healthcaresystem has become too complex andcostly to continue business as usu-al. Inefficiencies, an overwhelmingamount of data, and other economicand quality barriers hinder progress inimproving health and threaten the na-tion’s economic stability and globalcompetitiveness. At the same time,the report notes there is significant ev-idence that the knowledge and toolsexist now to put the health system on

the right course to achieve continuous improvementand better quality care at lower cost.In the area of costs, including both financial and

harm, the system’s current inefficiency underscores theurgent need for a system-wide transformation. Health-care costs have risen at an unsustainable rate – increas-ing at a greater rate than the economy as a whole for 31of the past 40 years. Yet, the report found that a substan-tial amount of this investment was wasted. It calculatedthat about 30% of health spending in 2009 – roughly$750 billion – was wasted on unnecessary services, ex-cessive administrative costs, fraud, and other problems.

Healthcare Economics

Institute of Medicine Report: Best Care at Lower Cost:The Path to Continuously Learning Health Care inAmerica. Highlights for the Cancer CommunityJames ConwayHarvard School of Public HealthBoston, Massachusetts

James Conway

James Conway is a member of the Institute of Medicine committee for this report, the faculty of Harvard School of PublicHealth, and a board member of the American Cancer Society New England Region. He previously served as Executive VicePresident and COO of the Dana-Farber Cancer Institute, Boston.


Part of the reason for this waste comes from the way thathealthcare is paid for and reimbursed. Most payment sys-tems emphasize volume over quality and value by reim-bursing providers for individual procedures and testsrather than paying a flat rate or reimbursing based onpatients’ outcomes, the report notes. Regardless of thecause, these inefficiencies cause needless suffering. Byone estimate, roughly 75,000 deaths might have beenaverted in 2005 if every state had delivered care at thequality level of the best performing state.The report says better use of data is a critical element

of a continuously improving health system. About 75million Americans have more than 1 chronic condition,requiring coordination among multiple specialists andtherapies, which can increase the potential for miscom-munication, misdiagnosis, potentially conflicting inter-ventions, and dangerous drug interactions. Healthprofessionals and patients frequently lack relevant anduseful information at the point of care where decisionsare made. And it can take years for new breakthroughsto gain widespread adoption; for example, it took 13years for the use of beta-blockers to become standardpractice after they were shown to improve survival ratesfor heart attack victims.The committee found that engaging patients and

their families in care decisions and management of theirconditions leads to better outcomes and can reducecosts. Yet, such participation remains limited. Increasedtransparency about the costs and outcomes of care alsoboosts opportunities to learn and improve and shouldbe a hallmark of institutions’ organizational cultures, thecommittee said. Linking providers’ performance to pa-tient outcomes and measuring performance against in-ternal and external benchmarks allow organizations toenhance their quality and become better stewards oflimited resources, the report says.In framing the plan for moving forward, the report

finds that incremental upgrades and changes by individ-ual hospitals or providers will not suffice. Achievinghigher quality care at lower cost will require an across-the-board commitment to transform the US health sys-tem into a “learning” system that continuously improves

by systematically capturing and broadly disseminatinglessons from every care experience and new research dis-covery. It will necessitate embracing new technologiesto collect and tap clinical data at the point of care, en-gaging patients and their families as partners, and estab-lishing greater teamwork and transparency withinhealthcare organizations. Also, incentives and paymentsystems should emphasize the value and outcomes ofcare. The ways that healthcare providers currently train,practice, and learn new information cannot keep pacewith the flood of research discoveries and technologicaladvances. How healthcare organizations approach caredelivery and how providers are paid for their servicesalso often lead to inefficiencies and lower effectivenessand may hinder improvement.

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

Implications for the CancerCommunityCancer is frequently cited in the report for its suc-

cesses, such as the improvements cancer care hasachieved in 5-year survival rates, for its experience indeveloping and using evidence-based practice guide-lines, and for often generating evidence from routinecancer care. The cancer professional considering therecommendations will be struck with their resonancenot only in successes but also challenges and gaps. Nodoubt they will also be energized with the possibilitiesand power of a learning healthcare system for cancer.


Engaging patients and their families incare decisions and management of theirconditions leads to better outcomes andcan reduce costs.


Familiar to cancer care are the struggles in the trans-lation from science to evidence to care to improved pa-tient and family experience. There are challenges inperforming high-quality, coordinated care in the exist-ing disaggregated environment. Cancer care is deliveredby many, and often unconnected, players – in the home,

office, local hospital, regional academic setting, and hos-pice by patient and family, healthcare providers, not-for-profit associations, and others. Furthermore,clinicians must confront the complexity of different

treatment options and understand the variations of thepatient populations in their treatment responses. Toovercome these challenges, cancer providers are en-hancing, and will need to accelerate, evidence-basedpractice; implement shared decision making in all as-pects of clinical care and research; and improve accessand optimize the flow of their patients.Drawing from leading-edge practices in cancer, the

authoring committee emphasizes the power and privi-lege of patient- and family-centered care. The commit-tee makes special note of the increasing role thatcommunities must play in care, with care designedacross the continuum. At the moment, patients andfamilies are shuffled from place to place. In the future,the system must be integrated, designed to manage careacross the continuum and facilitate outcomes throughaccess, care, flow, and the reduction of waste and in-equity. Note is frequently made of the growing emphasis


Foundational Elements

Recommendation 1: The digital infrastructure. Improve the capacity to capture clinical, care delivery process, and finan-cial 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 ofclinical 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 im-proving 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 caredelivery, 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 pro-vision 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 inAmerica. 2012 by the National Academy of Sciences, Courtesy of the National Academies Press, Washington, DC.www.nap.edu/catalog.php?record_id=13444.

Table. Categories of the Committee’s Recommendations

Familiar to cancer care are the struggles inthe translation from science to evidenceto care to improved patient and familyexperience.


in cancer on health and prevention as well as health-care. Stakeholder organizations in communities mustcome 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 pal-liative care quickly come to mind. With the growingemphasis on waste and value, the question is increas-ingly being asked on how we can assure the right cancercare in the right place at the right time; nothing more,nothing less. Efforts such as the ABIM-led ChoosingWisely campaign are consistent with recommendationsin the report and inform our journey to answer thesequestions in partnership with the patient and family.Cancer care providers are already seeing the growingfocus on outcomes and calls for greater transparency,particularly around financial outcomes. While financialoutcomes are essential, they must be considered in thecontext of transparency of all outcomes: clinical, finan-cial, service, and experience (staff and patient). Thiswill require an accelerated emphasis in the cancer com-munity; in the absence of other outcomes, finance willtrump. Finally, leadership driven by a culture of team-work, collaboration, and adaptability must deepen notonly in organizations but, even more crucially, acrossthem. Cancer care providers must continue to seize thepower of communities of learning – in research, care,prevention, operations – and become master collabora-tors and continuous improvers across all organizationsin the cancer space.

ClosingSince its release, the IOM report Best Care at Lower

Cost: The Path to Continuously Learning Health Care inAmerica has garnered considerable attention. At oneend people are struck at the potential power of the rec-ommendations to transform, the clarity of the path for-ward, the strength of the evidence, and the centrality of

patient, family, and community in partnership with theircare team. They are sobered, if not stunned, by the ex-tent of the missed opportunities, waste, and harm whenpresented in the aggregate. Most already know them intheir own experience or that of someone they love. It isnow time the cancer community rapidly accelerates ef-forts to take, inform, and improve the Path to Contin-uously Learning Health Care in America. u

References1. Institute of Medicine. Best Care at Lower Cost: The Path to ContinuouslyLearning Health Care in America. Washington, DC: National AcademiesPress; 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 Systemfor the 21st Century.Washington, DC: National Academies Press; 2001.4. Institute of Medicine. Unequal Treatment: Confronting Racial and EthnicDisparities in Health Care. Washington, DC: National Academies Press;2002.


Leadership driven by a culture ofteamwork, collaboration, and adaptabilitymust deepen not only in organizations but,even more crucially, across them.

SECOND ANNUAL CONFERENCE

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Clinical Approaches to Targeted Technologies#

REGISTER TODAY AT www.globalbiomarkersconsortium.com

October 4-6, 2013The Seaport Boston Hotel • 1 Seaport Lane • Boston, MA 02210

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The incidence of melanoma inthe United States is increasingat an alarming rate (Figure 1).1

In men, melanoma is increasing morerapidly than in any other cancer; inwomen, it is increasing more rapidlythan any other cancer except lung can-cer.2 In 2012, an estimated 76,250 newcases of melanoma (44,250 in men and32,000 in women) are expected in theUnited States, and 9180 people are ex-pected to die of this cancer.3

More than 80% of melanoma pa-tients present with localized disease, 10% to 13% withregional disease, and 2% to 5% with distant metastases.2

The prognosis is excellent for patientswho present with localized disease andprimary tumors ≤1.0 mm in thickness,with 5-year survival achieved in >90%of patients. However, survival ratesrange from 50% to 90% when the lo-calized melanomas are >1.0 mm inthickness. When regional nodes are in-volved, survival rates are roughlyhalved. However, within stage III, 5-year survival rates range from 20% to70%, depending primarily on the nodaltumor burden. Long-term survival in

patients with stage IV disease is <10%.2

Systemic therapy is the primary treatment option formost patients with stage IV disease.2 For the past 30years, there were no major advances in treatment formetastatic melanoma, and until recently people withthe disease had few options.2 However, the therapeuticlandscape for metastatic melanoma is rapidly changingwith the recent development of novel agents that havedemonstrated better efficacy than traditional chemo -therapy2 (Figure 2). Importantly, melanomas can nowbe classified according to the underlying molecular aber-rations that drive tumor progression, and these biomark-ers are now being used in therapeutic practice.2

ChemotherapyDTIC (dacarbazine) (Table 1) is the only FDA-ap-

proved chemotherapy agent for the treatment of stageIV melanoma. It is administered as an IV infusion.4-6

Temozolomide is an oral chemotherapy agent that isconsidered an oral form of DTIC, but it is not approvedby the FDA for the treatment of melanoma.4,6

A number of combination therapies, including theDartmouth regimen (DTIC, cisplatin, carmustine, and


Melanoma

The New Therapeutic Paradigm for PersonalizedTherapy of MelanomaAt 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 inBethlehem, Pennsylvania, discussed the use of personalized therapy in the management of melanoma.

Case 1• 47-year-old male with a history of melanoma 6 years ago;no adjuvant therapy given

• Routine follow-up shows “spots on chest x-ray”• CT scan confirms 4 lesions, 2 in each lung; biopsy confirmsmetastatic melanoma

• Lactate dehydrogenase (LDH) within normal limits; noother metastases; performance status 0

• Tumor is BRAF V600E positive

Case 2• 56-year-old male with history of melanoma on left upperback; T4b N2a M0 in 2008

• Received high-dose interferon for 1 year, tolerated with33% dose reduction

• Now presents with multiple cutaneous metastases, lungmetastases

• Biopsy positive for metastatic melanoma; LDH normal• BRAF wild-type; NRAS positive

Sanjiv Agarwala, MD


tamoxifen), have been used for the treatment ofmetastatic melanoma. However, a phase 3 study of 240patients with stage IV melanoma compared the 4-drugDartmouth regimen with single-agent DTIC and foundno difference in survival time and only a small, statisti-cally nonsignificant increase in tumor response for pa-tients treated with the Dartmouth regimen (Figure 3).7

ImmunotherapyInterferon alpha-2b is the FDA-approved standard

treatment for patients with metastatic melanoma, butinterferon therapy is associated with significant adversereactions in most patients. Interleukin-2 (IL-2) has beenused for the treatment of melanoma with modest successfor several decades, but many acute toxicities are asso-ciated with interleukin therapy, and extremely closemonitoring is essential for safe administration.8-10

Ipilimumab, a monoclonal antibody that binds toCTLA-4, was approved by the FDA on March 25, 2011,making it the first drug in 13 years to be approved forthe treatment of melanoma. Approval was based on arandomized phase 3 trial of 676 patients with unre-sectable metastatic disease that progressed during sys-

temic therapy.11 Patients received ipilimumab 3 mg/kgplus a glycoprotein 100 peptide vaccine (gp100), ipi -limumab alone, or gp100 alone in a 3:1:1 ratio. Overallsurvival (OS) was significantly longer in patients receiv-ing the combination (10.0 months; hazard ratio [HR] =0.68 compared with gp100 alone; P<.001) or ipili-mumab alone (10.1 months; HR = 0.66 compared withgp100 alone; P=.003) compared with those receiving

gp100 alone (6.4 months). The best objective responserates were 5.7% for ipilimumab plus gp100, 10.9% foripilimumab alone, and 1.5% for gp100 alone. Ipili-mumab stimulates T cells and is associated with a sub-stantial risk of immune-related reactions. Grade 3 or 4immune-related adverse events occurred in 10% to 15%of patients treated with ipilimumab and in 3% of those

Melanoma

Figure 1. Incidence and Mortality Rates for Melanoma in the United States (1976-2008)

Reprinted from Romano E, Schwartz GK, Chapman PB, et al. Treatment implications of the emerging molecular classification system formelanoma. Lancet Oncol. 2011;12:913-922. Copyright 2011, with permission from Elsevier.

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IL-2 has been used for the treatment ofmelanoma with modest success for severaldecades, but many acute toxicities areassociated with interleukin therapy.


treated with gp100 alone. There were 14 deaths relatedto the study drugs (2.1%), and 7 were associated withimmune-related adverse events.11

A second phase 3 study was conducted in 502 pa-tients with previously untreated metastatic melanoma.12

OS was significantly longer in the group receiving ipi -limumab plus DTIC than in the group receiving DTICplus placebo (11.2 months vs 9.1 months), and survivalrates were higher for the group receiving ipilimumab-DTIC at 1-, 2-, and 3-year time points (Table 2). Grade3 or 4 adverse events occurred in 56.3% of patientstreated with ipilimumab plus DTIC versus 27.5% ofthose treated with DTIC and placebo (P<.001).

Ipilimumab is the first im-munotherapy to show an OS advantage for patients withmetastatic melanoma. An OSbenefit was seen as a singleagent compared with a vaccineand in combination with DTICcompared with DTIC alone,and the drug is effective for bothfrontline and second-line ther-apy. As yet, however, there is noconfirmed biomarker to predictresponse to ipilimumab.

BiochemotherapyBiochemotherapy is the

combination of chemotherapyand biological agents. Recentstudies have shown that out-comes in patients treated withbiochemotherapy are no better

than outcomes in patients treated with combinationchemotherapy. In a phase 3 randomized study,biochemotherapy (cisplatin, vinblastine, DTIC, IL-2,and interferon alpha-2b) produced a slightly higher re-sponse rate and progression-free survival (PFS) than cis-platin, vinblastine, and dacarbazine (CVD) alone, butit was not associated with either improved quality of re-sponse or OS, and biochemotherapy was substantiallymore toxic than CVD.13 Other studies that attemptedto decrease the toxicity of biochemotherapy by admin-istering subcutaneous outpatient IL-2 did not show asubstantial benefit of biochemo therapy versus chemo -therapy alone.14-16 A meta-analysis also showed that al-though bio chemo therapy improved overall responserates, there was no survival benefit for patients withmetastatic melanoma.17

Targeted TherapyMelanoma is not 1 disease. Evidence increasingly

shows that melanoma is not 1 malignant disorder butrather a family of distinct molecular diseases.1 Exposure

Melanoma

Figure 2. Metastatic Melanoma Treatment Landscape

CVD indicates cisplatin-vinblastine-DTIC; Dartmouth, DTIC-cisplatin-carmustine-tamoxifen; DTIC, dacar-bazine; IFN, interferon; IL-2, interleukin-2; TMZ, temozolomide. Figure courtesy of Sanjiv Agarwala, MD.

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Melanoma is not 1 disease. Evidenceincreasingly shows that melanoma is not 1malignant disorder but rather a family ofdistinct molecular diseases.


to the sun is generally accepted as a majorcausative factor of melanoma; however,the role of exposure to ultraviolet light iscomplex. For example, in light-skinnedpeople, the group that is predominantlyaffected by melanoma, tumors are mostcommon on areas that are intermittentlyexposed to the sun, such as the trunk,arms, and legs, rather than on areas thatare chronically exposed to the sun, suchas the face. A small proportion ofmelanomas arise without obvious expo-sure to ultraviolet light, because they af-fect sites that are relatively or absolutelyprotected, such as the palms and soles(acral melanoma), and mucosal membranes.18

Curtin and colleagues examined 102melanomas from 4 groups in which thedegree of exposure to ultraviolet light dif-fered: 18 melanomas from skin withchronic sun-induced damage and 18melanomas from skin without such dam-age; 28 melanomas from palms, soles, andsubungual (acral) sites; and 18 mucosalmelanomas, and genetic analysis showed significant dif-ferences in the distribution of genetic mutations inBRAF, NRAS, and KIT among the 4 groups (Figure 4).18

Vemurafenib, a selective inhibitor of the activatedBRAF V600E gene, a gene found in 70% of malignant

melanomas,19 was approved by the FDA in August 2011for both first- and second-line treatment of unresectableor metastatic melanoma with a V600E mutation in theBRAF gene, as detected by an FDA-approved test. Thecobas 4800 BRAF V600 Mutation Test, a companion

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.

Table 1. Therapies for Metastatic Melanoma

Figure 3. Survival: Single-Agent DTIC vs 4-Drug DartmouthRegimen

Dartmouth indicates DTIC-cisplatin-carmustine-tamoxifen; DTIC, dacarbazine.Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dart-mouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17:2745-2751. Reprinted with permission. © 1999 American Society of Clinical Oncology. All rights reserved.

Months

Proportion Surviving

1.0

0.8

0.6

0.4

0.2

0.00 12 24 36 48 60 72 84


diagnostic test to determine the tumor mutational status, received approval along with the agent.The FDA approval of vemurafenib in previously un-

treated patients was based on an international, random-ized, open-label trial in 675 subjects.20 Patients were

randomized to receive either vemurafenib orally twicedaily or DTIC IV on day 1 every 3 weeks. Treatment con-tinued until disease progression, unacceptable toxicity,and/or consent withdrawal. The major efficacy outcomemeasures were OS and investigator-assessed PFS. Theoverall response rate was 48% in the vemurafenib armversus 5% in the DTIC arm. There were 2 complete re-sponses and 104 partial responses in the vemurafenib arm,

and all 12 responses in the DTICarm were partial responses. Themedian PFS was 5.3 months inthe vemurafenib arm versus 1.6months in the DTIC arm. Skincomplications were frequentlyassociated with the agent: 18%of vemurafenib-treated patientsdeveloped cutaneous squamouscell carcinoma or keratoacan-thoma that required simple exci-sion, while 12% experiencedgrade 2 or 3 photosensitivity skinreactions. Arthralgia was themost common (21%) noncuta-neous side effect.The FDA approval of vemu-

rafenib in patients who receivedprior systemic therapy was basedon a single-arm, multicenterphase 2 study in 132 patients.21

The confirmed best overall re-sponse rate was 53%; 6% with acomplete response and 47%with a partial response. The me-dian time to response was 1.4months, with 75% of responsesoccurring by month 1.6 of treat-ment. The median duration of

response was 6.5 months. Median survival was 15.9months. Secondary skin lesions were detected in 26%of patients.Imatinib, a tyrosine kinase inhibitor that is FDA

approved as therapy for gastrointestinal stromal tumors

Melanoma

Ipilimumab Plus DTIC DTIC Plus Placebo

1-Year Survival 47.3% 36.3%



DTIC indicates dacarbazine.

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

Figure 4. Distribution of Genetic Alterations in BRAF, NRAS, and KITAmong the 4 Groups of Melanomas

CSD indicates chronic sun-induced damage.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. © 2006 American Society of Clinical Oncology. All rights reserved.


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

The New Therapeutic Paradigm forPersonalized Therapy of MelanomaThe most important first step in treating a patient

with metastatic melanoma today is to test the tumor, atleast for BRAF status, and then choose a therapy basedon BRAF status (Figure 5). If the tumor is BRAF posi-tive (ie, mutant), vemurafenib is probably the bestchoice. If it is BRAF positive, and vemurafenib therapyhas failed, then ipilimumab or IL-2 can be tried. If thetumor is BRAF negative (ie, wild-type), choices includeipilimumab, IL-2, or a clinical trial. It is important toalways consider clinical trials.Because not every patient is a candidate for im-

munotherapy, and not all patients are BRAF positive,chemotherapy will still play a role in the new therapeu-tic paradigm, but probably as a single agent in second-or third-line therapy.Based on these new considerations, a good first-line

choice for treating Case 1 would be vemurafenib, withipilimumab as second-line treatment. A good first-linechoice for treating Case 2 would be ipilimumab, withhigh-dose IL-2 as second-line treatment. According to the National Comprehensive Cancer

Network guidelines, “Although approval of ipilimumaband vemurafenib has significantly altered the initialmanagement of patients with stage IV melanoma, eachagent has unique limitations. For ipilimumab, there isthe potential for serious autoimmune toxicity, clinicalresponses may take months to become apparent, and theoverall response rate is less than 20%. However, whenresponses are seen, they can be quite durable. Vemu-rafenib, on the other hand, is associated with a 40% to50% response rate in patients with a V600 mutated

BRAF gene, and responses may be seen in days to weeksafter starting the drug. Unfortunately, the median dura-tion of response is only 5 to 6 months. The success ofthese 2 agents has prompted a new wave of questions re-garding their use in the adjuvant setting, augmentingresponse by combining them with cytotoxic chemother-apy, and defining mechanisms of drug resistance. Thepace of change underscores the importance of partici-pating in a clinical trial whenever possible.”2 u

References1. Romano E, Schwartz GK, Chapman PB, et al. Treatment implicationsof the emerging molecular classification system for melanoma. LancetOncol. 2011;12:913-922.2. National Comprehensive Cancer Network. NCCN Clinical PracticeGuidelines in Oncology (NCCN Guidelines). Melanoma. Version 2.2013.www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. AccessedNovember 16, 2012.3. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA:American Cancer Society; 2012. www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf. AccessedNovember 16, 2012.4. Melanoma Research Foundation. Melanoma Treatment. www.melanoma.org/learn-more/melanoma-101/melanoma-treatment. AccessedNovember 9, 2012.5. Serrone L, Zeuli M, Sega FM, et al. Dacarbazine-based chemotherapyfor 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 studyof temozolomide versus dacarbazine in the treatment of patients with ad-vanced metastatic malignant melanoma. J Clin Oncol. 2000;18:158-166.7.Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter ran-domized trial of the Dartmouth regimen versus dacarbazine in patients withmetastatic melanoma. J Clin Oncol. 1999;17:2745-2751.8. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecu-tive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271:907-913.

Melanoma

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.


9. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant inter-leukin 2 therapy for patients with metastatic melanoma: analysis of 270patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105-2116.10. Atkins MB, Kunkel L, Sznol M, et al. High-dose recombinant inter-leukin-2 therapy in patients with metastatic melanoma: long-term survivalupdate. Cancer J Sci Am. 2000;6(suppl 1):S11-S14.11. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ip-ilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.12. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazinefor 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 concurrentbiochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2,and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alonein patients with metastatic malignant melanoma (E3695): a trial coordi-nated 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 ran-domized trial of polychemotherapy (CVD regimen) versus the samechemotherapy (CT) plus subcutaneous interleukin-2 and interferonalpha2b in metastatic melanoma. Ann Oncol. 2006;17:571-577.15. Keilholz U, Punt CJ, Gore M, et al. Dacarbazine, cisplatin, and inter-feron-alfa-2b with or without interleukin-2 in metastatic melanoma: a ran-domized 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, dacarbazinewith or without subcutaneous interleukin-2, and interferon alpha-2b inadvanced melanoma outpatients: results from an Italian multicenter phaseIII randomized clinical trial. J Clin Oncol. 2002;20:1600-1607.17. Ives NJ, Stowe RL, Lorigan P, et al. Chemotherapy compared withbiochemotherapy for the treatment of metastatic melanoma: a meta-analy-sis 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 dis-tinct subtypes of melanoma. J Clin Oncol. 2006;24:4340-4346. 19. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activatedBRAF in metastatic melanoma. N Engl J Med. 2010;363:809-819.20. Chapman PB, Hauschild A, Robert C, et al. Improved survival withvemurafenib 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-mu-tant 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 therapeutictarget 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 ima-tinib mesylate in patients with metastatic melanoma harboring c-Kit mu-tation or amplification. J Clin Oncol. 2011;29:2904-2909.24. Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinibmesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26:2046-2051.

Melanoma

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In my article in the inaugural issue of PersonalizedMedicine in Oncology, I got a bit dogmatic in pro-claiming that personalized medicine (PM) drug

treatment selectivity spelled the end ofpopulation-based medicine, and withit, the blockbuster drug. This is trueonly insofar as we define blockbusterdrug from within the population-baseddrug utilization process that PM is re-placing. As PM establishes itself, a newkind of blockbuster drug is emergingwith a criterion that supersedes itspredecessor. Since blockbusters havesustained the pharmaceutical industryfor decades, concern about the demiseof the blockbuster drug has beenstrong: if PM and its reliance on bio-logicals in cancer care is incompatible with blockbusterdrugs, could this spell the collapse of the pharmaceuti-cal/biologicals industry? The question is worth answer-ing. PM, after all, must be more than a Pandora’s box ofunintended consequences.The new blockbuster drug model is form-fitted to PM

dynamics. The old blockbuster model required massive,population-based drug utilization. If randomized con-trolled trials showed positive results, the drug would findindiscriminate use in practice and payer coverage just asindiscriminate – almost an urge to “put it in the tapwater,” especially when it went generic. PM alters that,of course, aligning drugs to patients based on bodychemistry, not empirical averages. This is an enrichedpopulation, and it is guided, even empowered, by com-panion diagnostics, to shrink patient populations to bou-tique levels. This only redefines, not eliminates,blockbuster drugs, by achieving targeted value proposi-tions. Blockbuster drugs provide the profits needed forthe technologically ambitious research for biologicals.The new targeted model accommodates this need,

which augurs well for a robust pipeline of quality drugssupportive of the PM cancer care revolution. It may turnthe blockbuster drug model on its head, but it achieves

the same results: stabilization of thehealthcare system and affordable can-cer treatment.The old blockbuster rules of engage-

ment entailed expanding utilization tothe furthest limits of credibility, court-ing off-label usage, and blindly search-ing to bring the drug to the rightpatient through a massive process ofelimination. The process was toleratedbecause companion diagnostics tech-nology did not exist. Now that it does,drug utilization can be limited to anenriched patient population based on

individual patient chemistry. Last year the FDA got rad-ical and simultaneously approved 2 drugs with compan-ion diagnostics. One was Roche’s vemurafenib, forpatients with metastatic or inoperable melanoma withtumors testing positive for the BRAF V600E mutation,with its companion diagnostic, the Roche cobas 4800BRAF V600 Mutation Test. The other was Pfizer’s crizo-tinib, approved for late-stage non–small cell lung cancer,and Abbott’s Vysis ALK Break Apart FISH Probe Kit,for detecting abnormal anaplastic lymphoma kinase(ALK) gene expression.These simultaneous approvals signal the dawn of this

new era of the minibuster, increasing drug effectivenesswhile facilitating payer coverage. Now pharma can gowith the flow of PM’s smaller patient populations andstill end up with a blockbuster, only now its financialsuccess is based on value, not volume. Never has “less ismore” meant more to every stakeholder in the processof care. Results, not waste usage, now form the basis forblockbuster drug status. This can allow for a rationalpricing and utilization strategy, helping cancer care stay

The Last Word

Companion Diagnostics and the Paradoxical Returnof the Blockbuster Drug

Robert E. Henry


on the high road where it belongs. Diagnostics pave theway for drug utilization based on clinical merit, not du-bious patient selection methods. It allows pharma toachieve its financial goals while remaining true to itsclinical mission.The selectivity of biologicals usage will see high unit

costs, but it is attractive to payers who recoil at theprospect of an onslaught of aging baby boomers receiv-ing unsustainable levels of biologics. This is making di-agnostics as valued as the drugs they measure, since theykeep biologics affordable by cutting waste – and not justin clinical treatment, but also in research. The averagecost of a new drug launch hovers near $2 billion, a prob-lem aggravated by research failures. Companion diag-nostics not only lessen payer worries over waste drugusage, they also help fast-failure research, which willallow 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 Comprehen-sive Cancer Center, described the process: “Developingdrugs is so expensive that the industry can’t afford anylonger to take a drug to phase 1 or 2 clinical trials andfind out that it’s not working like they hoped. It’s clearthat the biomarker or markers should be embedded in theprocess very early. In my opinion, even phase 1 trialsshould be biomarker-driven for patient selection and pre-diction of response.” He predicts that pharma will pursue

the companion diagnostics approach, relying on this fast-fail approach to identify winning products worth takingto phase 2 and beyond. Pharma can afford the small pa-tient populations it previously could not afford to attendto because payers will tolerate a higher price tag for a drugwith a higher likelihood of clinical success.The role of companion diagnostics in the new block-

buster model demonstrates the intricacy of PM and theinterlocking stakeholder relationships that sustain it.The blockbuster drug has been retooled in boutique pro-portions to fulfill the PM quest for targeted, predictable,low-waste usage. This will attract investors, whose fund-ing has never been more critically needed, at this youngstage of research into biomarkers and other methods forpredicting biologicals’ clinical utility. Pharma will haveto master this transition, titrating the price-to-treatmentratio to balance their financial needs with those of pa-tients and payers. Breakthrough biologicals usage is nowbeing sustained by equally remarkable companion diag-nostics. Together they make possible a flourishing ofvalue: the elusive balance of cost, quality, and accessthat brings the process of care from theory into practice.

To Our Health,

Robert E. Henry

The Last Word

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July 26-28, 2013Hyatt Regency La Jolla • at Aventine

3777 La Jolla Village Drive • San Diego, California

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


BiomarkersClinical Trial Designs for Biomarker Evaluation. Mandrekar SJ, Sargent DJ....................................1:26

Precision Medicine: Applying Predictive and Prognostic Indices to Risk-Adapted Treatment Selection. Kurtin S...............................................1:50

Implementing the Promise of Personalized CancerCare: Highlights From the Inaugural Conference ofthe Global Biomarkers Consortium. Hehlmann R,Rugo HS...............................................................2:22

Clinical Approaches to Targeted Technologies: Implementing the Promise of Prognostic PrecisionInto Personalized Cancer Care............................5:26

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

Clinical Trial DesignAdaptive Clinical Trial Design: From Simple Dose-Finding Trials to Large-Scale Personalized MedicineTrials. Ye F, Shyr Y................................................4:36

Colorectal CancerKRAS and Colorectal Cancer: Shades of Gray. AtreyaCE, Ostrem JM, Kelley RK.................................6:22.

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

EditorialPersonalized Medicine in Oncology: The Landscape of the Next Generation of Cancer Care. Henry RE..............................................................1:12

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

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

Institute of Medicine Report: Best Care at Lower Cost:The Path to Continuously Learning Health Care inAmerica. Highlights for the Cancer Community.Conway J.............................................................6:32.

ImmunotherapyThe 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

Interview With the InnovatorsAccelerating Personalized Medicine Approaches inMultiple Myeloma: An Interview With Kathy Giustiand Deborah Dunsire, MD...................................1:38

Personalized Medicine Advances in Melanoma: AnInterview With K. Peter Hirth, PhD...................2:15

Incorporating Genomics Into Practice: An InterviewWith Kimberly J. Popovits...................................3:18

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

Cultivating Personalized Medicine Clinical Acumenin the Management of Breast Cancer: An InterviewWith Edith Perez, MD.........................................5:17

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

Lung CancerCrizotinib Miracle: A Nursing Perspective. Rich TL................................................................2:54

MelanomaManagement of Ipilimumab-Related Toxicities. Ott PA, Kaufman HL, Hodi FS...........................2:43

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

Myelodysplastic SyndromePersonalized Therapy in the Management ofMyelodysplastic Syndrome. Borthakur G............4:49

Multiple MyelomaThe Role of Personalized Therapy in the Managementof Multiple Myeloma: Case Study of a Patient Witha Cytogenetic Abnormality. Lonial S..................5:41

Annual Index2012

MOP


PharmacogenomicsPharmacogenomics in Cancer Care: Adding Some Science to the Art of Medicine. Pinto N, Ratain MJ..............................................4:56

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

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

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

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

Annual Index2012

MOP

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December 2012 Volume 1, Number 6

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