Clinical Insights 29th Annual Miami Breast Cancer …...4 / 4.12 29th Annual Miami Breast Cancer Conference Would short-term therapy with an oral medication used to treat malaria help

V.13, N.4, 4.12

F O R T H E O N C O L O G Y S P E C I A L I S T

Hematologic Report16th Annual International Congress on Hematologic Malignancies:Focus on Leukemias, Lymphomas, and Myeloma

William G. Wierda, MD, PhD, delvesinto developments in CLL markers

John Leonard, MD, examinespotential alternatives to R-CHOP-21

Clinical InsightsGynecologic MalignanciesPARP Inhibitors IntriguingDespite Research SetbacksMichael J. Birrer, MD, PhD, discussesimplications of overall survival results

Head & Neck CancerHypothyroidism RisksWith MKIs ExaminedEric J. Sherman, MD, commentson study of sunitinib and sorafenib

MelanomaVemurafenib Study Buildson Positive Response DataSanjiv S. Agarwala, MD, talksabout longer follow-up data

Prostate CancerSipuleucel-T Stimulates Responsein Localized Setting, Study FindsLeonard G. Gomella, MD, seesearly trial results as exciting

Expert Insights Into Oncology Research and Technology

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29th Annual MiamiBreast Cancer ConferenceNovel DCIS Strategy, Chemo Review, and More

O F F I C I A L P U B L I C A T I O N

W W W . C A N C E R L E A R N I N G . C O M

July 19-22, 2012 13th International Lung Cancer Congress Huntington Beach, CA

July 26-28, 2012 11th International Congress on the Future of Breast Cancer Coronado, CA

H E M A T O L O G I C O N C O L O G I S T S · M E D I C A L O N C O L O G I S T S · G Y N E C O L O G I C O N C O L O G I S T S ·

D E R M A T O L O G I S T S · U R O L O G I S T S · H E M A T O L O G I C O N C O L O G I S T S · M E D I C A L O N C O L O G I S T S · ·

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More on Breast Cancer

José Baselga, MD, PhD, on 3 Landmark Trials

A Closer Look at Brachytherapy Controversy

With perspectives from:

José Baselga

Lance A. Liotta

Julie R. Gralow

Kathy D. Miller

Matthew J. C. Ellis

ONG_Cover_4'12 copy.indd 1 4/17/12 11:01 AM

onclive.com 4.12 / 3

Interested in joining our Advisory Board?

Contact Christina Loguidice, Editor, at [email protected].

Jame Abraham, MDSection of Hematology/OncologyMary Babb Randolph Cancer CenterWest Virginia UniversityMorgantown, WV

Ross Abrams, MDDepartment of Radiation OncologyRush University Medical CenterChicago, IL

Alex A. Adjei, MD, PhDDepartment of MedicineRoswell Park Cancer InstituteBuffalo, NY

Lawrence Afrin, MDDivision of Hematology/OncologyMedical University of South CarolinaCharleston, SC

Sanjiv S. Agarwala, MDDivision of Oncology/HematologySt. Luke’s Hospital & Health NetworkBethlehem, PA

Nita Ahuja, MDSurgery & OncologyThe Johns Hopkins HospitalBaltimore, MD

Lowell Anthony, MDSection of Hematology & OncologyLouisiana State UniversityNew Orleans, LA

David Artz, MD, MBAInformation Systems Memorial Sloan-Kettering Cancer CenterNew York, NY

J. Robert Beck, MDFox Chase Cancer CenterPhiladelphia, PA

Tomasz Beer, MDProstate Cancer ProgramOregon Health & Science University Cancer InstitutePortland, OR

E. Roy Berger, MDNorth Shore Hematology AssociatesEast Setauket, NY

Ralph V. Boccia, MDCenter for Cancer and Blood DisordersBethesda, MD

Jeffrey Bumpous, MDDivision of Otolaryngology-HNS University of LouisvilleLouisville, KY

Barbara A. Burtness, MDHead and Neck Medical OncologyFox Chase Cancer CenterPhiladelphia, PA

John Caton Jr, MDMedical OncologyWillamette Valley Cancer CenterEugene, OR

Emily Chan, MD, PhDVanderbilt UniversityNashville, TN

Helen Chan, MDGI Surgical OncologyLakeland Regional Cancer CenterLakeland, FL

Tarek Chidiac, MDMid-Ohio Oncology/Hematology Inc, dbaThe Mark H. Zangmeister CenterColumbus, OH

Patrick Wayne Cobb, MDHematology-Oncology Centers of the

Northern RockiesBillings, MT

Ezra E. W. Cohen, MDSection of Hematology/OncologyUniversity of ChicagoChicago, IL

Richard Cohen, MDCohen Hufford Koltzova MedicalSan Francisco, CA

Allan Cohn, MDRocky Mountain Cancer CenterDenver, CO

Sandra Cuellar, PharmD, BCOPDepartment of Pharmacy PracticeUniversity of Illinois at ChicagoChicago, IL

Mary Daly, MD, PhDPopulation ScienceFox Chase Cancer CenterPhiladelphia, PA

Don Dizon, MDProgram in Women’s OncologyWomen & Infants HospitalProvidence, RI

Habib Doss, MDTennessee Oncology, PLLCNashville, TN

Anthony Elias, MDBreast Cancer & Sarcoma ProgramsUniversity of Colorado Cancer CenterAurora, CO

Fadi Estephan, MDMedical OncologyHutchinson ClinicHutchinson, KS

Evelyn Fleming, MDGynecologic OncologyDartmouth-Hitchcock Medical CenterLebanon, NH

Michele Fox, MDPathologyMyeloma Institute for Research & TherapyUniversity of Arkansas for Medical SciencesLittle Rock, AR

Sharon L. Francz, BHA, BS, ONational Coalition of Oncology Nurse

NavigatorsRockville, MD

David R. Gandara, MDDivision of Hematology and OncologyUC Davis Cancer CenterSacramento, CA

Leonard G. Gomella, MDDepartment of UrologyThomas Jefferson UniversityPhiladelphia, PA

Andre Goy, MD, MSChairman and DirectorJohn Theurer Cancer CenterHackensack University Medical CenterHackensack, NJ

David Graham, MDClinical Trials Carle Clinic AssociationUrbana, IL

Gregory Griffin, MDDivision of Hematology/OncologyAlfred I. duPont Hospital for ChildrenWilmington, DE

Reuben Guerrero, MDDivision of Oncology/HematologyStraub Clinic & HospitalHonolulu, HI

Mahendra Gupta, MDMedical OncologyInnovis HealthFargo, ND

Daniel Hamstra, MD, PhDPediatric Radiation OncologyGenitourinary Radiation OncologyUniversity of MichiganAnn Arbor, MI

Robin Hanson, MD, PhDCardinal Kids Cancer CenterSt. John’s Mercy Medical CenterCreve Coeur, MO

Roy S. Herbst, MD, PhDDivision of Medical OncologyYale School of MedicineNew Haven, CT

William Hocking, MDHematology/OncologyMarshfield ClinicMarshfield, WI

Clifford A. Hudis, MDBreast Cancer Medicine ServicesMemorial Sloan-Kettering Cancer CenterNew York, NY

Dennie Jones, Jr, MDNew Mexico Cancer Care AllianceUniversity of New MexicoAlbuquerque, NM

Emad Kandil, MDDepartment of SurgerySection of Endocrine & Oncological SurgeryTulane Cancer CenterNew Orleans, LA

Song Kang, MDVirginia Oncology AssociatesSentara Careplex HospitalHampton, VA

Gary Lyman, MD, MPH, FRCP(Edin)Duke University Medical CenterDurham, NC

David G. Maloney, MD, PhDClinical Research DivisionFred Hutchinson Cancer Research CenterSeattle, WA

Robert Meister, MDArlington-Fairfax HematologyArlington, VA

Wilson Mertens, MDCancer ServicesBaystate HealthSpringfield, MA

Joseph Mikhael, MDDivision of Hematology/OncologyDepartment of Internal MedicineMayo ClinicScottsdale, AZ

Mohamed Mitwally, MDDepartment of Obstetrics & Gynecology University of MinnesotaMinneapolis, MN

Janaki Moni, MDMichiana Hematology OncologySouth Bend, IN

Hyman Muss, MDUniversity of Vermont and Vermont

Cancer CenterHematology Oncology UnitBurlington, VT

Leigh Neumayer, MDIntegrated Breast ProgramHuntsman Cancer InstituteSalt Lake City, UT

Anthony Nguyen, MDMedical OncologyComprehensive Cancer Centers

of Nevada-SienaHenderson, NV

Joyce A. O’Shaughnessy, MDDivision of Breast Cancer ResearchTexas Oncology/US OncologyDallas, TX

Daniel A. Osman, MDBreast Cancer SurgeonMiami, FL

Andrew L. Pecora, MDChief Innovations OfficerJohn Theurer Cancer CenterHackensack University Medical CenterHackensack, NJ

Edith A. Perez, MDDepartment of Hematology/OncologyMayo ClinicJacksonville, FL

Román Pérez-Soler, MDDivision of OncologyAlbert Einstein College of MedicineBronx, NY

Daniel P. Petrylak, MDGenitourinary Oncology SectionColumbia University Medical CenterNew York, NY

Aarati Rao, MDDivision of Pediatric Hematology/

OncologyUniversity of South AlabamaMobile, AL

Douglas Reding, MD, MPHMarshfield CenterMarshfield, WI

John Rhee, MDMedical Oncology & Hematology, PCYale-New Haven HospitalNew Haven, CT

Adam I. Riker, MDCancer ServicesOchsner Cancer InstituteNew Orleans, LA

Steven Rosen, MDRobert H. Lurie Comprehensive

Cancer CenterNorthwestern UniversityChicago, IL

Richard J. Rosenbluth, MD John Theurer Cancer CenterHackensack University Medical CenterHackensack, NJ

Oliver Sartor, MDDepartment of UrologyTulane Cancer CenterNew Orleans, LA

Lee Schwartzberg, MDThe West ClinicMemphis, TN

Maureen Sheehan, MDKansas City Cancer CenterKansas City, MO

Edibaldo Silva, MD, PhDDivision of Surgical OncologyEppley Cancer Center University of Nebraska Medical Center Omaha, NE

David Spigel, MD Lung Cancer ProgramThe Sarah Cannon Research InstituteNashville, TN Kellie Sprague, MDBone Marrow TransplantationTufts Medical CenterBoston, MA

Richard Tenglin, MDOncology AssociatesRapid City Regional HospitalRapid City, SD

J. Tate Thigpen, MDDivision of Medical OncologyUniversity of MississippiJackson, MS

Katherine Tkaczuk, MDMedicine & Oncology University of Maryland Cancer CenterBaltimore, MD

Debu Tripathy, MDWomen’s Cancer ProgramUniversity of Southern CaliforniaLos Angeles, CA

Philip Villiotte, MDSpectrum Medical GroupScarborough, ME

Roland Walter, MD, PhDClinical Research DivisionFred Hutchinson Cancer Research Center Seattle, WA Ronald Walters, MD, MBA, MHAMedical Operations & InformaticsBreast Medical OncologyMD Anderson Cancer CenterHouston, TX

Richard Wein, MDDepartment of Otolaryngology-Head &

Neck SurgeryTufts Medical CenterBoston, MA

H. Jack West, MDThoracic Oncology ProgramSwedish Cancer InstituteSeattle, WA

James Wheeler, MDRadiation Oncology ProgramGoshen Center for Cancer CareGoshen, IN

Andrew D. Zelenetz, MD, PhDDepartment of MedicineMemorial Sloan-Kettering Cancer CenterNew York, NY

Paul Zeltzer, MDNeurosurgeryDavid Geffen School of MedicineUniversity of California, Los AngelesLos Angeles, CA

Jeffrey Zonder, MDHematology/OncologyKarmanos Cancer CenterDetroit, MI

TM

Editor-in-Chief

Maurie Markman, MDSenior Vice President, Clinical AffairsNational Director, Medical Oncology Cancer Treatment Centers of AmericaPhiladelphia, PA

Interested in joining our Advisory Board?

Contact Anita T. Shaffer, [email protected].

ONG_Front_4'12.indd 3 4/20/12 3:48 PM

4 / 4.12

29th Annual Miami Breast Cancer ConferenceWould short-term therapy with an oral medication used to treat malaria help women with early-stage breast cancer? That thought-provoking possibility was among a plethora of research initiatives explored at the March gathering. A report on chemotherapy regimens also appears here, with more stories and exclusive videos at www.OncLive.com.BY ANITA T. SHAFFER and ANNA AZVOLINSKY, PhD

Clinical Insights

Prostate Cancer . . . 38Section editor: Leonard G. GomeLLa, md

Sipuleucel-T Stimulates Response in Localized Setting, Study Finds

Head & Neck Cancer . . . . . . . . . . . 41Section editor: ezra e. W. cohen, md

Hypothyroidism RisksWith MKIs Examined

Melanoma . . . . . . . . 42Section editor: Sanjiv S. aGarWaLa, md

Vemurafenib Study Buildson Positive Response Data

Gynecologic Malignancies . . . . . 43Section editor: j. tate thiGpen, md

PARP Inhibitors IntriguingDespite Research Setbacks

10

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C O N T E N T SVolume 13, Number 4, April 2012

TM MARQUEEMet Inhibitor ARQ 197 plus Erlotinib vs Erlotinib plus placebo in NSCLC

Investigating c-MET InhibitionA global phase 3, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus placebo plus erlotinib in previously treated subjects with locally advanced or metastatic, non-squamous NSCLC

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mutation status(N=988)

tivantinib (ARQ 197) 360 mg PO BID

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NOW RECRUITINGPHASE 3 NON–SMALL-CELL LUNG CANCER (NSCLC)

To learn more about this study, please call 1-877-4DS-PROD (1-877-437-7763), e-mail [email protected], or visit www.clinicaltrials.gov/ct2/show/NCT01244191

Please note that tivantinib (ARQ 197) is an investigational agent and is not approved by the FDA or any other worldwide regulatory agency as a treatment for any indication. Effi cacy and safety have not been established. There is no guarantee that tivantinib will become commercially available.

STUDY DESIGN

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SECONDARY ENDPOINTS

Marquee_Ad_Queen.indd 1 10/24/11 10:42 AM

DepartmentsColumn7 FromtheEditor Going Beyond the Label: Targeted Therapies Present New Questions in Clinical Use By Maurie Markman, MD

18Leading Researcher Sees Turning Point in Breast Cancer

José Baselga, MD, PhD, associate director of Massachusetts General Hospital Cancer Center, is the lead author of three potentially practice-changing studies in three different subtypes of breast cancer. In this interview, he discusses his research in the BOLERO-2, CLEOPATRA, and NeoALTTO trials.BY ANITA T. SHAFFER

2616th Annual International Congress on Hematologic Malignancies

This report from the conference, held in Utah in February, features discussions of emerging tumor markers for chronic lymphocytic leukemia and options in chemotherapy regimens for diffuse large B-cell lymphoma.BY BEN LEACH AND SUSAN R. PECK, PhD

8 Updates32 Pathways Targeting Hsp90: Researchers Aim to Thwart Chaperones of the “Guardian of the Proteome” By Jane de Lartigue, PhD

36 Science&Technology Brachytherapy in Breast Cancer Emerges as Source of Controversy By Andrew D. Smith

Andr

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An

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ONG_Front_4'12.indd 4 4/20/12 3:48 PM

PHYSIC IANS’EDUCAT IONRE SOURCE , LLC

Conferences and Chairs

School of Breast Oncology 11th International Congress on the Future of Breast Cancer Joyce A. O’Shaughnessy, MDCo-Director, Breast Cancer ResearchBaylor Charles A. Sammons Cancer CenterTexas Oncology/US OncologyDallas, TX

29th Annual Miami Breast Cancer ConferenceDaniel A. Osman, MDBreast Cancer SurgeonMiami, FL

Debu Tripathy, MDCo-Leader, Women’s Cancer ProgramProfessor of MedicinePriscilla and Art Ulene Chair in Women’s Cancer USC/Norris Comprehensive Cancer Center University of Southern CaliforniaLos Angeles, CA

11th International Congress on Genitourinary MalignanciesOliver Sartor, MDMedical Director C.E. and Bernadine Laborde Professor

of Cancer ResearchProfessor, Department of MedicineSection of Hematology & Medical OncologyDepartment of UrologyTulane Cancer CenterNew Orleans, LA

8th Annual Multidisciplinary Symposiumon Head and Neck CancerEzra E. W. Cohen, MDAssociate ProfessorSection of Hematology/OncologyCo-Director, Head and Neck Cancer ProgramDirector, Hematology/Oncology Fellowship

ProgramUniversity of Chicago Medical CenterChicago, IL

Barbara A. Burtness, MDChief, Head and Neck Medical OncologyCo-Leader, Developmental TherapeuticsFox Chase Cancer CenterPhiladelphia, PA

16th Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and MyelomaAndrew D. Zelenetz, MD, PhDChief, Lymphoma ServiceDepartment of MedicineMemorial Sloan-Kettering Cancer CenterAssociate Professor of MedicineWeill Cornell Medical CollegeNew York, NY

10th International Congress on Targeted Therapies in CancerAlex A. Adjei, MD, PhDProfessor and Chair, Department of MedicineKatherine Anne Gioia Chair in Cancer MedicineSenior Vice President, Clinical ResearchRoswell Park Cancer InstituteBuffalo, NY

13th International Lung Cancer CongressRoy S. Herbst, MD, PhDChief of Medical OncologyAssociate Director, Translational ResearchYale Comprehensive Cancer CenterSmilow Cancer Hospital at Yale-New HavenYale School of MedicineNew Haven, CT David R. Gandara, MDProfessor of MedicineDivision of Hematology and OncologyDirector, Thoracic Oncology ProgramAssociate Director, Clinical ResearchUC Davis Cancer CenterSacramento, CA

7th Annual New York Lung Cancer Symposium Román Pérez-Soler, MDProfessor of MedicineChief, Division of OncologyMontefiore Medical CenterAlbert Einstein College of MedicineBronx, NY

9th International Symposium on Melanoma and Other Cutaneous MalignanciesSanjiv S. Agarwala, MDProfessor of MedicineTemple University School of MedicineChief, Oncology/HematologySt. Luke’s Hospital & Health NetworkBethlehem, PA

8th Annual Symposium on Controversies and Clinical Challenges in Myeloma, Lymphoma, and LeukemiaDavid G. Maloney, MD, PhDMember, Clinical Research DivisionFred Hutchinson Cancer Research CenterProfessor, Medical Oncology DivisionUniversity of Washington School of MedicineSeattle, WA

4th Annual National Coalitionof Oncology Nurse Navigators (NCONN)Sharon L. Francz, BHA, BS, OOncology Nurse NavigatorPresident and Co-Founder NCONNRockville, MD

9th International Symposium on Ovarian Cancer and Other Gynecologic MalignanciesJ. Tate Thigpen, MDProfessor, Department of Internal MedicineDirector, Division of Medical OncologyUniversity of Mississippi Medical CenterJackson, MS

5th Annual Interdisciplinary Prostate Cancer Congress (IPCC) Leonard G. Gomella, MDThe Bernard W. Godwin Jr. Professor

of Prostate CancerChairman, Department of UrologyDirector, Clinical AffairsKimmel Cancer CenterThomas Jefferson UniversityPhiladelphia, PA Daniel P. Petrylak, MDProfessor of Medicine Co-Leader, Prostate CancerProgram Director, Genitourinary Oncology SectionHerbert Irving Comprehensive Cancer CenterColumbia University Medical CenterNew York, NY

Undertreatment of Cancer Painwww.painlive.com

Express Scripts-Medco Merger Approvedwww.pharmacytimes.com

Value-Based Insurance Design Resource Center Availablewww.ajmc.com

From the Publisher

A Sense of ExcitementA key measure of success for any oncology conference is the “buzz” that emanates from presenters and attendees. At the 29th Annual Miami Breast Cancer Conference in March, the level of engagement and excitement was clearly palpable among the hundreds of medical oncologists, breast surgeons, and other oncology specialists who gathered to exchange ideas and discuss treatment controversies.

Daniel A. Osman, MD, a Miami breast surgeon, founded the conference at a time when the concept of performing breast-conserving surgery rather than mastectomy had not been widely adopted. This year’s program, hosted and accredited through Physicians’ Education Resource (PER), reflects the extent to which the treatment of breast cancer has changed—and the knack that Osman has of staying abreast of important clinical considerations. Sessions ranged from novel immunotherapeutics and molecular diagnostics to advances in ultrasonography and surgical techniques.

The articles in this issue of OncologyLive that discuss the potential for the malaria drug chloroquine to be helpful in the treatment of early-stage breast cancer and review the options in chemotherapy regimens are among the many highlights of a conference that offered four days of presentations by leading researchers.

We believe strongly that attending conferences is vital for the exchange of ideas in oncology but, of course, it is not the only avenue for discourse.

In fact, the news from Miami dovetails with another offering in this issue in which we explore more fully research that was presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. We are pleased to feature an interview with José Baselga, MD, PhD, associate director of the Massachusetts General Hospital Cancer Center in Boston, who has the remarkable distinction of serving as the lead author on three much-heralded studies in breast cancer in less than two months.

We salute Baselga’s accomplishments and appreciate his willingness to share his thoughts with our readers.

These are indeed exciting times in oncology research, particularly in breast cancer. We are pleased to be able to present these reports, and at times are awed by the strides that all of those who treat patients with cancer are making.

I invite you to share your feedback and suggestions by emailing me at [email protected]. As always, thank you for reading.

—Mike Hennessy

Don’t miss these articles from our sister publications:

ONG_Front_4'12.indd 6 4/20/12 3:48 PM

Molecular analyses of tumors increasingly will yield a relatively

large or relatively small subpopulation

of patients who may be favorably

impacted by a previously approved

targeted therapy.


The long-sought aim of treating malignant disease by targeting particular molecular abnormalities revealed to be present within an individual tumor is becoming a reality in

an increasing number of clinical settings.With the regulatory approval of a number of

antineoplastic agents whose biological and clinical activity appears to be strongly related to a particular molecular signature, it is natural to consider whether it is appropriate to treat patients in other settings where the specific individual’s cancer possesses the same, or very similar, genetic abnormalities. It is possible that such a situation may arise at a point in time preceding regulatory approval for that clinical indication, or may occur in a setting where the drug sponsor does not intend to pursue regulatory approval for that specific group of patients.

Further, with the spectacularly rapid advances in whole genomic sequencing, it will become increasingly commonplace for a relatively large or relatively small subpopulation of patients with a particular tumor type to be found to have a unique molecular abnormality that may be favorably impacted by a previously approved antineoplastic specifically directed at that molecular target.

Consider, for example, the recent report of a retrospective examination of more than 1000 patients with non-small cell lung cancer where approximately 5% of the adenocarcinomas in this series were found to have a mutation in the BRAF gene.1 Perhaps even more provocative, greater than 50% of these mutations were V600E, the specific molecular abnormality targeted by the novel antineoplastic vemurafenib (Zelboraf), recently approved for treatment of metastatic melanoma in the presence of a documented mutation in BRAF.2 The lung cancer patients with the V600E abnormality were smokers, had a particularly poor prognosis, and, except in very rare circumstances, this finding was not demonstrated in individuals with a documented activating epidermal growth factor receptor mutation. (Table)

Thus, the obvious question is whether it is reasonable to treat patients with metastatic adenocarcinoma of the lung who have a confirmed V600E (or perhaps any BRAF) mutation with vemurafenib. Should a randomized phase III trial be required before such a decision is made, or at least phase II trial data? And, if such therapy is recommended by an individual oncologist based on a demonstrated BRAF mutation, is it fair to conclude that payment for the costs of the drug and any associated medical care should be

covered by responsible third-party payers?It must be emphasized that, at least in the United States,

there is no legal requirement for a pharmaceutical company to conduct such a trial for a marketed drug before it is employed by an individual treating physician in routine clinical practice. Further, assuming a decision is actually made to conduct a study, optimistically, a minimum of several years will likely pass before the results are available to inform clinical decision-making. And what happens to patients presenting with this clinical scenario prior to the establishment of these so-called “evidence-based data?”

It is virtually certain that these difficult questions will increasingly need to be addressed by a number of interested groups (eg, healthcare plans, governmental authorities). It can only be hoped that the goals of the patient to optimize both the quantity and quality of life are kept at the center of such discussions.

Maurie Markman, MD, editor-in-chief, is senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, Pennsylvania. [email protected].

References

1. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011; 29(26):3574-3579.

2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation [published online ahead of print June 5, 2011]. N Engl J Med. 2011; 364(26):2507-2516.

Going Beyond the Label:Targeted Therapies PresentNew Questions in Clinical Use

from the editorMaurie Markman, MD

Table. Overall Survival Analysis Using Clinicopathologic and Genomic Factors in 331 Patients With Lung ADC

Variable CategoryUnivariate HR(95% CI)

Multivariate* HR(95% CI)

Sex Female/male1.39(0.91-2.13)

1.2(0.63-2.27)

Smoking Never smoker/smoker

1.1(0.69-1.76)

1.09(0.56-2.09)

Stage III+ IV/I + II3.26(2.21-4.80)

2.92(1.95-4.37)

BRAFV600E Mutated/wild type

2.97(1.96-5.81)

2.18(1.17-4.04)

BRAFNon-V600E Mutated/wild type

1.56(0.51-5.04)

1.46(0.46-4.64)

*Sex, smoking, and non-V600E variables were removed from model at last step of multivariate analysis.

ADC indicates adenocarcinoma; HR, hazard ratio; CI, confidence interval.

Adapted from Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011; 29(26):3574-3579.

ONG_Columns_4'12.indd 7 4/20/12 3:50 PM

mailto:[email protected]

8 / 4.12 onclive.com

■ FDA DigestODAC Backs New Vincristine FormulationAn FDA advisory panel has recommended that the agency approve Marqibo, a

nanoparticle-based formulation of the longtime cancer therapeutic vincristine

sulfate, for the treatment of patients with Philadelphia chromosome-negative

(Ph-) acute lymphoblastic leukemia (ALL). The Oncologic Drugs Advisory Com-

mittee (ODAC) voted 7-4 with two abstentions to support the drug, and the FDA is

scheduled to make a final decision by May 13.

Marqibo consists of intravenously injectible vincristine sulfate encapsulated in

the aqueous core of a specially developed liposome, according to Talon Therapeu-

tics, Inc, the San Mateo, California-based company sponsoring the drug. The com-

pany is seeking approval to use Marqibo for patients with Ph- ALL following at least

two relapses or progression after at least two anti-leukemia therapies.

http://tiny.cc/hmttbw

Panel Splits Votes on Two Sarcoma DrugsODAC issued a split opinion on two drug applications for the treatment of pa-

tients with sarcoma. The panel members voted 11-2 in support of pazopanib

(Votrient) for patients with advanced soft-tissue disease who have received prior

chemotherapy, and 13-1 against recommending ridaforolimus (Taltorvic) as main-

tenance therapy for patients with metastatic soft-tissue or bone sarcoma.

For pazopanib, pivotal study results include the phase III VEG110727 trial, in

which patients in the pazopanib arm demonstrated progression-free survival

(PFS) of 4.6 months, compared with 1.6 months in the placebo arm. There was no

statistically significant improvement in overall survival (OS).

For ridaforolimus, key data emerged from the phase III P011 trial. Patients in

the ridaforolimus arm experienced a median PFS of 16.1 weeks compared with 14

weeks in the placebo arm. The median OS for patients on ridaforolimus was 20.8

months compared with 19.6 months in patients on placebo. However, approxi-

mately half the ridaforolimus patients discontinued therapy due to adverse events.

Merck, which is developing ridaforolimus in partnership with Ariad Pharmaceuti-

cals, Inc, expressed confidence in ridaforolimus and said efforts to obtain a new drug

approval would continue. The FDA, which can accept or reject ODAC’s recommenda-

tion, is scheduled to decide on ridaforolimus by June 5. http://tiny.cc/wnttbw

Pazopanib, initially approved in 2009 for patients with advanced renal cell

carcinoma, is being developed by GlaxoSmithKline. The FDA is expected to

make a decision by May 6. http://tiny.cc/bpttbw

Updates > follow us on twitter @ http://twitter.com/ONClive

Algorithm for Breast Tissue Analysis ApprovedThe FDA has approved a new algorithm for analyzing progesterone receptor (PR)

expression in images of normal and neoplastic breast tissue stained through im-

munohistochemistry to be used as part of the Virtuoso System. The instrument-

plus-software system includes the iScan

Coreo Au scanner and image analysis

applications to assess samples tested

with a Ventana rabbit antibody assay.

The Ventana Companion Algorithm

Progesterone Receptor (PR) (1E2) applica-

tion is designed to assist pathologists

in detecting and measuring PR expres-

sion in patients who are candidates for

endocrine treatment. Ventana Medical

Systems, Inc, a member of the Roche

Group, developed the system. http://tiny.

cc/hhttbw, http://tiny.cc/rdsncw

New Indication for Dacogen DeclinedThe FDA declined to approve the use of Dacogen (decitabine) for older adults with

acute myeloid leukemia (AML), saying that the primary study (DACO-016) did not

provide convincing evidence of the safety and effectiveness for the proposed new

indication, according to Eisai Inc, which is developing the drug.

The phase III trial involved 485 patients randomized 1:1 to receive either Daco-

gen versus either patient’s choice of supportive care or low-dose cytarabine, with

treatment continuing as long as participants continued to derive benefit. The me-

dian duration for patients receiving Dacogen was 4.4 months, compared with 2.4

months for those taking cytarabine.

Eisai had sought the indication in adults with AML aged ≥65 years who are not

considered candidates for induction therapy. The company has not yet announced

its next step.

In 2006, the FDA approved Dacogen, a DNA methylation inhibitor, as treatment

for myelodysplastic syndromes. http://tiny.cc/4b9lcw

■ NewsMaking the Next Generation Into Nonsmokers The younger people are when they start smoking, the more likely they are to become

addicted, according to a Surgeon General Report that is part of a fresh public health

campaign against tobacco use. More than 3 million high school students and more

than 600,000 middle school students smoke, the report indicates. Nearly 90% of the

young people who smoke try their first

cigarette by the age of 18, and approxi-

mately 3 out of 4 high school smokers con-

tinue the habit well into adulthood.

“The addictive power of nicotine

makes tobacco use much more than a

passing phase for most teens,” Surgeon

General Regina Benjamin, MD, said in a

press release.

The report, entitled “Preventing To-

bacco Use Among Youth and Young

Adults,” is available at www.surgeonge-

neral.gov. New

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The Campaign for Tobacco-Free Kids sponsored the 17th Annual Kick Butts Day on March 21. Hundreds of events were held nationwide.

The iScan Coreo Au scanner is part of the Virtuoso System, which is used to analyze breast tissue samples.

Nasal septum

Sagittal cross-section of head and neck

Sagittal cross-section of pelvis

Bone

Abdomen

Extremities(arm and leg)

Nasopharynx

Peritoneum

Rectusabdominismuscle

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JOB#: 22147 CLIENT: Genentech DESC: Journal Ad FILE NAME: GNH_TDM_Q22147_JA_D01.indd DATE: 3-12-2012 7:56 PM ROUND: 1PG: Cruz, Felix/kuak AD: JHong TC: EAnonuevo AE: tbd CW: tbd Last Saved: 3-12-2012 7:56 PMTRIM: 7.75” x 10.5” BLEED: 8.5” x 11.25” SAFETY: 6.75” x 9.75” PROD: MHaight INK Spec: 4C PRINT SCALE: 100%FONTS: Trade Gothic LT Std (Light, Bold No. 2, Regular, Bold, Light Oblique)

IMAGES: 22147_B_JA_Antibodies_fn.tif (CMYK; 300 ppi; 100%), Genentech_AMOTRG_KO.eps (76.5%), 22147 QRcode.eps (76.5%), BioOnc_WM_R_4C_KO.ai (49.72%)INKS: Cyan, Magenta, Yellow, BlackDOC PATH: Macintosh HD:Users:cruzf:Deskt..._JA_D01:GNH_TDM_Q22147_JA_D01.inddNOTES:

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ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic agent.

ADCs are designed to deliver potent anticancer agents to tumors in a targeted manner to limit systemic exposure.1-5

These investigational ADCs have multiple proposed mechanisms of action, including antibody-mediated anticancer

activities and targeted intracellular delivery of a potent cytotoxic agent.6

Visit www.ResearchADCs.com to learn more

Antibody-drug conjugates: Taking targeted therapy to the next level

the sum of its parts?

Antibody-drug conjugates (ADCs):

Can an ADC be greater than

1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Ghose T, Blair AH. Antibody-linked cytotoxic agents in the treatment of cancer: current status and future prospects. J Natl Cancer Inst. 1978;61:657-676. 6. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 9. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.

© 2012 Genentech USA, Inc. All rights reserved. BIO0000903001 Printed in USA.

References:

Monoclonal antibodytargets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer effects1,3,6-8

Cytotoxic agentincorporated into an ADC, may be up to 1000-fold more potent than currently used chemotherapies7

Stable linkerdesigned to allow an ADC to remain inactive while in circulation1,2,7-9

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29th Annual Miami Breast Cancer ConferenceThe 29th Annual Miami Breast Cancer Conference, held March 14-17 in Miami Beach, Florida, featured thought leaders in medical and surgical oncology discussing practical implications of emerging research and technology. In this issue, reports on a novel approach to early breast cancer and best uses for various adjuvant chemotherapy agents are presented. For more stories and exclusive video interviews, visit www.OncLive.com.


As mammography has grown increasingly sophisticated, the incidence of ductal carcinoma in situ (DCIS) has risen dramatically. Indeed, the diagnosis of DCIS has grown from a relatively rare finding in the 1970s to up to 25% of all breast cancers by 2004, according to the federal Agency for Healthcare Research and Quality.

In recent years, some researchers have expressed concerns about overdiagnosis and overtreatment of DCIS, suggesting that a preventive approach that includes active surveillance might be appropriate for lower-grade lesions.

Taking a different view is Lance A. Liotta, MD, PhD. He believes DCIS lesions, even at low grades, can hold

the seeds for invasive cancers.Liotta has been researching the stages of cancer

metastases and tumor cell–extracellular matrix interac-tions for 40 years. He formerly served as chief of the Laboratory of Pathology at the National Cancer Institute and as a deputy director at the National Institutes of Health. Since 2005, he has served as co-director of the Center for Applied Proteomics and Molecular Medicine at George Mason University in Manassas, Virginia.

His current research focus includes potential uses for chloroquine, an oral small-molecule compound used in the United States to treat patients with malaria since

the late 1940s. Based on experiments conducted by his research colleague Virginia Espina, MS, an assistant professor, the team has been exploring chloroquine as a neoadjuvant therapy for DCIS and as a potential means to kill preinvasive breast lesions. The clinician of the research team is Kirsten H. Edmiston, MD, a breast surgeon and medical director of the Inova Breast Care Institute in northern Virginia.

The group is seeking to enroll 90 patients in a clinical trial testing the efficacy of chloroquine in

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Daniel A. Osman, MD, right, the pioneering Miami breast surgeon who founded the conference, introduces a speaker during the four-day event at the Fontainebleau Miami Beach Hotel.

Taking a Novel Look at an Established Agent Malaria Drug Chloroquine Studied in a Preventive Setting for Early DCIS

By Anita T. Shaffer


ONG_CS_4'12.indd 10 4/20/12 3:53 PM


500-mg/wk and 250-mg/wk doses as a neoadjuvant therapy for DCIS. The trial, listed on the Clinical Trials.gov website (NCT01023477), is sponsored by the US Department of Defense Breast Cancer Research Program (DOD BCRP).

In this interview, Liotta discusses the hypothosis that led to the study and the research thus far into chloroquine.

OncologyLive: What are your views on the management of DCIS?Liotta: Some oncologists have said that we shouldn’t even use the word “carcinoma” to describe ductal carcinoma in situ because it’s wrong, it’s too scary, and these are low-risk lesions. But our experimental studies absolutely show that indeed there can be carcinoma cells lurking in those lesions. We found genetically altered cells that look the same as the genetic alterations in invasive cancer cells lurking in human DCIS lesions.

It’s very important for clinicians to understand that a DCIS lesion is not a benign lesion that should be left alone. Something should be done about it because we know that there could be carcinoma cells lurking in there waiting to be unleashed.

We see in our clinical trials that the women who have DCIS seem to be much more eager to get their lesion surgically removed and treated than even the physicians who are used to seeing a very bad outcome with invasive cancer. To the patient, it is just as signif-icant as invasive cancer, and I would say the patient’s concern should be respected.

Please explain the goals of your approach to DCIS.Our approach is to try to kill the DCIS lesion, kill the premalignant lesion, with one short-term therapy. It’s a new concept in prevention. Imagine a woman coming in to her doctor, getting a short-term therapy with something that’s not very toxic, or not toxic at

all, and it kills the premalignant lesions lurking in the breast that we know are to become cancerous. That treatment will clean out all of the potential cancer that could develop in the future for that woman. You might administer this therapy once a year, once every couple of years, or perhaps only once in a woman’s lifetime.

How is this a different concept in prevention?Standardized prevention trials will require five to 10 years to find out whether your vitamin therapy or your hormonal therapy is going to prevent cancer in that population. By then, science will have changed tremendously and there might be much better strategies with which to treat the patient. We can’t really wait that long to see the result of a prevention trial. We would like to have a trial where we’re treating premalignant lesions.

How is the chloroquine trial structured?We want to take advantage of the time period between the diagnosis, the biopsy of the original DCIS lesion, and surgery. A woman is told that she has DCIS, that she has a premalignant lesion. She would enroll in our trial, and take chloroquine for 30 days, and then receive the standard-of-care surgical removal of the lesion that she would receive anyway. (Figures 1, 2)

There is usually a waiting period between the diag-nosis and surgery. The patient is simply taking an oral medication during the waiting period, and then we can compare the lesion before she gets the drug, and after she has been on the drug, at the time of surgery. By comparing the DCIS lesion before and after ther-apy in the same patient, we will know if the therapy kills DCIS premalignant lesions or not. A positive re-sult will strongly support the value of chloroquine as a potential short-term prevention therapy.

How did your theory unfold?Our first question in our experimental studies was: Do these invasive carcinoma cells really exist in the

premalignant lesions waiting to emerge? Are there “terrorist” cells waiting to launch an attack? We had a DOD BCRP-sponsored clinical trial where we took living DCIS tissue from patients who volunteered to give their lesions to us at surgery, and we grew them with a new method and put them into animals. Sev-enty percent were able to produce tumors. They were genetically abnormal, similar to what we know the genetic abnormalities are of invasive cancer.

Our conclusion, based on experimental studies, was that the genetic changes that make a cell cancerous occur early—right in the premalignant lesion—and the cells are waiting in there to emerge and invade. Some-thing is holding them back, maybe the microenviron-ment, but they are already there, and they exist much earlier than we thought.

What were the next questions in your investigations?We recognized the stressful environment inside of the milk duct of the woman where the cells are proliferating to form atypical ductal hyperplasia or ductal carcinoma in situ. The neoplastic cells are crowding and building up inside those ducts. There are no blood vessels inside the ducts, so they have limited oxygen. There are very few nu-trients. Nevertheless, they proliferate. Usually under high

stress, many tissues or cells shut down and go into hibernation. But instead, in the DCIS lesions, when we look at proliferation markers, the cells are growing even though they’re under a high-stress environment.

Based on Ginny Espina’s experi-ments, we hypothesized that they use autophagy to survive. Au-tophagy is a pathway that’s a hot topic in science these days but has never been applied before to DCIS or premalignant breast lesions.

What is the role of autophagy in normal cells? Autophagy is a special mechanism that’s very primordial. When cells

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Lance A. Liotta, MD, PhD, addresses attendees in Miami Beach.

(continued on page 14)

Figure 1. PINC Trial: Preventing Invasive Breast Neoplasia with Chloroquine

DCIS indicates ductal carcinoma in situ; ER+, estrogen receptor-positive; ER-, estrogen receptor-negative; MRI, magnetic resonance imaging.

Identify patients, screen for eligibility,

obtain consent

Follow-up MRI,surgery, pathology for

biomarkers;Radiation for

lumpectomy patients;Clinical follow-up

DCISER+

any grade

Randomizepatients to chloroquine

500 mg/wk or250 mg/wk

x4 wks

DCISER-

any grade

Randomizepatients to chloroquine

500 mg/wk or250 mg/wk

x4 wks

For patients with diagnosis of DCIS: Image-guided core biopsy for baseline biomarker analysis,

breast MRI

Miami Breast Cancer Conference

ONG_CS_4'12.indd 11 4/20/12 3:53 PM

f e a t ur e

are under high stress, they start eating internal parts of the cell and digesting the meals in the lysosomal compartment. The proteins that are digested in the compartment are transformed into ATP [adenosine triphosphate] energy for the cells.

Autophagy is a way for the cell to store up some energy and fill up its cookie jar, so to speak, when it’s hungry. When cells are under physical or chemical stress, or when they’re under starvation conditions, autophagy is switched on so that the cells can get alternative sources of energy. Autophagy is also used in the central nervous system to get rid of proteins that accumulate and to clean up misfolded proteins. In addition, autophagy is used in the immune system when a cell is making too much immunoglobulin, as in myeloma cells, for example.

So it’s a vacuum cleaner system, and a self-eating process. It allows a cell to get energy during emergency conditions. Autophagy is tightly regulated. It’s turned on when needed. But then when the cell is satiated, autophagy is turned off, and the cell goes back into a resting state.

How does autophagy function in cancerous cells?The same way that it functions in normal cells. It is a way for cancerous cells to survive in the face of stress. We don’t know whether part of being a cancer cell is to turn on autophagy when it shouldn’t be on, but we certainly know that the cancer cell is using it to stay alive.

We see the autophagy being switched on just at the time that the cell is under stress inside the duct or when it’s under stress because it has just been treated with tamoxifen or anti-HER2 therapy. It allows the cell to deviate. Instead of going into apoptosis, instead of going into cell death, the cell prevents itself from dying by going into autophagy and staying alive.

How can autophagy be used as a therapeutic target?When autophagy was first discovered in cancer, it was believed to be a different kind of apoptosis, a different


(continued from page 11)

Fear Factor Persistsin Mastectomy ChoicesJ. Michael Dixon, BSc, MBChB, MD,discusses how patients make decisions

Challenges Loomingin Preventive StrategiesDebu Tripathy, MD, reviewschemoprevention advances

Conference MirrorsMilestones in CareFounder Daniel A. Osman, MD, offers perspective on genomics

Bone Metastases Choices,Management ChangingJulie R. Gralow, MD, notes ways to integrate new agents

“Pinkwashing” MerchandiseNot Always a Positive TrendPatrick I. Borgen, MD, commentson downsides of fundraising tactics

“Seed and Soil” Approachto Cancer Remains Vital Neil L. Spector, MD, focuseson emerging complexities

Research Needed to TranslateGenomics to Clinical PracticeCharles M. Perou, PhD, detailstimeline, challenges ahead

A Call for Broader Useof Chemoprevention Nancy E. Davidson, MD, findstherapies are not being applied

Video Interviews on

way for the cell to die. The thought was, let’s just figure out how we can stimulate autophagy to make the cell eat itself to death as a treatment modality. But cells are much smarter than we think—normal cells and cancer cells. They’ll use autophagy to survive, but if it starts hurting them too much, they’ll stop doing it.

We think the better approach would be to use autophagy as a therapeutic target to block the process, at least for a short period of time during the premalignant period.

How does chloroquine block autophagy?Autophagy is a complicated, multistep process. Proteins inside the cell are targeted for degradation; it does not seem to be just random. A double-walled membrane is formed around those proteins that are going to be metabolized, and then that membrane carries the proteins to a lysosome, which is already waiting with digestive enzymes inside of it. The proteins are degraded, and the output of that is then released for the mitochondria to make ATP and energy.

Chloroquine blocks the ability of that encapsulated protein from fusing with the lysosome and getting digested. The whole autophagy process becomes constipated. Chloroquine rapidly enters cells and blocks their lysosomes from working by changing the pH inside the lysosome.

What is the adverse-event profile of chloroquine?The side effects are very low. We use oral slow-release chloroquine (Aralen; Sanofi) so the patients only have to take it once a week. It is immediately absorbed into the cells of the body. A low percentage of side effects has been seen in the multiple thousands of individuals treated with chloroquine in the past, including nausea and headaches. For some preparations of chloroquine, patients have very rarely reported blurry vision. We don’t know if that same effect is seen with Aralen; our patients are screened by an ophthalmologist and followed.

In addition, the reported side effects in past studies are experienced by patients who have been on long-

Figure 2. Treatment of Preinvasive Breast Lesions

Lance A. Liotta, MD, PhD, is focusing his research on ways to kill intraductal neoplastic cells before they become invasive.

Presented at 29th Annual Miami Breast Cancer Conference. March 15, 2012.

Time

Therapy

Normal BreastAtypicalDuctal

Hyperplasia

Ductal Carcinomain Situ

InvasiveCarcinoma

Normal BreastAtypicalDuctal

Hyperplasia

Ductal Carcinoma

in Situ

term therapy with chloroquine. For the short 30 days that we’re administering it to the patients, the likelihood that there would be side effects is very low.

Are there implications for chloroquine research in tumor types other than breast cancer?Yes, others have proposed the use of chloroquine to treat frankly malignant cancers. This includes pancreatic cancer, glioblastoma, and melanoma. There has been a study in animals to show that chloroquine prevents progression of lymphoma—all for the same reasons that we propose, that it prevents the cells of genetic damage from surviving and going on to become cancerous, or it prevents the cells from being resistant to therapy.


ONG_CS_4'12.indd 14 4/20/12 3:54 PM


Is There a Best Adjuvant Chemotherapy Regimen for Breast Cancer?By Anna Azvolinsky, PhD

Many adjuvant treatment options exist, and yet there is no definitive go-to regimen to treat women with early breast cancer. At the 29th Annual Miami Breast Cancer Conference, three prominent breast cancer clinicians and researchers presented overviews of three adjuvant compo-nents: anthracyclines, fluoropyrimidines, and taxane agents.

Adjuvant chemotherapy regimens have seen an evolution of three successive generations. Insights into these treatment trends are gleaned from adjuvant ear-ly-stage breast cancer clinical trial data that are pooled together every five years in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).

Cytotoxic therapy consisting of cyclophosphamide–methotrexate–5-fluorouracil (CMF)-based regimens showed a 24% reduction in breast cancer recurrence and 14% reduction in death, compared with placebo.1 Anthra-cycline therapy showed an advantage, although modest, over CMF-based chemotherapy.2 The reduction in risk of recurrence was 11%, and reduction in risk of breast-cancer mortality was 16% for anthracyclines compared with CMF. Finally, the 2006 EBCTCG overview showed that the third-generation adjuvant therapy of anthracycline and taxane-based chemotherapy further reduced the risk of breast cancer recurrence by 17% compared with anthracycline-based chemotherapy.3 The breast cancer-specific, abso-lute improvement in survival with these generations of adjuvant chemotherapy is approximately 4% to 5%.

The anthracyclinesJulie R. Gralow, MD, director of Breast Medical Oncol-ogy at the Fred Hutchinson Cancer Research Center

in Seattle, Washington, provided an overview of the evidence for anthracycline-based adjuvant therapies. “Anthracyclines have been extensively tested in clinical trials over several decades,” said Gralow. “Currently, there are insufficient data to recommend replacing them

in adjuvant treatment of breast cancer.” She added that for a patient with a “high enough risk

of recurrence to warrant chemotherapy, it is hard to con-fidently identify a population who will not benefit from an anthracycline-based regimen”—channeling the key message of a 2009 review on the topic.4 “We are desperately looking for anthracycline response and resistance,” she added.

In Gralow’s view, most patients are eligible for an-thracyclines—except when heart toxicity may be an issue—but she generally gives maximal endocrine thera-py over a chemotherapy regimen.

The current anthracycline regimens use a 60 mg/m2 dose based on the Cancer and Leukemia Group B (CALGB) 9344 trial that did not show an added benefit in increased

REFERENCES1. Polychemotherapy for early breast cancer: an overview of the

randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;352(9132):930-942.

2. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.

3. Peto R, for the Early Breast Cancer Trialists’ Collaborative Group. The worldwide overview: new results for systemic adjuvant therapies. Presented at the 30th Annual San Antonio Breast Cancer Symposium; December 13-16, 2007. San Antonio, TX.

4. Gianni L, Norton L, Wolmark N, et al. Role of anthracyclines in the treatment of early breast cancer. J Clin Oncol. 2009;27(28):4798-4808.

5. Levine MN, Pritchard KI, Bramwell VHC, et al. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005;23(22):5166-5170.

6. Hutchins LF, Green SJ, Ravdin PM, et al. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005;23(33):8313-8321.

7. Muss HB, Berry DA, Cirrincione CT, et al. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065.

8. Martin M, Rodriguez-Lescure A, Ruiz A, et al. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008;100:805-814.

anthracycline (doxorubicin) dosage. In contrast, epirubicin tri-als have not stuck to a consistent dose, according to Gralow.

Gralow highlighted major trials that led to the utilization of anthracyclines in the adjuvant setting. The EBCTCG 2006 meta-analysis of CMF versus anthracycline regi-mens showed a 5% absolute difference in mortality at 10 years, favoring anthracycline. The magnitude of the ben-efit was probably underestimated in this analysis, as many of the included studies used anthracyclines at much lower doses than those used today, Gralow said.

Two large North American trials have compared anthra-cycline with CMF. The NCIC-CTG MA5 trial, which compared CMF with cyclophosphamide-epirubicin-fluorouracil (CEF) in node-positive patients, showed an overall survival of 58% to 62%, respectively.5 “Clearly a positive trial,” Gralow stated. However, the conclusion of the SWOG-8897 node-negative patient trial (new analysis is expected shortly) at the 10-year mark suggested that a regimen of cyclophosphamide, doxorubicin, and fluorouracil (CAF) is not superior to the CMF regimen. Gralow stated that she did not agree with the conclusion of that study, mainly because the disease-free survival was likely confounded by events that could not have been impacted by the adjuvant regimen.6

FluoropyrimidinesKathy D. Miller, MD, of the Simon Cancer Center, Indiana University, Indianapolis, discussed the evolution of fluoro-pyrimidine in breast cancer treatment. “Once the mainstay of adjuvant therapy, a crucial component of CMF, the use of 5-fluorouracil plummeted through the last two decades,” according to Miller. Based on clinical trials, it is difficult to

determine the actual contribu-tion of fluoropyrimidine to multi-component adjuvant regimens.

A reason for reviving the ques-tion of whether fluoropyrimidines contribute to long-term patient benefit is the recent introduction of capecitabine, a pro-drug that is metabolized to 5-fluorouracil in the tumor. Capecitabine had

the promise of a targeted chemotherapy with lower toxic-ity and greater efficacy, said Miller, but the results never panned out. Adding or substituting capecitabine increases toxicity but without an increase in efficacy, Miller stated, citing the CALGB 49907 trial, among others.7

Capecitabine has not shown an improvement in any primary endpoint when added to standard therapy, and with an increase in toxicity that has led to dose omissions and reductions. Miller sees this as “worrisome in a cura-tive setting.” Miller’s final conclusion about the fluoropy-rimidines: “More relic than relevant.”

TaxanesTaxanes have been tested in more than 20 trials involv-

ing over 35,000 women with early-stage breast cancer. While taxanes have been shown to be beneficial for a wide range of patients, irrespective of lymph node sta-tus, hormone receptor expression, or HER2 status, their optimal use has still not been established.

Matthew J. C. Ellis, BSc, MB, BChir, PhD, director of the Breast Cancer Program at the Siteman Cancer Center in St. Louis, Missouri, provided an overview of the taxane-based regimens. Ellis emphasized that the three standard

chemotherapy drugs— taxane, anthracycline, and cyclophos-phamide—can be given to-gether, sequentially, as a com-bination of anthracycline plus cyclophosphomide followed by a taxane, or as a combination of any of the two chemothera-pies. The actual benefit of an anthracycline-taxane combina-

tion for recurrence is modest, analogous to the benefit of anthracycline compared with CMF, Ellis said.

Paclitaxel, a widely used taxane, can be given every three weeks, every two weeks, or weekly, said Ellis. He pointed out that the biweekly or weekly dosage schedule is preferred over the every three-week dosage schedule. However, he was not sure whether biweekly or weekly paclitaxel is better.8 Ellis said he prefers the weekly schedule largely due to its lower cost.

Because the absolute benefit of paclitaxel on mortal-ity is only about 3%, Ellis recommended that therapy should be stopped if a patient cannot tolerate the toxic-ity. “I don’t give a taxane in combination with anthracy-cline. It is toxic, and it looks like the sequential approach is effective and safe,” he said.

As with the other discussed adjuvant chemotherapy op-tions, “We need to do a lot more work on prediction of tax-ane efficacy, because clearly a lot of patients are receiving these drugs for very little benefit,” Ellis concluded.

Julie R. Gralow, MD Kathy D. Miller, MD

Matthew J. C. Ellis, BChir, PhD

Miami Breast Cancer Conference

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Baselga is the lead author on: (1) BOLERO-2, which found a significant progression-free survival (PFS) benefit for combining everolimus (Afinitor) with ex-emestane in postmenopausal women with estrogen receptor-positive, HER2-negative metastatic breast cancer1; (2) CLEOPATRA, which established a PFS ben-efit for using the novel therapeutic pertuzumab with trastuzumab (Herceptin) as a dual HER2 blockade for HER2-positive patients with late-stage disease2; and (3) NeoALTTO, which found that administering lapatinib (Tykerb) plus trastuzumab in the neoadjuvant setting for HER2-positive patients produced a significant ad-vantage in pathologic complete response.3

It was perhaps a once-in-a-lifetime confluence of events in a lifetime of achievement for an oncology leader who has spent more than 20 years in the field.

Baselga built the oncology program at Vall d’Hebron University Hospital in Barcelona, Spain, into an in-ternationally known research institute and served as president of the European Society of Medical Oncol-ogy. Earlier in his career, he completed a fellowship in medical oncology at Memorial Sloan-Kettering Cancer Center, New York, New York.

Two years ago, Baselga was named chief of the Divi-sion of Hematology/Oncology and associate director of the Massachusetts General Hospital (MGH) Cancer Center in Boston. MGH, which conducts nearly 400 clinical trials annually, has established one of the na-tion’s most extensive tumor genotyping initiatives.

For much of his career, Baselga has been explor-ing HER2 gene mutations in breast cancer. His work includes research that led to the development of trastu-

By Anita T. Shaffer

Leading Researcher Sees Turning Point in Breast CancerAn Interview With José Baselga, MD, PhD

In a recent six-week span, José Baselga, MD, PhD, notched a stunning series of milestones in breast cancer research: the publication of the results of three separate clinical trials with the potential to change practice in different subtypes of the disease.

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José Baselga, MD, PhD, discusses the CLEOPATRA study during the 2011 CTRC-AACR San Antonio Breast Cancer Symposium in December.

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zumab (Herceptin) for the treatment of HER2-positive disease in the 1990s.

During a recent interview, Baselga couched his lat-est research highlights in modest terms. “You do mul-tiple things, and to have more than one project coming to the end at the same time and having the three stud-ies positive—that’s never going to happen again,” he said. “It’s just a coincidence.”

On the subject of breast cancer research as a whole, Baselga expressed excitement about the pace of dis-covery and the implications of recent findings.

“We now have the capacity to interpret much better what’s going on in the tumor and to adopt our thera-pies based on that,” he said. “This is powerful, and yes, I do believe that we are at a turning point.”

Baselga discussed his own research more exten-sively in this interview with OncologyLive.

OncologyLive: Is there a theme in these three studies?Baselga: Yes, in the three cases we have combined new, targeted therapies to whatever was the standard of care. That’s the theme—trying to look for synergistic interactions with targeted therapeutics in breast cancer.

What are the challenges of investigating combination therapies?Perhaps the most important one is trying to design a clinical trial that will be able to answer the questions that you’re looking for in a way that is error-free and that has good, strong support. It requires a lot of time and effort to do the right and appropriate clinical trial design, and you have to base that on your laboratory data or on data from earlier studies. Trying to model in the clinic what has hap-pened in the lab—that’s the most challenging part of all.

The second challenge is in the case of these newer, more avant-garde, if you wish, clinical trial designs such as NeoALTTO. The challenge there is to set up a whole new set of conditions. The concept of neoadju-vant therapy, and doing clinical trials with neoadjuvant therapy, is not an easy one. On top of that, you want the concept of having a window period of time in which you only administer anti-HER2 therapy without chemo-therapy. That gives us yet another level of complexity.

So we need to get the buy-in from investigators and from the patients. You need pathologists to help. You need to build in very complex imaging. This is not easy, I can tell you that.

BOLERO-2

What is the mechanism of action of the combination therapy used in BOLERO-2?While anti-estrogen therapy is the backbone of therapy in estrogen receptor-positive tumors, hormone resis-tance either presents up front (primary resistance) or eventually develops (acquired resistance). Taken to-gether, hormonal resistance is clearly one of the largest challenges that we are facing today in the clinic. So we were looking for ways to revert endocrine resistance.Data from multiple labs had shown, over the last few years, that the mTOR pathway that is downstream from the PI3 kinase is one of the most important me-diators of endocrine resistance, and it can activate es-trogen receptor transcription in a ligand-independent fashion. So even if you are using an aromatase inhibi-tor [AI], even if you are blocking access of ligand to the estrogen receptor, if you have an abnormally activated mTOR pathway, that estrogen receptor will signal and will be transcriptionally active.

The obvious next approach is to combine an anti-estrogen that will interfere with an mTOR inhibitor that will prevent ligand-independent estrogen recep-tor transcription. And that was the basis for the initial studies. We had done a small pilot neoadjuvant study of the combination of everolimus with an AI, and we had seen a very dramatic improvement in the inhibition of proliferation with everolimus. So we had the clinical data supporting the notion that mTOR inhibitors would revert resistance, and that’s exactly what we saw in BOLERO-2.

What role do you think everolimus will play in this subtype of breast cancer?I think everolimus is going to be a major addition to therapy. In the patient population that was part of the BOLERO-2 study, the addition of everolimus had very meaningful clinical improvement of patients. I would think that everolimus will become a standard of care in that indication.

Are there broader implications for everolimus in other cancers? Absolutely. In breast cancer, I think another area that’s extremely important is in tumors that are HER2-posi-tive. We have small phase II studies showing that evero-limus can overcome resistance to HER2 therapies, and there are two large randomized trials going on. One is BOLERO-1 and the other is BOLERO-3, which are study-ing everolimus with trastuzumab and chemotherapy in patients who have failed trastuzumab. If those studies are positive, that means that everolimus will also have a role in therapy of HER2-positive breast cancer.

Now, the data from BOLERO-2 are in second-line therapy. I think a very important question is what’s going

(continued on page 23)

CLEOPATRA* BOLERO-2* NeoALTTO†

Placebo+trastuzumab

+docetaxel

Pertuzumab+trastuzumab

+docetaxel

Progression-free survival(median)

12.4 months(n = 406)

18.5 months(n = 402)

Objective response rateComplete response ratePartial response rate

(n = 336) 69.3% 4.2%65.2%

(n = 343) 80.2% 5.5%74.6%

*Based on data presented at 2011 CTRC-AACR San Antonio Breast Cancer Symposium, Texas, December 6-10, 2011.

Placebo+exemestane

Everolimus+exemestane

Progression-free survivala

3.2 mo 7.4 mo

Clinical benefit rate b

25.5% 50.5%

aLocally assessed.bIncludes complete response, partial response, stable disease >6 months.*Based on data presented at 2011 CTRC-AACR San Antonio Breast Cancer Symposium, Texas, December 6-10, 2011.

Lapatinib Trastuzumab Lapatinib+ trastuzumab

Pathologiccomplete response (pCR)

24.7% 29.5% 51.3%

Locoregionalc (pCR)

20.0% 27.6% 46.8%

cExcluded 15 patients because nodal status could not be assessed.†Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial [published online ahead of print January 17, 2012]. Lancet. 2012;379(9816):633-640.

Placebo+

Trastuzumab

Pertuzumab+

Trastuzumab

Docetaxel

Docetaxel

Patients withHER2-positive

metastatic breast cancer

centrally confirmed(N = 808)

n = 406

n = 402

Everolimus+

Exemestane

Placebo +

Exemestane

N = 724• Postmenopausal

estrogen receptor-positive

• Unresectable locally advanced or metastatic breast cancer

• Recurrence or progression after letrozole or anastrozole

n = 485

n = 239

Lapatinib

Lapatanib+

Trastuzumab

Trastuzumab

Patients withHER2-positive primary

breast cancertumors > 2 cm

(N = 455)

n = 154

n = 149

n = 152

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Andrew D. Smith is a freelance technology journalist living in New Jersey.

to happen in first-line. I think it would be very important to launch, as soon as possible, a study in the adjuvant setting.

I think the data of BOLERO go far beyond the special population or the indication of BOLERO. And what it does is that it opens up the whole field of mTOR and PI3 kinase therapy in breast cancer.

CLEOPATRA

How was pertuzumab developed?Pertuzumab was developed at the same time as Her-ceptin (trastuzumab). If you look at the initial papers by Genentech, they have an antibody called 4D5 that became trastuzumab, and they had another one called 2C4, and that was the murine version of pertuzumab. So that antibody was there from the beginning.

Work by investigators at Genentech showed that pertuzumab was binding to HER2, but it was binding to HER2 in a different site than trastuzumab, and it was preventing a different type of activation than Herceptin did. Now, there were two theories: that pertuzumab may work in breast cancer where HER2 is not overex-pressed or that pertuzumab would work together with Herceptin in tumors that overexpress HER2.

I have been involved with pertuzumab for many, many years. I was an early believer in the compound. Pertuzumab in the lab was clearly a better inhibitor of signaling than Herceptin. So I led the phase II study of pertuzumab in breast cancer. That was a beautifully designed study. We had patients who had metastatic disease and they had progressed to Herceptin. Despite having stopped responding to Herceptin, we kept them on Herceptin and we added pertuzumab in these patients, without chemotherapy. We saw that 50% of these patients had either response or stable disease for six months or more. This was remarkable and the

turning point in the development of pertuzumab.Then we went on to expand the study in two addi-

tional parts. It is unique to have a study with so many parts, but we really wanted to know whether Herceptin was required on top of pertuzumab. The second part of the study involved patients who had progressed on Herceptin. We added pertuzumab alone to see what pertuzumab alone would do. The answer was very little. Pertuzumab alone had minimal response.

So then the next question was part three of the study. Those patients who had not responded to pertuzumab as a single agent we kept on pertuzumab and we added, again, Herceptin. What happened was a very high response rate. I think it’s the first time in oncology in which you have patients who had progressed to two therapies, in this case trastuzumab and pertuzumab, and we put them together and we saw responses. These agents have truly comple-mentary mechanisms of action, and from that the bold move was made to go straight to a first-line phase III regis-tration study. And that was the birth of CLEOPATRA.

The path with pertuzumab has not been easy. It wasn’t clear that pertuzumab was going to be an addition. Initial-ly, there were some concerns about the potential toxicity.

Do the agents work well together because they attack HER2 differently, or because of a cumu-lative effect? The two antibodies work together because they have complementary mechanisms of action. One mechanism of HER2 activation is via ligand-independent HER2 activation. That is being blocked by Herceptin. Now, there’s another mechanism of HER2 activation and that’s via the formation of dimers with other members of the HER2 family of receptors and, most importantly, with HER3. HER3 plays a critical role and pertuzumab blocks HER3 from binding to HER2. What happens is that the ligand binds to HER3, HER3 gets close to HER2, they dimerize, and they signal. With trastuzum-ab and pertuzumab together, you are blocking at the same time the two known mechanisms of HER2 activa-tion. That’s the basis of the effects that we’re seeing.

What role do you expect pertuzumab to play in treatment regimens? I think pertuzumab will become a standard first-line therapy in HER2-positive disease. We also have started a worldwide adjuvant study with pertuzumab. In the same way that Herceptin has had the biggest impact in the early adjuvant disease setting, it is very likely that pertuzumab will be the same.

Will pertuzumab always be paired with trastuzumab?It will have to be paired with trastuzumab, or with a trastuzumab-like concept. For example, there is a new compound that is being studied called T-DM1 that has a trastuzumab component, and possibly the combina-tion of T-DM1 and pertuzumab also is going to have a synergistic interaction. Pertuzumab will always need a partner. This is not a solo drug to give.

NeoALTTO

Please discuss the results of the NeoALTTO trial.NeoALTTO was a large neoadjuvant study in patients with resectable, HER2-positive breast cancer. The question we were asking is whether the combination of Herceptin and the tyrosine kinase inhibitor lapatinib is better than Herceptin alone. The study also questioned lapa-tinib alone versus the combination versus trastuzumab.

The way we decided to study that was by having, as a primary endpoint, complete pathological remission. In the field of HER2-positive breast cancer, there are a number of studies, including our own prior study NOAH, that have shown very consistently that patho-logical complete remission is a good surrogate marker of disease-free survival in the early-disease setting. So we felt that the primary endpoint of pathological com-plete remission was a solid endpoint.

The study design had six weeks of just biological therapy: in one arm, trastuzumab; in the other, trastu-zumab/lapatinib; and in the third, lapatinib alone. Then at week 6, we would continue with the same biological therapy and we would add paclitaxel weekly for a total of 12 more weeks. So the total duration of therapy was 18 weeks. After surgery, everybody was to receive three cycles of chemotherapy, followed by one year of the HER2 biological therapy that they were getting.

The study had mandatory biopsies on week 2 on everybody and a tumor assessment of response at week 6 at the end of the biological window period. We wanted to know the response rate to biological therapy. So it was a complex clinical trial design that would be able to provide us with many answers.

What we reported in the journal The Lancet were the results of the primary endpoint, which is the patho-logical complete remission, but what we observed is that the combination of trastuzumab and lapatinib im-proved the rate of pathological complete remission. We went from 24% to 52% complete remission, and lapa-tinib was not that different than trastuzumab in this


(continued from page 19)

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José Baselga, MD, PhD, in his office at Massachusetts General Hospital Cancer Center in Boston.

“ Things are moving so quickly that if you’re asking me what’s going to be the standard of care two years from now, I could not possibly tell you.”

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setting. The important information is the very positive outcome of the study that validates the concept of dual HER2 blockade, and that we also have various tumor samples from all participating patients, so now we have the capacity to investigate biomarker responses.

The NeoALTTO study has a companion study called the ALTTO that is addressing the same questions in the adjuvant setting. It is a huge study with 8000 patients. The study is fully accrued, and we should be getting results soon.

NeoALTTO is the experimental arm of the ALTTO study. We’re looking at the samples and at the tumor biopsies, and we are able to postulate hypotheses that we can then check. It’s a new model in which you have an approach that goes with the neoadjuvant study and an adjuvant study. These two studies are companions, and we can obtain information from both that is meaningful.

What are the implications of the NeoALTTO results?We were very happy to see these results, and I think they provide support for the concept that dual HER2 blockade is better than single blockade. And also, it gives us a very strong message that it is feasible and appropri-ate to test new drugs earlier in disease. We have been developing therapies in patients with late-stage can-cer, and there’s a level of concern that in that patient population we might be missing some very active com-pounds. I think that NeoALTTO is a tribute to the possi-bility of studying new concepts earlier in disease.

What are the potential indications for lapatinib regimens?The mechanism of action of lapatinib is partially com-plementary to Herceptin. Lapatinib is a tyrosine kinase inhibitor and a very good signaling inhibitor of HER2.

If the ALTTO study is positive, the new first-line standard of care in the adjuvant setting or in the neo-adjuvant setting could be lapatinib plus Herceptin plus chemotherapy. Then the new standard in the first-line setting would be pertuzumab with Herceptin. In a way, they are very similar concepts. Dual HER2 blockade, in both settings, could become the new standard of care.

Things are moving so quickly that if you’re asking me what’s going to be the standard of care two years from now, I could not possibly tell you.

Did the tumors of any participants in the NeoALTTO study disappear with lapatinib, eliminating the need for surgery?We had a lot of patients who had major responses with the HER2 therapy alone prior to the entry of chemo-therapy. We had close to 60% of patients who had a response. In 50% of the cases with the combination, when surgeons go in, they don’t find any tumor left. One could question whether surgery would be indi-cated. We don’t know the answer.

BIOMARKERS AND GENOMICS

Where do you see the need for biomarkers in breast cancer?I think the need for biomarkers is in every single area of breast cancer. We need to understand which are the HER2-positive tumors that are really sensitive to therapies. Biomarkers and genomics should assist us in making better choices of therapy.

We need to continually connect our efforts to breast cancer up front and to incorporate tumor sequencing early in the game. So, for example, we have here very vibrant clinical trials with PI3 kinase inhibitors. And we know that tumors that harbor PI3 kinase mutations

may be more sensitive to PI3 kinase alpha inhibitors. So that’s a marker that we are using to select the right patients for some of our trials.

How is Massachusetts General Hospital Cancer Center researching gene mutations in patients?This center is one of the pioneers, if not the pioneer in sequencing gene mutations and doing so very efficiently. Last year, we sequenced, in collaboration with pathology, over 2000 tumors from patients that we see in the clinic. For example, the HER2 patients we see here have their tumors sequenced. Within 15 days, we have the results in our system. Those data go into the chart, along with proto-cols that could help that patient based on the mutation.

We are building a Web-based system that will have, for any given mutation, a layman’s explanation on what that mutation means, and potential clinical trials available here and elsewhere against that mutation. Another area will be for the referring physician; it will be a technical page ex-plaining what the analysis shows, what the implications of that finding are, and then the clinical trials available.

That’s the way we envision the future. That’s one of the ways we need to implement personalized can-cer care—by sequencing these tumors and putting the information in the chart so that it’s available to the patient and to the physician so they can make decisions.

REFERENCES1. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal

hormone-receptor-positive advanced breast cancer [published online ahead of print December 7, 2011]. N Engl J Med. 2012; 366(6):520-529.

2. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer [published online ahead of print December 7, 2011]. N Engl J Med. 2012;366(2):109-119.

3. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial [published online ahead of print January 17, 2012]. Lancet. 2012;379(9816):633-640.

Physicians’ Education Resource is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

This activity has been approved for AMA PRA Category 1 CreditTM.

Lung CancerCONGRESS™

13th International

Program Directors

David R. Gandara, MDUniversity of CaliforniaDavis Cancer CenterSacramento, CA

Roy Herbst, MD, PhDSmilow Cancer Hospital at YaleNew Haven Yale School of MedicineNew Haven, CT

Educational ObjectivesUpon completion of this activity, participants should be able to:

• Interpret the updated American Joint Committee on Cancer (AJCC) staging guidelines and identify the changes to the way you assess and treat your patients with non-small cell lung cancer (NSCLC) that may be needed in order to adopt these guidelines.

• Refer to the AJCC Staging Guidelines relative to tumor-node-metastasis (TNM) classification when selecting your patients with NSCLC for surgery, radiation, and chemotherapy.

• Use histologic and molecular data, tumor and patient characteristics, in order to individualize therapy choices for your patients with NSCLC.

• Evaluate the clinical data presented about new agents in development for lung cancer and determine which of your patients may be appropriate candidates for clinical trial enrollment.

Conference Overview & PurposeThe 13th International Lung Cancer Congress will provide physicians with practical information regarding the clinical implications of lung cancer screening and staging, the latest clinical data impacting the management of lung cancer, the integration of targeted agents, and innovations in combined modality therapy that are changing the future of lung cancer therapy. The importance of personalized medicine will be emphasized, followed by other current topics of interest. State-of-the-art treatment for non–small-cell lung cancer (NSCLC) by stage, SCLC, and mesothelioma will be discussed. Didactic lectures will be used to reinforce current standards and to present emerging clinical data. Faculty will be encouraged to discuss practice-changing data in a case-based framework that will provide physicians with the necessary context to integrate the information into their practice to improve treatment selection and patient outcomes. Panel discussions, multidisciplinary tumor boards, and question-and-answer sessions will allow the faculty to share their personal experiences and opinions on specific clinical scenarios and ongoing controversies in the treatment of lung cancer. Furthermore, a recurring session will highlight clinical research activity of Cooperative Groups in the United States, Europe, and Asia. This will provide invaluable education to practicing physicians to increase their knowledge and improve their performance in managing patients with lung cancer.

Target AudienceThis educational activity is directed toward medical, surgical, and radiation oncologists interested in the treatment of patients with lung cancer. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other health care professionals interested in the treatment of lung cancer.

For more information and registration, visit

LungCongress2012.CancerLearning.com

Fu tu ra med ium condensedspaced 94p t

July 19-22, 2012Hyatt Regency

Huntington Beach, CA

Register online before June 1, 2012 and receive $100 discount*

Use code: OncLive

*Discount must be used at time of registration.

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March 7-10, 2013 Fontainebleau Miami Beach Hotel • Miami, FL

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This activity has been approved for AMA PRA Category 1 Credit™.



16th Annual International Congress on Hematologic Malignancies:Focus on Leukemias, Lymphomas, and MyelomaHematologists, medical oncologists, and other specialists gathered for the 16th Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma to discuss the latest in research and treatment options. The conference was held at The Cliff Lodge Conference Center in Snowbird, Utah, February 23–26, 2012.

During the conference, William G. Wierda, MD, PhD, associate professor of Medicine and an internist in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, discussed the management of chronic lymphocytic leukemia (CLL), a slowly progressing form of the disease that tends to affect older adults. CLL accounts for approximately one-third of all leukemias, and the average age of diagnosis is about 72, according to the American Cancer Society.

In this interview, Wierda explains current and emerging strategies to manage the disease.

OncologyLive: What tests are essential to establish a diagnosis of CLL?Wierda: The patient should receive the standard diagnos-tic workup, which includes flow cytometry of the blood to characterize the lymphocyte population. Typically, the way patients present to their referring physician is that they will have their blood count checked and their white count will be elevated, and there will be an abnormally high number of lymphocytes. The standard practice or ap-proach would be to send a blood sample for flow cytometry and confirm that the diagnosis is CLL. The typical markers on the surface of the cells are demonstrated through flow cytometry. They should be monoclonal by light-chain restriction, and should express CD5, CD19, and CD23.

Fluorescence in situ hybridization (FISH), mutation status, and prognostic factor tests are not required at the time of diagnosis to make the diagnosis or confirm the di-

agnosis of CLL. They are, I think, helpful in terms of coun-seling patients and determining the frequency of their follow-up. In the watch-and-wait phase, the prognostic factors are additional information that isn’t really used to manage the patient, other than determining what the fre-quency of their visits should be in the first year or two after their diagnosis. When patients need treatment, one of the prognostic factors that is very important to test is the FISH, because that allows us to identify chromosome abnormalities, and we can make modifications in how we manage patients based on the results of that test.

How do you determine the time to first treat-ment in patients with CLL? For CLL, there haven’t been any trials that have shown that early treatment improves outcome. We wait to treat them until they develop an indication for treatment—the indications being bone marrow failure reflected by low hemoglobin or low platelet count, or if patients develop disease-related symptoms that can be improved with treat-ment. We watch and wait for patients who don’t have one of the formal indications to start therapy.

Some of the prognostic factors that have been reported and are being evaluated are independently associated with a shorter time to first treatment. Factors that cor-related with a shorter time to first therapy include the presence of a 17p deletion, an unmutated immunoglobu-lin heavy-chain variable (IGHV) gene, extensive lymph-adenopathy (more than one involved nodal area), the size

of the cervical lymph nodes, and lactate dehydrogenase (LDH), as well as beta-2 microglobulin.

The treatment should be initiated based on the formal criteria for treatment. But the prognostic factors are informative in terms of identifying high-risk patients. We have several ongoing clinical trials at MD Anderson looking at patients with high-risk features and whether or not we can delay, for example, time to treatment by giving them monoclonal antibody therapy.

Emerging Markers Point to Future Strategies in CLL An Interview With William G. Wierda, MD, PhD

By Ben Leach

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William G. Wierda, MD, PhD




Beyond R-CHOP-21: What’s New in Diffuse Large B-Cell Lymphoma

By Susan R. Peck, PhD

The current standard for patients with advanced diffuse large B-cell lymphoma (DLBCL) is R-CHOP-21 (21-day rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone). However, while this regimen cures approximately two-thirds of patients, a significant fraction of patients will still relapse, and the prognosis for these patients is poor.

At the 16th Annual International Congress on Hematologic Malignancies, John Leonard, MD, professor of Medicine and Richard T. Silver Distinguished

Professor of Hematology and Medical Oncology at Weill Cornell Medical College in New York City, discussed several novel therapies currently under investigation for DLBCL.

One approach being evaluated is the substitution of an alternate chemotherapy regimen for CHOP in combination with rituximab. One such regimen, R-ACVBP (dose-intensive rituximab-doxorubicin-cyclophosphamide-vindesine-bleomycin-

prednisone), features increased dose intensity compared with R-CHOP, sequential consolidation using second-line agents, and central nervous system prophylaxis. This regimen has been compared with R-CHOP in patients with DLBCL who are younger than age 60 years with an age-adjusted International Prognostic Index equal to 1. Phase III results showed significant improvements in both progression-free survival (PFS) and overall survival (OS), but with markedly higher hematologic toxicities in the experimental arm, as well as more toxic deaths. Concerns about these high toxicity rates have prevented wide adoption of the R-ACVBP regimen, even in selected patient populations.

A second regimen under evaluation is R-EPOCH (rituximab-etoposide-prednisone-vincristine-doxorubicin-cyclophosphamide), which demonstrated a 5-year PFS of 79% in a phase II trial. A phase III trial, CALGB 50303, is now comparing R-EPOCH with R-CHOP in patients with newly diagnosed DLBCL.

Another approach being tested by many groups involves adding a new agent to R-CHOP-21. According to Leonard, “It’s hard to break away from R-CHOP-21, given that for two-thirds of the patients, it does the job.” Epratuzumab, bortezomib, lenalidomide, enzastaurin, and radioimmunotherapies are just a few of the novel agents being evaluated in combination with R-CHOP. The challenge is to select combinations that show promise in phase II studies to move forward into phase III trials.

“Every [phase II] study looks at different patient populations, at different time points, using different statistical measures like progression-free or failure-free survival, so at the end of the day it is really hard to know, is this phase II data worthy of pursuing in a phase III trial? That’s why in large-cell lymphoma, many groups are pursuing a randomized phase II strategy or other novel statistical approaches to try to take forward a new regimen,” explained Leonard.

One such promising regimen is R-CHOP in combination with the proteasome inhibitor bortezomib. This regimen is being evaluated in nongerminal center B-cell (non-GCB)-like tumors, based on the observation that nuclear factor-kappa B (NF-κB) transcriptional activity is upregulated in this subtype. While non-GCB lymphomas generally do poorly with R-CHOP in comparison with GCB-like tumors, when bortezomib was added in a phase II trial, PFS and OS outcomes were similar between the two subtypes. This combination is now being evaluated in non-GCB DLBCL in two phase III trials: PYRAMID (NCT00931918) and LYM2034 (NCT01040871).

“I think these are important studies. I think ultimately what we will be seeing is novel agents that target molecular subtypes of large cell lymphoma that are defined in more modern ways,” said Leonard. “The message here is that for this [high-risk] group of patients, we really need to continue to look and place a high priority on assessing some of these novel approaches.”

John Leonard, MD

Please discuss your research into fludara-bine, cyclophosphamide, and rituximab (FCR)-based treatment for CLL.1

Assume you have a patient who has developed an indication for treatment. If they have anemia, thrombocytopenia, or fatigue that needs to be treated, then we will initiate therapy. We’ve done a lot of work with FCR, which is our standard front-line therapy for patients who can tolerate it.

You can generally categorize patients who are getting front-line therapy into two categories: those who can tolerate a chemoimmunotherapy such as FCR, and those who cannot and need some other, less toxic treatment. For patients who could tolerate the FCR regimen, we reported in historic comparison improved survival for pa-tients in the front-line setting. German research-ers have confirmed that in a randomized trial.

There are a number of prognostic factors that correlate with the outcomes: response to treatment, time to treatment failure, and overall survival for patients who were treated with front-line therapy. (Table)

For example, beta-2 microglobulin is a very strong factor that correlates with outcomes in all three of those parameters. Presence of 17p deletion also is highly correlated with outcome, although the frequency of that in the front-line setting is relatively low; in front-line trials, probably 8% of the patients have a 17p deletion.

There were other parameters that were corre-lated with various endpoints, whether they were response, progression-free survival, or overall sur-vival. We’ll be using those parameters to identify high-risk patients and, in terms of developing new therapies for them, adding agents to FCR to try to improve response rate for maintenance strategies. There haven’t been any strategies that have been shown to be effective in terms of maintaining remission or consolidating patients.

You mentioned lenalidomide with the ad-dition of a CD20 monoclonal antibody as a potentially promising treatment. What is known about that combination so far, and why do you find it exciting?There were about 500 patients in a study that we’re in the process of analyzing. Several prog-nostic factors did correlate with outcomes—the presence of 17p deletion was a high-risk feature, patients with an unmutated V-gene were higher risk, and patients with an 11q deletion were higher risk, although not for shorter survival but for shorter remission duration.

We know treatment makes a difference in terms of the front-line patient population. It also makes a difference in terms of the relapsed patient population. In the 500 patients we ana-lyzed, there were a number of different treatments that the patients received. One of the treatments was outstanding in terms of its ability to have a prolonged remission duration, or a prolonged time to treatment failure, as well as an improvement in overall survival when we compare it with the others and in our historic comparisons, and that was lenalidomide plus rituximab.

That data were somewhat striking because we hadn’t seen improvement in overall survival for a particular treatment regimen until these analyses. I’m excited about that combination. We are just now in the process of submitting the manuscript for publication for lenalidomide plus rituximab.

We also have an ongoing trial with lenalido-mide plus nofetumomab in the salvage setting. I’m hopeful that that regimen will be further investigated in a randomized trial in previously treated patients. That needs to be confirmed, but it potentially represents an advance for patients with chronic lymphocytic leukemia.

In summary, where do we stand with CLL research?This field is continuously evolving. We’re getting new data. As follow-up on our trials continues, we get more and more information about endpoints like overall survival. Because this is a chronic disease, patients live a long time, and it takes a lot of follow-up before we can appreciate the true weight and significance of the various prognostic factors.

Hopefully, we will see in the future that the utility of these factors will be in identifying high-risk patient populations and developing treatments for those high-risk groups based on chromosome abnormalities or mutation analyses, etc. So it’ll be a more personalized strategy to therapy for patients with CLL.

REFERENCE1. Wierda WG, O’Brien S, Wang X, et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia [published online ahead of print October 3, 2011. J Clin Oncol. 2011; 29(31):4088-95.

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Table. Prognostic Factors in First-Line FCR-Based Treatment

17p deletion

High-risk: lower response rate, shorter TTF & OS

Consider stem cell transplant in first remission

β-2 Microglobulin ( ≥4 mg/L)

High-risk: lower response rate, shorter TTF & OS

11q deletion & IGHV unmutated

High response rate with FCR, but shorter TTF

Consider maintenance strategies

Advanced age is high-risk feature

FCR indicates fludarabine/cyclophosphamide/rituximab; IGHV, immunoglobulin heavy-chain variable; OS, overall survival; TTF, time to treatment failure.

For more stories and videos, visit www.OncLive.com .


W hile p53 is often called the “guardian of the genome” for its important role in preventing the accumulation of cancer-caus-ing DNA mutations, Hsp90 might equally be referred to as the “guardian of the proteome” (a cell’s protein complement), since it regulates the correct structure and function of many

of the important proteins encoded by our DNA. Like p53, Hsp90 has become recog-nized as an important anticancer therapeutic target. A number of Hsp90-targeted agents are now in development.

What Is Hsp90?Hsp90 is a member of the heat shock protein (Hsp) family, first described in 1962 as proteins induced during thermal stress. Despite the name, Hsp90 is actually active in most, if not all, cells under normal nonstress conditions; in fact, it makes up as much as 1% to 2% of total cellular protein content. Under conditions of stress (eg, lack of oxygen or nutrients, extreme temperatures), the expression of Hsp90 is further activated beyond normal levels in order to promote cell survival.

Hsps play a very important role in the cell as molecular chaperones. Once genes have been translated into proteins, they need to be folded into the correct three-dimensional structure in order to become biologically active. Hsps “chaperone” these proteins to ensure that they fold correctly and interact appropriately with other proteins. If proteins are damaged, Hsps facilitate protein refolding, or, if the damage is irreversible, they target the protein for degradation by the proteasome (the cell’s protein degradation machinery). Hsps ultimately guard the cell against the dangers of protein misfolding and aggregation.

Hsps form large multiprotein complexes with other chaperones and adaptor molecules, which aid in their function. Each Hsp has a range of different target proteins, known as clients, and exerts its chaperone activity upon these clients through cycles of binding and release, driven by the cellular energy source adenos-ine triphosphate (ATP).

Studies have identified more than 200 potential Hsp90 clients within the cell. Hsp90 is a particularly important chaperone in relation to cancer because many of its client proteins are cancer hallmark-causing signal transduction proteins. They in-clude HER2, c-KIT, AKT, MET, telomerase, and the matrix metalloproteinase MMP-2.

Hsp90 is predominantly found in the cytoplasm in two different isoforms: Hsp90α (the heat shock-induced form) and Hsp90β (the constitutively active form). However, three other isoforms of Hsp90 exist in the cell. There are two isoforms localized to the endoplasmic reticulum (ER) and the mitochondria and a third membrane-bound form. Hsp90 also has been reported to be secreted into the extracellular matrix. The secreted and membrane-bound forms are thought to have important roles in angiogenesis and metastasis.

Pathways


Targeting Hsp90Researchers Aim to Thwart Chaperonesof the “Guardian of the Proteome” By Jane de Lartigue, PhD W

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Sample Hsp90 Interactions

This figure illustrates some of the many channels through which Hsp90 can team up with co-chaperones to target client proteins that in turn activate hallmarks of cancer. More than 200 potential Hsp90 clients within the cell have been identified. Didier Picard, PhD, a professor in the Department of Cell Biology at the University of Geneva in Switzerland, maintains a database of Hsp90 interactors at http://www.picard.ch/downloads.

Co-Chaperones (examples)

Clients(examples)

Processes

RegulationDegradation

Hsp90

p50 p23 Proteins with TPR motifs Aha1

Apoptosis Angiogenesis Invasion Tumor growth

Protein kinasesbcr-alb HER2/HER3 JAKs c-Kit VEGFR1/VEGFR2

Transcription factorsp53 Stat 3/5 HIF signaling

ONG_Pathways_4'12.indd 32 4/17/12 11:37 AM


Cancer Hijacks the ChaperonesThe important chaperone function of Hsp90 is hijacked during cancer, so that mutated and overexpressed proteins are protected from misfolding and degradation. This promotes cancer survival in its stressful environment and promotes the ability of cancer cells to tolerate the many genetic alterations associated with cancer.

Increased expression of Hsps is common in both solid tumors and hema-tologic malignancies. In particular, the overexpression of Hsp90 correlates with poor prognosis in breast cancer patients.

Targeting Hsp90Hsp90 is the only chaperone for which targeted cancer agents have been developed thus far. It is considered an attractive therapeutic target because, unlike targeting individual components of signal transduction pathways, Hsp90 agents have the potential to target multiple oncogenic pathways si-multaneously, by enabling the cell to degrade a variety of mutant proteins. Although there are currently no approved Hsp90 agents, there are many in clinical development.

The prototypical Hsp90 inhibitor is a naturally occurring antibiotic called geldanamycin. The first generation of Hsp90 inhibitors to enter the clinic were synthetic analogs of geldanamycin. 17-AAG (tanespimycin) entered clinical trials back in 1999 and has been evaluated in phase I, II, and III trials, the lat-ter in combination with the proteasomal inhibitor bortezomib in patients with multiple myeloma. However, the development of 17-AAG has been plagued by problems with poor solubility and significant hepatotoxicity, and it has demon-strated only moderate clinical activity. A second agent, 17-DMAG (alvespimycin) entered clinical trials in 2004 and improved on the solubility and toxicity is-sues associated with 17-AAG, but still demonstrated poor clinical response.

A second generation of Hsp90 inhibitors is now in development. These are mostly small-molecule inhibitors targeting the amino-terminal ATP-binding domain of Hsp90. (Sidebar) These inhibitors have demonstrated significantly increased potency and reduced toxicity, so hope for Hsp90 inhibitors remains high.

A significant problem with many of these inhibitors has been the develop-ment of resistance. Recent studies have indicated that Hsp90 inhibition may actually drive a heat shock response (rapid induction of Hsps in response to stress), which increases the cellular levels of prosurvival chaperones, and is likely one of the primary causes of resistance. Currently in preclinical devel-opment are carboxy-terminal inhibitors, which do not induce this response and may help overcome resistance. These molecules are based on the couma-rin antibiotic novobiocin.

Selected Hsp90 Inhibitors Under DevelopmentWhile there are currently no approved Hsp90-targeted drugs, nearly 20 agents are in clinical development, many of which are now reaching more advanced stages in a variety of different cancers. This list includes small-molecule inhibitors targeting the amino-terminal domain of Hsp90, also called the N-terminal.

Ganetespib (formerly STA-9090; Synta Pharmaceuticals Corp)

This intravenously administered molecule is currently undergoing phase IIb/III investigation in non-small cell lung cancer (NSCLC). The GALAXY trial (Ganetespib Assessment in Lung CAncer with DocetaXel) is a randomized, international study evaluating docetaxel versus ganetespib plus docetaxel in patients with stage IIIb or IV NSCLC.

The drug also is being tested in patients with metastatic hormone-resistant prostate cancer, solid tumors, myeloproliferative disorders, and esophagogastric cancer, among others. Interim data from clinical trials indicate that ganetespib shows promise in the treatment of lung cancer and solid tumors; in a phase I, open-label, dose-escalation study of twice-weekly ganetespib in 36 patients with metastatic solid tumors, there was one partial response and 10 incidences of stable disease, and it was well tolerated.

Clinicaltrials.gov identifiers: NCT01348126; NCT01270880; NCT01183364; NCT00858572; NCT01167114; NCT00688116

Retaspimycin hydrochloride (IPI-504; Infinity Pharmaceuticals)

Also intravenously administered, retaspimycin hydrochloride is currently in phase II trials in combination with docetaxel in patients with NSCLC, and in a phase II trial of patients with previously treated NSCLC. It is also being studied in combination with everolimus in patients with KRAS-mutant NSCLC.

NCT01362400; NCT01427946

NVP-AUY922 (Novartis)

This agent is undergoing investigation in phase I/II trials in patients with NSCLC, HER2-positive advanced breast cancer, gastric cancer, and gastrointestinal stromal tumor (GIST). It is also being studied alone and in combination with trastuzumab in HER2-positive breast cancer and with the proteasomal inhibitor bortezomib in patients with multiple myeloma. In a phase I dose-escalation study, 14% of patients experienced prolonged disease stabilization. It also is administered intravenously.

NCT01124864; NCT01404650; NCT01402401

KW-2478 (Kyowa Hakko Kirin Pharma, Inc)

Phase I/II trials are underway to evaluate the drug in combination with bortezomib in patients with relapsed or refractory multiple myeloma.

NCT01063907

BIIB021 (Biogen Idec)

This agent is an orally administered drug that recently completed phase II testing in patients with GIST, and in combination with exemestane in patients with hormone receptor-positive metastatic breast cancer.

NCT00618319; NCT01004081

BIIB028 (Biogen Idec)

This intravenously administered version recently completed phase I testing in patients with advanced solid tumors.

NCT00725933

Debio 0932 (Debiopharm)

Formerly CUDC305 (Curis), the orally administered, small molecule is in phase I trials in patients with advanced solid tumors or lymphoma.

NCT01168752

NVP-HSP990 (Novartis)

This orally administered version of the inhibitor is undergoing phase I clinical testing in patients with advanced solid tumors.

NCT00879905

MPC-3100 (Myrexis, Inc)

Also an orally administered small molecule, MPC-3100 recently completed phase I testing in patients with relapsed or refractory cancer. MPC-3100 also served as parent molecule in the development of MPC-0767, which has better solubility and is more easily formulated. MPC-0767 is undergoing preclinical testing.

NCT00920205

The ATP binding pocket of Hsp90, depicted as a ball-and-stick figure atop the surface of the protein, is situated in the N-terminal domain, which has emerged as a target for small-molecule inhibitors.

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Leonard M. Neckers, PhD, is chief of the Tumor Cell Biology Section, Urologic Oncology Branch of the National Cancer Institute, Rockville, Maryland. His lab has been studying the role of the molecu-lar chaperone Hsp90 in signal transduction and the translational development of Hsp90-targeted anticancer agents for two decades. Research con-ducted in his laboratory uncovered the importance of Hsp90 in the growth and survival of cancer cells and led to the first clinical trials of Hsp90 inhibitors.

1 What role does Hsp90 play in normal cells?Molecular chaperones help nascent polypep-

tides fold correctly and multimeric protein complexes assemble productively, while minimizing the dan-ger of aggregation in the protein-rich intracellular environment. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that participates in stabilizing and activating more than 200 proteins— referred to as Hsp90 “clients”—many of which are essential for constitutive cell signaling and adaptive responses to stress. To accomplish this task, Hsp90, the chaperone Hsp70, and additional proteins termed co-chaperones form the dynamic complex known as the Hsp90 chaperone machine.

2 How is Hsp90 implicated in the development of cancer?

Cancer cells use the Hsp90 chaperone machinery to protect an array of mutated and overexpressed onco-proteins from misfolding and degradation. Hsp90 is recognized as a crucial facilitator of oncogene ad-diction and cancer cell survival.

3 How has the role of Hsp90 been exploited in cancer research and drug development?

Like the prototypic Hsp90 inhibitor geldanamycin (which was identified in 1994), Hsp90 inhibitors currently under clinical evaluation interact with Hsp90’s N domain ATP-binding pocket, prevent ATP binding, and stop the chaperone cycle, leading to client protein degradation.

Hsp90 inhibitors have proven to be very useful as probes of Hsp90 function in both normal and cancer cells. Progress has been made in the clinical evalu-ation of targeting Hsp90 in cancer. Patient selection

based on tumor molecular characterization indicating heightened dependence on Hsp90 and sensitivity to Hsp90 inhibition is proving fruitful, as exempli-fied by RECIST responses in a recent clinical trial involving patients whose non-small cell lung cancers expressed EML4-ALK fusion protein, and in a trial involving HER2-positive breast cancer patients.

Another strategy that has shown promising re-sults is the combination of Hsp90 and proteasome inhibitors to treat multiple myeloma. The first Hsp90 inhibitor, 17-AAG (tanespimycin), entered clinical trials in 1999. In 2004, a second Hsp90 inhibitor, 17-DMAG (alvespimycin), entered a first-in-human study. Owing to extensive efforts in rational drug design and discovery, 13 additional Hsp90 inhibitors are currently undergoing clinical evaluation in can-cer patients. Ten of these agents have entered the clinic in the past three years.

4 Can Hsp90 be used as a biomarker or prognostic indicator in cancer?

Numerous published studies have reported elevated Hsp90 expression to be a characteristic of cancer cells in vivo. Further, a recent study reported a significant inverse correlation between prolonged survival and tumor Hsp90 level in patients with non-small cell lung cancer. Studies are now in progress to confirm the link between tumor Hsp90 expres-sion and tumor grade.

5 What is the future of research with regard to our understanding of Hsp90 or the

development of Hsp90-targeted cancer therapy?Although many Hsp90 clients are oncogenes, and many of the compensatory mechanisms used by tu-mors to overcome other molecularly targeted and cy-totoxic therapies are vulnerable to Hsp90 inhibition, it is now apparent that Hsp90 is also a key regulator of host cell biology at the systems level. These systemic effects can either enhance or antagonize the antitu-mor activity of Hsp90 inhibitors in cancer patients.

Studies of the impact of targeted therapy in oncol-ogy trials have tended to focus on the predicted ef-fects of the drug on the tumor without consideration of the impact of therapy on the host, and the evalua-tion of Hsp90 inhibitors is no exception. As we move forward in developing these agents, it will be critically important to consider the impact of Hsp90 inhibitors on the patient as well as on the tumor, in order to identify the most fruitful indications for Hsp90 inhibi-tor therapy in oncology.

Leonard M. neckers, PhdChief Tumor Cell Biology SectionUrologic Oncology BranchNational Cancer Institute Rockville, Maryland

5 Questions for Leonard M. Neckers, PhDThe Future of Hsp90-Targeted TherapySeveral studies have demonstrated improved effective-ness of combining chemotherapy, radiation therapy, or other targeted agents with Hsp90 inhibitors. For example, Hsp90 inhibitors are undergoing phase I trials in combination with the topoisomerase inhibitor irinotecan and phase II trials with the chemothera-peutic agent gemcitabine.

The expression of co-chaperones and posttranslational modification of Hsp90 can affect the efficacy of Hsp90 and its inhibitors. Targeting co-chaperones or their interaction with Hsp90 might prove to be a therapeuti-cally beneficial strategy, especially when combined with Hsp90 inhibitors. For example, p50 is an important co-chaperone of Hsp90 that helps to recruit many of its protein kinase clients. It may therefore provide a target for the design of kinase-specific Hsp90 inhibitors.

Hsp90 is subject to several posttranslational modi-fications, including phosphorylation and acetylation. Studies have shown that Hsp90 function can be im-paired by the inhibition of the enzyme histone deacet-ylase (HDAC). The HDAC inhibitor LBH589 (panobi-nostat; Novartis) is currently in phase I/II trials and may be a promising combination therapy with Hsp90 inhibitors, to offer a double hit on Hsp90 function.

Development of cell location-specific or isoform-specific inhibitors may also provide a future avenue of research. For example, the cell surface isoform of Hsp90 could prove to be an effective antimetastatic agent, given the proposed role of this isoform in metastasis and invasion.

Now that we have overcome some of the developmen-tal issues with Hsp90 inhibitors, and have a number of agents showing clinical promise, choosing the appropriate indication and identifying patients who may benefit from their use will become increasingly important. Studies have shown the value in choosing cancers driven by Hsp90 client proteins. For example, both HER2 and bcr-abl are Hsp90 clients, and promising results have been observed in HER2-positive breast cancer, acute myelogenous leu-kemia, and drug-resistant chronic myelogenous leuke-mia, which have a dependence on the bcr-abl protein.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.

Key Research Bohonowych JE, Gopal U, Isaacs JS. Hsp90 as a gatekeeper of tumor angiogenesis: clinical promise and potential pitfalls. J Oncol. 2010;412985. doi:10.1155/2010/412985.

Holzbeierlein JM, Windsperger A, Vielhauer G. Hsp90: a drug target? Curr Oncol Rep. 2010;12:95-101.

Piper PW, Millson SH. Mechanisms of resistance to Hsp90 inhibitor drugs: a complex mosaic emerges. Pharmaceuticals. 2011;4:1400-1422.

Ramalingam SS. The use of Hsp90 inhibitors in the treatment of lung cancer. Oncology Business Review. March 2012. www.oncbiz.com.

Staufer K, Stoeltzing O. Implication of heat shock protein 90 (Hsp90) in tumor angiogenesis: a molecular target for anti-angiogenic therapy? Curr Cancer Drug Targets. 2010;10(8):890-897.

Travers J, Sharp S, Workman P. Hsp90 inhibition: two-pronged exploitation of cancer dependencies. Drug Disc Today. 2012;17(5-6):242-252.

Trepel J, Mollapour M, Giaccone G, Neckers L. Targeting the dynamic Hsp90 complex in cancer. Nat Rev Cancer. 2010;10:537-549.

Pathways

July 26-28, 2012Hotel del Coronado • Coronado, CA

Overview and PurposeThe 11th International Congress on The Future of Breast Cancer is an educational and scientific meeting that focuses on the clinical implications of breast cancer genetic and phenotypic subtyping, as well as novel agents and strategies changing the future of breast cancer therapy. New data and promising studies that provide information about how to optimally individualize breast cancer therapy will be discussed, and controversial issues will be debated. The conference provides a unique opportunity for medical, surgical, and radiation oncologists and other health care professionals to learn from and interact with international leaders in breast cancer in order to increase knowledge, apply new data to practice, and ultimately improve patient outcomes.

Topics• Therapeutic implications of DNA repair defects in breast cancer• The bone microenvironment and breast cancer outcomes• Novel therapeutic approaches to overcome resistance to HER2-targeted agents• Breast cancer biology and benefit from angiogenesis inhibitors• New insights into preoperative therapies for HER2-positive breast cancer• Axillary dissection: where are we in 2012?• Update on accelerated and partial-breast irradiation• State-of-the-art oncoplastics advances• What’s new in optimizing endocrine therapies?• The PI3K pathway: what you need to know• Triple-negative breast cancer: can we identify subtypes?• Emerging insights into benefits from novel cytotoxic agents• Therapeutic insights into targeting breast cancer stem cells• Adjuvant chemotherapy in 2012• Prognostic and predictive factors in obesity: emerging interventions• New considerations in biomarkers and multigene assays


This activity has been approved for AMA PRA Category 1 Credit ™.

Breast Cancer11 t h I N T E R N A T I O N A L C O N G R E S S™

The Future of

Register Online Now at: BreastCongress2012.CancerLearning.com

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Register online before June 1, 2012 and receive $100 discount*

Use code: OncLive

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Science&Technology


RADIATION THERAPY

S

Brachytherapy in Breast CancerEmerges as Source of ControversyA Closer Look at SABCS Research

urprise, questions, and controversy surround a recent study that found patients with breast cancer who underwent breast-conserving surgery (BCS) and then received a week of brachytherapy, rather than five to seven weeks of whole-breast irradiation, suffered more complications and underwent more mastectomies.

Researchers from The University of Texas MD An-derson Cancer Center in Houston announced their numbers—mined from more than a million Medicare benefits claims—at the CTRC-AACR San Antonio Breast Cancer Symposium in December. They say their findings are “extremely robust,” but some critics have sharply criticized the work.

Yet given their extreme disagreement about the merits of this indi-vidual study, the researchers and clinicians interviewed for this article sounded surprisingly similar notes on the vital importance of an ongoing randomized phase III study, NSABP B-39/RTOG 0413 (B-39), sponsored by the National Surgical Adjuvant Breast and Bowel Project and the Ra-diation Therapy Oncology Group.

Today, in the absence of concrete evidence, opinions vary about the appropriate use of brachytherapy. However, even some experts who dis-count the MD Anderson study have concerns about overuse.

“Until we see definitive results from a large, randomized study, doc-

tors should follow the guidelines developed by the American Society for Radiation Oncology [ASTRO], which put women into ‘suitable,’ ‘cautionary,’ and ‘unsuitable’ categories for all types of accelerated partial-breast irradiation [APBI], including brachytherapy,” said Thomas B. Julian, MD, associate director of the Allegh-eny Breast Care Center in Pittsburgh, Pennsyl-vania, who also is associate director of medical

affairs for the NSABP and protocol officer for the B-39 study.“For physicians who were not following those guidelines—and studies

show that a disturbing number of women from the ‘unsuitable’ category are receiving APBI outside of clinical trials—perhaps this study will be a wake-up call,” he said. “For physicians who were following those guidelines be-forehand, though, nothing in this study should radically alter your practice, except to consider appropriate patients for our B-39/RTOG 0413 study.”

Some Question the Underlying DataThe MD Anderson study contains some of the first negative findings about the comparative efficacy and tolerability of brachytherapy, a fast and targeted radiation technique that has grown hugely popular since 2002, when the FDA approved the first brachytherapy device, the Mam-moSite balloon catheter. Surveys have found that as many as 10% of BCS patients were receiving a brachytherapy follow-up to lumpectomy rather than whole-breast irradiation by 2006, and doctors say the treatment has become considerably more common since then.

Eliminating five or six weeks of daily treatment saves countless hours for patients, many of whom struggle to get transportation and time off. It also saves them the emotional wear-and-tear that comes with dozens of depressing trips to the oncologist. As for efficacy, many patients and some physicians intuitively assumed that they would get better results and see fewer adverse events from the more-targeted treatment. But both those assumptions may be wrong, according to the MD Anderson data.

The study compared outcomes and complications between two groups: 123,244 women who underwent lumpectomy and whole-breast irradia-tion and 7291 women who underwent lumpectomy followed by brachy-therapy. In the five years after initial treatment, doctors billed Medicare for mastectomies on 2.2% of the whole-breast irradiation patients and 4% of brachytherapy patients. Brachytherapy patients also generated more benefits claims for complications and other negative outcomes.

The study’s findings surprised the research community—even its lead au-thor said that he had not expected to find substantial differences in outcomes—

Events Among 130,535 Patients

in Medicare Claims Database,

2000-2007

Benjamin D. Smith, MD,assistant professor at MD Andersonand lead investigator on the study

Whole-Breast Irradiation vs Accelerated Partial-Breast Irradiation Brachytherapy

WBI APBI-Brachy

Mastectomy incidence 2.2% 4%

Risk of hospitalization 5.7% 9.6%

Infection 4.5% 8.1%

Rib fracture* 3.6% 4.2%

Fat necrosis* 3.7% 9.1%

Breast pain* 11.7% 14.9%

Pneumonitis* 0.8% 0.1%*5-y cumulative incidence.

WBI indicates whole-breast irradiation; APBI-Brachy, accelerated partial-breast irradiation brachytherapy.

Adapted from Smith GL, Xu Y, Buchholz TA, et al. Partial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation in older patients. Presented at: CTRC-AACR San Antonio Breast Cancer Symposium; December 7, 2011; San Antonio, TX. Abstract S2-1.

By Andrew D. Smith

Thomas B. Julian, MD

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and generated headlines. Controversy soon fol-lowed, though, as some researchers and clinicians began to question many aspects of the study.

“All large databases have errors, but I got re-ally worried about this one when I read the claim that 9% of brachytherapy patients were hospital-ized with complications from their treatment. Hundreds of my patients have been treated with brachytherapy, and never has one been hospital-

ized with complications of brachytherapy. I’ve called colleagues and they said the same thing. Many of the numbers here are just implausible,” said Peter Beitsch, MD, a Dallas surgeon, coprincipal investigator of the American Soci-ety of Breast Surgeons MammoSite Registry, and coauthor on 12 APBI papers.

But that’s not the only database problem, according to Beitsch, who is frequently quoted in press releases from brachytherapy device maker Cianna Medical but says he has no financial ties to any company, other than honoraria paid as a course instructor.

“Even more importantly, this particular database has almost no patient in-formation beyond bills for service. There’s no data on how severe each cancer was before treatment or how badly it recurred, or even if it recurred,” Beitsch said. “If you can’t ensure comparable patient populations, you can’t compare treatment efficacy. Period. Poor data in result in a poor study coming out.”

Researchers Say Information Is AccurateBenjamin D. Smith, MD, assistant professor at MD Anderson and lead investigator on the study, counters that a trail of bills, while not as reveal-ing as full medical records, still provides a huge amount of information, particularly when investigators use 130,000 patients and can control for age, race, income, and chemotherapy (though not other factors).

“It’s true that the database does not provide enough patient information to ensure perfect comparability between the brachytherapy group and the whole-breast group,” Smith said. “But our data indicate that patients with more favorable tumors were more likely to receive brachytherapy than whole-breast irradiation, which should bias our findings toward showing a benefit from brachytherapy.”

As for the quality of the database, there’s every reason to expect accuracy, said Smith.

“Healthcare providers who fail to submit claims don’t get paid. Those who submit false claims commit fraud,” Smith said. “While no data set is perfect, the claims generated by patients reveal important information and are recognized by the NIH [National Institutes of Health] and others as a means of conducting comparative effectiveness research, which is

currently a national priority.” Database aside, critics level two more major

charges against the MD Anderson study.“The study measures the wrong endpoint.

Mastectomy doesn’t correlate perfectly with re-currence,” said Robert R. Kuske, MD, a radiation oncologist with Arizona Breast Cancer Special-ists, who helped develop APBI and who is a coprincipal investigator on B-39.

“There are healthy women who get scared by false positive MRIs or BRCA gene issues and ask for prophylactic mastec-tomies,” said Kuske. “On the other hand, some doctors will do a second lumpectomy after recurrence to try to save a breast. Such cases, even if rare, could tip the scales in a study where efficacy rates are found within 1.8 percentage points.”

As for the type of brachytherapy treatment studied, a single-channel balloon catheter is a dinosaur, according to Kuske, who also appears fre-

quently in Cianna releases but states that he has no financial conflicts.“It’s natural to want some numbers on comparative effectiveness, but

you cannot really do it by going back and studying procedures from a de-cade ago because the procedure was still being developed,” he said.

Smith concedes some truth in both these arguments but says his team’s study still imparts surprising and valuable information for doctors and patients.

“The point of breast-conserving surgery—which every woman in this study received before brachytherapy or whole-breast irradiation—is to con-serve the breast,” Smith said. “Measuring when mastectomies take place, when the breast is not conserved, is a clinically meaningful endpoint. It is, indeed, an endpoint that has been used in many studies of various breast cancer treatments. . . . It was never deemed a controversial issue in studies conducted by our group that appeared favorable to whole-breast irradiation compared to no radiation.”

As for the change in brachytherapy, Smith said it’s a change in degree, not kind. “It’s a refinement, a logical one because it tries to better place the radiation, but the overall target volume and dosing remain similar. The changes with newer catheters may improve outcomes, but this re-mains to be evaluated with long-term follow-up.”

Significance of Study Debated In evaluating the quality of the study and the importance of its findings, even eminent experts disagree.

Some think it is quite significant, including Bhadrasain Vikram, MD, chief of the Clinical Radiation Oncology Branch of the Radiation Research Program, National Cancer Institute Division of Cancer Treatment and Diagnosis.

Vikram said the apparently small difference in efficacy rates is, in real-ity, quite large because most women, even if left untreated after lumpec-tomy, would not need mastectomies. Thus, the two follow-up treatment types varied considerably in their effectiveness in preventing problems in the small subset of women who stood any chance of having problems.

Julian, on the other hand, said that practitioners shouldn’t assign too much authority to this study, given all the places that errors and omissions could creep in, such as the retrospective billing code-based data, the lack of patient treatment information, the possibility of database errors, the relative infancy of brachytherapy at the time, and a dubious mastectomy endpoint.

The B-39 study will eventually settle this dispute and definitively dem-onstrate the relative efficacy of whole-breast radiation therapy and several APBI techniques, including brachytherapy.

Opinions Vary on Appropriate UseSo how should doctors use brachytherapy until B-39 produces findings? Opinions vary.

Beitsch said that a trio of studies—all of which found that women in ASTRO’s “unsuitable” group did just as well on brachytherapy as women in the “suitable” and “cautionary” groups— makes him comfortable using brachytherapy on many women in ASTRO’s “unsuitable” category, with-out enrollment in clinical trials.

Kuske will not present brachytherapy as a legitimate option to women in the “unsuitable” group, but he does feel the evidence justifies present-ing it as a legitimate option for women in the “cautionary” group.

Smith, however, feels that brachytherapy is best conducted within the context of a randomized trial, though it is a treatment option that he dis-cusses with women who fall in the “suitable” category of ASTRO’s consen-sus statement, which he helped to coauthor.

The evidence that will determine the correct standards is at least five years away.

Freelance medical reporter Alice Goodman contributed to this report.

Peter Beitsch, MD

Robert R. Kuske, MD

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Due to the positive results found in an interim review, researchers unblinded a phase III study of abiraterone acetate (Zytiga) plus prednisone ahead of schedule. The drug com-bination is being tested in asymptomatic or mildly symptomatic men with metastatic castration-resistant prostate cancer (CRPC) who have not received chemotherapy.

The Independent Data Monitoring Committee (IDMC) unanimously recommend-ed unblinding the study (COU-AA-302) early after a planned interim analysis found clinical benefit in radiographic progression-free survival and overall survival, the primary endpoints of the study, according to Janssen Research & Development.

In addition, the committee found a favorable safety profile among men in the treat-ment arm. The committee not only recommended unblinding the study, but also that patients on placebo be offered treatment with abiraterone, the company said.

The international, multicenter, double-blind study included 1088 patients who were randomized to receive abiraterone 1000 mg once a day with prednisone 5 mg administered twice daily or placebo plus the steroid.

A company official indicated that the IDMC analysis helps advance explorations of the drug. “The COU-AA-302 study has been a key priority for us as we expand our understanding of the utility of Zytiga in metastatic prostate cancer,” William N. Hait, MD, PhD, global head of Janssen R&D, said in a press release.

The company did not provide more details of the results because it plans to sub-mit them for publication in a peer-reviewed journal.

In April 2011, the FDA approved abiraterone in combination with prednisone to treat men with metastatic CRPC who have received prior chemother-apy containing docetaxel. Later this year, Janssen plans to seek an expanded indication in men with CRPC who have not received chemotherapy.

Abiraterone, which inhibits the CYP17 enzyme, is a first-in-class agent targeting testosterone, according to the National Cancer Institute. It blocks androgen production at three sources—the testes, the adrenal glands, and the tumor itself, the company said.

Prostate Cancer


Sipuleucel-T Stimulates Responsein Localized Setting, Study Finds

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Zytiga Study Unblinded After Interim Analysis

JAK targeted to make a difference

References: 1. Jaka� Prescribing Information. Incyte Corporation. November 2011. 2. Data on � le. Incyte Corporation.

Jaka� is a trademark of Incyte Corporation.© 2012, Incyte Corporation. All rights reserved. RUX-1008G 02/12

Indications and UsageJaka� is indicated for treatment of patients with intermediate or high-risk myelo� brosis, including primary myelo� brosis, post–polycythemia vera myelo� brosis and post–essential thrombocythemia myelo� brosis.Important Safety Information• Treatment with Jakafi can cause hematologic

adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jaka� . Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache

• Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jaka� . If clinically indicated, platelet transfusions may be administered

• Patients developing anemia may require blood transfusions. Dose modi� cations of Jaka� for patients developing anemia may also be considered

• Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jaka�

• Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi . Physicians should carefully observe

patients receiving Jaka� for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly

• A dose modifi cation is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and ef� cacy

• There are no adequate and well-controlled studies of Jaka� in pregnant women. Use of Jaka� during pregnancy is not recommended and should only be used if the potential bene� t justi� es the potential risk to the fetus

• Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

† As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modi� ed Myelo� brosis Symptom Assessment Form (MFSAF v2.0).1,2

‡ Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF including abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60.1,2

Visit www.jaka� .com/JAKfor more information on Jaka� and MF, plus valuable educational resources.

Jaka� —superior reductions in spleen volume and improvements in symptom scores at Week 241,2†‡

Signi� cantly more patients receiving Jaka� vs placebo had – A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2†

– A ≥50% improvement in Total Symptom Score (TSS) (45.9% vs 5.3%, respectively; P < 0.0001)1,2†‡

• At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group Reductions in spleen volume and improvements in TSS were seen with Jaka� in both

JAK2 V617F-positive and JAK2 V617F-negative patients, relative to placebo2

* Intermediate or high-risk MF.

Introducing Jaka� ™ (JAK-ah-fye) First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

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73607ha_a.indd 1 3/3/12 1:36 AM

By Ben Leach

The neoadjuvant administration of sipuleucel-T (Provenge) may stimulate an immune response in patients with localized prostate cancer without adversely affecting their surgeries, according to study results presented at the 2012 Genitourinary Cancers Symposium. The study explored the possibility of using the vaccine earlier in the treatment timeline than its current approved indication for patients with asymptomatic or minimally symptomatic metastatic castration- resistant prostate cancer.

In a phase II trial, 42 patients with localized prostate cancer who were slated for radical prostatectomy were given sipuleucel-T in three infusions administered 6 to 7 weeks prior to their surgeries. Prostate cell specimens were collected

prior to and following treatment with sipuleucel-T. Patients were followed for 72 weeks, and also randomly assigned to receive a booster treatment with the vaccine or no further treatment.

At the time of the presentation in February, immunohistochemistry analysis had been completed on 19 patients. “Significant increases (>2-fold) in CD3-

positive and CD4-positive T-cell populations were observed at the tumor rim, where benign and malignant glands interface, compared with the pretreatment biopsy,” researchers said in their abstract. Surgical impact was measured by operative complications, procedure time, and estimated blood loss.

In a companion abstract, investigators reported a “robust immune system activation,” including antigen-presenting cells and memory and activated mature B cells.

Although the results are preliminary, the study suggests more work should be done to explore the potential benefits in patients who have an earlier- stage prostate cancer, according to Leonard G. Gomella, MD, who served as chair of the conference program committee at the American Society of Clinical Oncology symposium.

“This is very exciting because if immunotherapies work, they tend to work when there’s a minimal amount of disease,” Gomella said.

He also said the study found tumor markers through which the impact of the treatment could be evaluated.

“One of the challenges that we have when we look at all immunotherapy, and particularly when we look at the sipuleucel-T immunotherapies, is that we don’t have a specific marker for response,” Gomella said. “This is very encouraging and very positive news that this study was able to show that there were specific markers of an immune response in the prostate.”

He noted that the study is among early-phase investigations into stimulating the immune cells in the preprostatecomy setting, but that major clinical trials are “a long way off.”

Investigators said in their abstract that “work is ongoing to more fully characterize the immune response within the prostate tumor tissue and in the peripheral blood.”

Fong L, Weinberg VK, Corman JM, et al. Immune responses in prostate tumor tissue following neoadjuvant sipuleucel-T in patients with localized prostate cancer. J Clin Oncol. 2012;30:(suppl 5). Abstr 181.

Sheikh NA, Wesley JD, Perdue N, et al. Evaluation of immune activation following neoadjuvant Sipuleucel-T in subjects with localized prostate cancer. J Clin Oncol. 2012;30:(suppl 5). Abstr 178.


Leonard G. GomeLLa, mdThe Bernard W. Godwin Jr. Professor of

Prostate CancerChairman, Department of UrologyDirector, Clinical AffairsKimmel Cancer CenterThomas Jefferson UniversityPhiladelphia, PA

ONG_ClinicalInsights_4'12.indd 38 4/17/12 11:52 AM

The first stage of enrollment has been completed in a phase III clinical trial that will examine the use of a human reovirus, in combination with chemotherapy, in patients with head and neck cancer. Oncolytics Biotech Inc. announced April 2 that it has enrolled 80 patients in the trial of Re-olysin, a variant of the respiratory enteric orphan virus. The patients, who have platinum-refractory head and neck cancers, will receive Reolysin in combination with paclitaxel and carboplatin.

“This is an important milestone for this study,” Brad Thompson, PhD, president and CEO of Onco-lytics in Calgary, Canada, said in a press release. “A data analysis that will involve examining evolving progression-free survival will now be performed on this patient group to determine the probability of success in the second stage of the study.”

The randomized, double-blind trial will assess the intravenous administration of Reolysin with the two che-motherapy drugs versus chemotherapy alone in patients with metastatic or recurrent squamous cell carcinoma of the head and neck, or squamous cell cancer of the nasopharynx, who have progressed on or after prior platinum-based chemotherapy. It is being conducted in 80 centers in 12 countries in North America and Europe.

The primary endpoint is overall survival.Reolysin works by infecting patients with the reovirus,

to which most people have been exposed by adulthood, and which typically causes few or no symptoms, the company said. Normal cells are able to fight the infec-tion, but cancer cells with Ras gene mutations cannot, and the unchecked multiplication of the virus kills them by causing them to rupture. Then, the virus moves on to destroy nearby tumor cells. (NCT01166542)

Head & Neck Cancer


By Ben Leach

A retrospective analysis of the risks of hypothyroidism in patients in Germany who received sunitinib and sorafenib is gaining attention in the field of head and neck cancers, where the drugs are being evaluated for clinical use.

A study published in the European Journal of Cancer earlier this year found that 13.7% of patients on sunitinib and 6.3% of those who took sorafenib were treated with thyroid hormone (TH) therapy typically prescribed to treat hypothyroidism. The study, with findings based on prescription data from 2509 patients, is believed to be the largest database examination of the endocrine disorder among people taking either of the drugs.

Both drugs are multikinase inhibitors (MKIs) that the FDA has approved for the treatment of advanced renal cell carcinoma (RCC). Sunitinib (Sutent) also is approved to treat certain gastrointestinal stromal tumors (GISTs) and pancreatic neuroendocrine tumors while sorafenib (Nexavar) is additionally indicated for hepatocellular carcinoma. A number of phase II trials are under way studying the efficacy of sunitinib and sorafenib in the treatment of thyroid cancer.

In reviewing the study, Eric J. Sherman, MD, said the findings are notable in his field because MKIs represent a promising class of drugs for thyroid patients. “This study is clinically relevant to anyone treating a patient with thyroid cancer,” he said.

Using prescription data from more than 80% of German pharmacies,

investigators started with an index of 6444 patients for whom one of the two anticancer therapies had been prescribed from July 1, 2006, through December 31, 2007. Clinical hypothyroidism requiring TH therapy was defined as thyroid-stimulating hormone (TSH) levels >10 mIU/L.

Patients who had been prescribed TH before the study period, those who were not registered in the database, and those who received TH within 29 days of the initial index date were excluded. Data for the remaining 2509 patients were examined based on TH prescriptions written during an observation period that began 30 days after the initial index date through August 31, 2009.

In all, 178 of 1295 patients taking sunitinib (13.7%) and 77 of 1214 patients taking sorafenib (6.3%) received TH therapy. Incidence rates were 24.2 per 100 person-years for sunitinib patients and 12.1 per 100 person-years for sorafenib patients, with the unadjusted hazard ratio for TH therapy calculated as 2.0 (95% confidence interval [CI], 1.5-2.6) for sunitinib as compared with sorafenib.

Sherman said hypothyroidism has been observed in patients, but that the study marks the first time that there are enough concrete data to

make the necessary recommendations.The German research team suggested clinicians

exercise caution in prescribing TH for cancer patients with slightly increased serum-TSH levels who are not displaying symptoms. “If clinical hypothyroidism occurs, it can be treated with TH, which leads to fast and complete correction of increased TSH values and should not restrict the use of sunitinib and sorafenib in malignant diseases in general,” they concluded.

The FDA-approved prescribing information (PI) for Sutent includes a recommendation for a baseline laboratory measurement of thyroid function prior to the start of treatment and advice about monitoring patients for signs of such problems. In May 2011, the PI was updated to include reports of higher rates of hypothyroidism than with placebo among small groups of patients.

The PI for Nexavar describes hypothyroidism as an “uncommon” adverse drug reaction and does not include it among the most serious reactions.

Sherman said that while hypothyroidism does pose a serious risk to the patient, it is also a very treatable condition. TH can be started as soon as hypothyroidism is identified, and dose rates are monitored throughout treatment. If a patient is taken off sorafenib or sunitinib, it is possible for thyroid levels to return to normal.

“It’s very easy to treat,” Sherman said. “It’s just one of those things that you want to make sure you don’t miss.”

Feldt S, Schüssel K, Quinzler R, et al. Incidence of thyroid hormone therapy in patients treated with sunitinib or sorafenib: a cohort study [published online ahead of print February 28, 2012]. Eur J Cancer. doi:10.1016/j.ejca.2012.01.036.

Hypothyroidism RisksWith MKIs Examined


eric J. Sherman, mdHead and Neck OncologyMemorial Sloan Kettering Cancer CenterNew York, NY


Reolysin Trial Reaches Enrollment Milestone

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By Jill Stein

Cutaneous melanoma is becoming increasingly com-mon in young adults, new data show.

Jerry D. Brewer, MD, assistant professor of der-matology at the Mayo Clinic in Rochester, Minne-sota, and colleagues used data from the Rochester Epidemiology Project (REP) to identify patients 18 to 39 years of age who were first diagnosed with cutaneous melanoma between January 1, 1970, and December 31, 2009, in Olmsted County, Minnesota. The REP is a medical records linkage system that archives data on patient care provided to Olmsted County residents.

Little information is available about cutaneous mela-noma in young adults, the investigators noted. Studies to date have been too small and populations have been poorly defined. Earlier research has also been limited by the underreporting and delayed reporting that typically occur with registry-based epidemiology studies.

Overall, 256 young adults were included in the analysis.

Results showed that the incidence of cutaneous melanoma increased more than 6-fold in the study population during the 40-year surveillance period, with an 8-fold increase among young adult females and a 4-fold increase among young adult males.

Investigators suggested that the increasing can-cer incidence in young women may be a function of “some gender-specific behaviors that lead to different ultraviolet exposure.” Younger women are more apt to engage in activities that increase the risk of cutaneous melanoma than young men, including the use of sun-lamps and tanning beds.

The overall age- and sex-adjusted incidence of cu-taneous melanoma for the entire cohort was 16.9 per 100,000 person-years. The age-adjusted incidence was higher in females than males (23.2 vs 10.8 cases per 100,000 person-years; P = .001).

The data also showed that each one-year increase in calendar year of diagnosis was associated with a significantly decreased risk of death from any cause (hazard ratio [HR], 0.92; P = .005) and a significantly decreased risk of death due to metastatic melanoma (HR, 0.91; P = .01).

The location of cutaneous melanoma among young adults apparently differs between sexes. For females in this age group, the most common location of cutaneous melanoma was the lower extremity, fol-lowed by the upper extremity. In males, melanoma was most often found on the back, followed by the upper extremity.

The authors cited the homogenous demographic makeup of the study population as a possible limita-

6-Fold Melanoma Increase Is FoundAmong Young Adults

tion. The population was largely white and highly educated, and the results may therefore not be universally applicable to young adults throughout the United States. It is also possible that some cases of melanoma among Olmsted County resi-dents were not included because the patients were treated elsewhere.

Reed KB, Brewer JD, Lohse CM, et al. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2012;87(4):328-334.

Vemurafenib Study Buildson Positive Response Data



By Ben Leach

Vemurafenib (Zelboraf) continues to demonstrate clinical response and overall survival (OS) benefits for patients with metastatic melanoma, according to a recent trial with a long-term follow-up period.

In the phase II trial, vemurafenib delivered an overall response rate, the primary endpoint of the study, in >50% of 132 patients with BRAF V600-mutated metastatic melanoma. The median OS, a secondary endpoint, was 15.9 months (95% confidence interval [CI], 11.6-18.3). Historically, patients diagnosed with metastatic melanoma survive an average of 6 to 10 months.

Patients in the study were followed for a median period of 12.9 months (range, 0.6-20.1). The study found that 8 patients (6%) achieved a complete response and 62 patients (47%) achieved a partial

response for an overall response rate of 53% (95% CI, 0.44 -0.62). The median duration of response was 6.7 months (95% CI, 5.6-8.6), and the median length of progression-free survival (PFS) was similar at 6.8 months (95%, 5.6-8.1). At the time of data cut-off, 33 patients (25%) had not progressed.

While these data were expected, they strengthen the status of vemurafenib as a go-to treatment for patients with metastatic melanoma, according to Sanjiv S. Agarwala, MD. He noted that the median OS data were particularly encouraging. “That’s the biggest number we’ve seen in melanoma survival yet,” Agarwala said.

Investigators said some of the patients were treated for up to 6 months before showing any sign of response. However, Agarwala noted that even if it took months to observe a response to the drug, the fact that the disease was stable in those patients

is significant in its own right.“Stable disease is still a very important clinical

benefit in these patients,” Agarwala said.Vemurafenib, an oral small molecule, was

approved by the FDA in August 2011 for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600 mutation. A DNA-based companion diagnostic, the cobas 4800 BRAF V600 Mutation Test, was approved along with it.

Plexxikon, a member of Daiichi Sankyo Group, and Genentech, a member of the Roche Group, are working together to develop and promote the drug.

Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707-714.

MelanomaC L I N I C A L I N S I G H T S

SanJiv S. aGarwaLa, mdProfessor of MedicineTemple University School of MedicineChief, Oncology/HematologySt. Luke’s Hospital & Health NetworkBethlehem, PA

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Gynecologic Malignancies


By Anita T. Shaffer

Early excitement over the potential for using PARP inhibitors in the treatment of patients with ovarian cancer has dissipated amid disappointing findings on overall survival, but the class of novel therapeutics remains under active investigation for patients with this tumor type.

At least three pharmaceutical companies are continuing development programs with various PARP agents, noted Michael J. Birrer, MD, PhD, in a recent interview. He spoke shortly after AstraZeneca announced its decision to halt studies of olaparib for maintenance treatment of serous ovarian cancer.

“I haven’t given up hope on this,” said Birrer, referring to the class of PARP inhibitors as a whole. “I think you’ll see trials with PARP inhibitors testing the ability and activity of bringing the PARP inhibitor up front in newly diagnosed patients in combination with chemotherapy. Most of those trials will also include a maintenance phase. In conjunction with that, there will be selective trials in BRCA1- and BRCA2-mutated patients with recurrent resistant disease.”

PARP, poly(adenosine diphosphate [ADP]–ribose) polymerase, plays an important role in the repair of single-strand DNA breaks. Birrer said single-strand breaks can become double-strand breaks that are, in turn, repaired by a complex that contains BRCA1 and BRCA2. Thus, he said, researchers have theorized that

inhibiting the PARP enzyme should selectively kill cells with those genetic abnormalities.

Earlier studies had demonstrated higher antitumor activity and objective response rates for patients with and without BRCA1/2 mutations, a phase II trial highlighted at the 2011 American Society of Clinical Oncology Annual Meeting in June did not require that mutation status. Eligible patients had recurrent, platinum-sensitive ovarian or fallopian-tube cancer or primary peritoneal cancer with high-grade (grade 2 or 3) serous features or a serous component.

The trial, which AstraZeneca sponsored, demonstrated that olaparib improved median progression-free survival by 65% among the 136 patients randomized to receive 400-mg doses twice daily, compared with 129 participants on placebo. Investigators believed the compound showed promise as monotherapy for this patient population.

In December, however, AstraZeneca announced the company would not move forward with phase III development in the maintenance setting after interim data “indicated that the previously reported

progression-free survival benefit is unlikely to translate into an overall survival benefit, the definitive measure of patient benefit in ovarian cancer. In addition, attempts to identify a suitable tablet dose for use in phase III studies have not been successful.”

In March, researchers detailed those results in The New England Journal of Medicine. They reported median progression-free survival of 8.4 months with olaparib versus 4.8 months on placebo. Adverse events were more prevalent among those who received olaparib, but most of those events were grade 1/2, with nausea, fatigue, vomiting, and anemia among the most frequently reported effects.

However, the interim survival analysis, conducted after 38% of the participants had died, did not show a significant advantage for olaparib, which demonstrated a hazard ratio of 0.94 (95% confidence interval, 0.63-1.39; P = 0.75).

“Maintenance treatment with olaparib was associated with a significant improvement in progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer,” the researchers concluded. “However, at the interim analysis, this did not translate into an overall survival benefit. As of this writing, 21% of the patients were still receiving olaparib (and 3% were still receiving placebo), which indicates that the disease is controlled for a prolonged period in some patients.”

Birrer said the trial results presented at ASCO were “remarkable,” but that the FDA would want to see an overall survival advantage before approving a new drug. He said there also remains “a fair amount of confusion” about what would be the best dosage for patients, with studies evaluating doses ranging from 100 mg to 400 mg twice daily.

Meanwhile, companies that are continuing to study PARP inhibitors in ovarian cancer include Abbott Laboratories, which is studying veliparib (ABT-888) as monotherapy for patients with relapsed ovarian cancer with a BRCA mutation; Clovis Oncology, which is exploring rucaparib (CO-338) in BRCA-associated ovarian cancer; and BioMarin Pharmaceutical Inc, which is investigating BMN-673 in patients with advanced or recurrent solid tumors, including ovarian cancers.

Key Research

Ledermann JA, Harter P, Gourley C, et al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer. J Clin Oncol. 2011;29(suppl; abstr 5003).

Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer [published online ahead of print March 27, 2012]. N Engl J Med. doi: 10.1056/NEJMoa1105535.

PARP Inhibitors IntriguingDespite Research Setbacks


michaeL J. Birrer, md, PhdProfessor of MedicineHarvard Medical SchoolDirector, Gynecologic Medical OncologyDirector, Gynecologic Cancer Research ProgramMassachusetts General Hospital Cancer CenterBoston, MA


This illustration depicts ovarian cancer at stage IIC. One noteworthy PARP study included patients with grade 2 or 3 serous ovarian cancer.

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