The February 2013 Digital Edition of Clinical Oncology News by McMahon Group

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • February 2013 • Vol. 8, No. 2

INSIDE SOLID TUMORS

ESMO Coverage Combining MEK, BRAF inhibitors in melanoma . . . . . . . . . . . . . . . ......... 22 Promising new antiandrogen drug for castration-resistant prostate cancer . . . . . ......... 23

ASTRO Coverage Radiation boosts survival in elderly breast cancer patients . . . . . . . . . . . . . . . . . . . ......... 24 Doxepin suggested as new mucositis standard of care . . . . . . . . . . . . . . . . . . . . .......... 24

Targeted Therapy:

Not All Mutations Are Created Equal Uncovering the abnormalities that dictate the e success or failure of existing drugs and determining tthe aberrations that drive tumor progression pLiverpool, England—A long-running goal in oncology drug develop ment is to create more targeted, personalized treatments for patientss. However, developing these treatments requires understanding which genetic and epigenetic aberrations drive individual cancers, which ones respond to a particular drug, and whether it’s necessary to hit a pathway at different points. “The key point in this is that not all mutations are created equal,” said Gordon Mills, MD, PhD, the chair of Systems Biology at the University of Texas MD Anderson Cancer Center in Houston, speaking at the session “Oncology Drug Development in 2012” at the 2012 National Cancer Research Institute (NCRI) conference in Liverpool, England. “Less than half in breast and 10% in ovarian have ‘hot spott’ mutations with known effects in known tumor suppressor genes.” That is why the approach to drug discovery has moved toward id dentifying and treating subsets of mutations that occur in a single dissease. see MUTATIONS, S page p 10

Special report: Are a tumor’s genetics more important than its location? . . . . . . . . . . . .......... 28

HEMATOLOGIC DISEASE New hematologic oncology society formed . . . . . . . . . . . . . . . . . . . ............ 3 New TKI ponatinib effective in resistant CML .. . . . . . . . . . . . . . . . . . . . . . . . ......... 14

CURRENT PRACTICE Tracking performance improves cancer care ...... 14 Clinical Conundrums ....... 29

ASH 2012

Vogl, NY...

Ibrutinib To Alter CLL Treatment Landscape

Faulty Rhetoric: ‘Save a Life’ Faulty End Point: ‘Cancer-Specific Survival’

Atlanta—Ibrutinib (Pharmacyclics), a first-in-class, oral Bruton tyrosine kinase inhibitor, has shown promise in two Phase II studies of patients with chronic lymphocytic leukemia (CLL). Both studies were presented at the recent American Society of Hematology annual meeting (abstracts 187 and 189). “Ibrutinib offers great potential to significantly change the treatment landscape in CLL,” said John Byrd, MD, the director of hematology at the Wexner Medical Center at Ohio State see IBRUTINIB, B page 8

he rhetorical argument of “saving a life” recently has been resurrected in public controversy about mammogram screening (frequency, age of onset, age of cessation) and prostate-specific antigen (PSA) screening (to screen or not to screen). Our goal as physicians— the well-being of our patients and the well-being of the population as a whole—is best served by avoiding this rhetoric altogether. The tacit assumption in this rhetoric is that only one “cause of death” counts. If

that is prevented, the subject “lives happily ever after.” Framing the issue in all-or-nothing terms, with this sort of solution (salvation vs. perdition), is more Steven Vogl, MD properly the place of religion, which deals with fundamental moral questions like “why do we die?” and “why do bad things happen to good people?” In medicine and public health, grounded in the practical and the empirical, the see VOGL, NY, Y page 6

RE VIE WS & COMMENTAR IES

Expert Insights From The US Oncology Network Genomic Variants Used To Further Stratify Risk in Breast Cancer . . . . . .... 13 Anne Favret, MD

Utility of Adjuvant Aspirin in CRC Now Has Biomarker ............... 16 Thomas H. Cartwright, MD

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Prostate Cancer

Charles F. von Gunten, MD University of California, San Diego, CA

Michael A. Carducci, MD AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Jennifer R. Brown, MD, PhD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Maura N. Dickler, MD

Harry Erba, MD, PhD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

University of Alabama Birmingham, AL

Oncology Nursing Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Michele Neskey, MMSc, PA-C University of Texas, MD Anderson Cancer Center Houston, TX

Cindy O’Bryant, PharmD

Edward Chu, MD

Mayo Clinic Rochester, MN

University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

University of Colorado Cancer Center Denver, CO

Richard Stone, MD

Sara S. Kim, PharmD

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

The Mount Sinai Medical Center New York, NY

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma

Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Rhonda M. Gold, RN, MSN The Pritchard Group Rockville, MD

Infection Control Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Policy and Management

Pharmacy Shaji Kumar, MD

Gastrointestinal Cancer

Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

Hematologic Malignancies

Andrew Seidman, MD

Bioethics

Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Mission Statement

he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

Genitourinary y Cancer Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Steven Vogl, MD Medical Oncologist New York, NY

Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Lung g and Head and Neck Cancers Edward S. Kim, MD University of Texas, MD Anderson Cancer Center Houston, TX

Lung g Cancer,, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

Editorial Philosophy The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print. Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content. Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Letter to the Editor Response to the December letter from Dr. Brooks To the Editor:

n a recent letter to Clinical Oncology News (Letters to the Editor, December 2012, page 5) regarding a previously detailed case presentation in your journal of a patient incorrectly diagnosed with metastatic bladder cancer who, upon reevaluation was found to actuallyy have a localized bladder cancer as well as metastatic disease from an unrelated (and far more treatable) Hodgkin’s lymphoma, Philip L. Brooks, MD, rather remarkably “questions the educational point” of the discussion. Further, he goes on to state “we need to be cognizant of the cost of

care. Tests should not be repeated unless there is a specific indication.” If this patient had simply accepted the original opinion, and if the doctors seeing him for the second opinion had not questioned this (incorrect) diagnosis, he would have received intensive (and highly inappropriate) systemic therapy for a metastatic carcinoma he did not have and his lymphoma would have gone untreated. Further, if this profoundly serious diagnostic error had not been corrected, the ultimate outcome for this patient is not difficult to predict. For some reason the doctors caring

for this individual missed the crucial fact that the presence of a localized cancer in one location (e.g., bladder) does not necessarily prove that physical (e.g., enlarged lymph nodes) or imaging (e.g., CT scan revealing pulmonary nodularity) abnormalities observed elsewhere in the body are caused by metastatic spread from the original malignancy. In most clinical situations, obtaining histologic confirmation of the presence and type of metastatic cancer is absolutely essential. And in this particular case, it took a second opinion undertaken by a second group of thoughtful and thorough clinicians for this critical evaluation to be performed. So, while Dr. Brooks does not appear to understand the “educational point” of this case presentation, hopefully others

will. After all, is this not the type of care you would want if this patient was a member of your family? Sincerely, Maurie Markman, MD Senior Vice President for Clinical Affairs Cancer Treatment Centers of America Philadelphia, Pa.

HEMATOLOGIC DISEASE

New Hematologic Oncology Society Formed I

n October, registration opened for a new society in the field: the Society of Hematologic Oncology (SOHO). The new society, spearheaded by hematology faculty at the University of Texas MD Anderson Cancer Center in Houston, focuses on hematologic malignancies and related disorders, with a view to promoting international research, education, prevention and optimal patient care, according to SOHO background information. Asked to state the society’s goals, SOHO acting president Emil J. Freireich, MD, the Ruth Harriet Ainsworth Professor of developmental therapeutics at MD Anderson, told Clinical Oncology News, “We want to cure cancer. And it’s been demonstrated that major advances are discovered in leukemia, lymphoma and myeloma. It’s the leading edge of cancer research.” Dr. Freireich also noted: “Leukemia is systemic from the outset—a model of metastatic cancer. A blood cancer can be sampled continuously, which you cannot do with solid tumors. … Innovation within cancer research begins with leukemia.

It is the road to the cure of cancer.” Hagop M. Kantarjian, MD, the secretary of SOHO and a professor of medicine and the chairman of the Department of Leukemia at MD Anderson, said in an interview that the founding of the new society is important “because of the amount of knowledge accumulating today, which is happening at a more

all hematologic disorders, as ASH [American Society of Hematology] does. We’re a small subset of ASCO [American Society of Clinical Oncology], but a very important subset, like breast cancer. Our prototype is the San Antonio Breast Cancer Symposium. Breast cancer was being swallowed up at ASCO. Now San Antonio has become very successful.”

‘Innovation within cancer research begins with leukemia. It is the road to the cure of cancer.’ —Emil J. Freireich, MD expanded pace than in the past. Formerly, hematologic malignancies were included with benign hematologic disorders, but knowledge has expanded to an extent that now we need a focused approach to deal with the patient with hematologic malignancies.” Dr. Freireich distinguished SOHO from other societies. “We’re more clinical than the AACR [American Association for Cancer Research]. We focus on leukemia, myeloma and lymphoma instead of

Dr. Kantarjian added, “We attempted partnership with ASCO and it may come about in the future.” Growing out of the Hematologic Malignancies conferences that began in 2000, SOHO was established as a nonprofit corporation in 2012 and is currently based in Houston. Its three founders—a secretariat consisting of Drs. Freireich and Kantarjian, and Dr. Michael J. Keating, MBBS (director)—are all affiliated with MD Anderson; however, said Dr. Kantarjian,

At the society’s first meeting last October, more than 400 of the 600 attendees became members of SOHO.

“We would like it not to be tied to MD Anderson. We would like it to be an international society.” With the help of a steering committee, SOHO plans to hold its first annual meeting Sept. 18-21, 2013, in Houston, with scientific research presented. The peer-reviewed journal Clinical Lymphoma, Myeloma & Leukemia has agreed to be SOHO’s official journal, said Dr. Freireich. Additionally, the society’s website, www.societyofhematologiconcology.com, is now live. —George Ochoa Dr. Freireich and Dr. Kantarjian reported no relevant financial conflicts of interest.

Ask an Expert Do you have an interesting or educational case about which you’d like an expert’s opinion? As part of a new column, Clinical Oncology News s will connect your difficult case with an expert on the disease type and publish his or her recommendations. Contact managing editor Gabriel Miller at gmiller@mcmahonmed.com for details.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

The Continuing Amazing Story of Thalidomide Is there a lesson to be learned here?

here is perhaps no darker story in the annals of modern medicine: A drug widely marketed as a completely safe sedative to be taken during pregnancy or as an effective remedy for pregnancy-associated “morning sickness” results in thousands of babies born with severe birth defects.1 In fact, the history of the marketing of thalidomide and the profound lack of appropriate preclinical testing is closely tied to the development of drug regulation in the United States over the past 50 years, including in the oncology arena. But, as we now know, these truly tragic events did not mark the end of the story for thalidomide. Subsequently conducted intensive preclinical investigative efforts demonstrated the drug to have extensive and rather profound biological effects, involving inflammatory and angiogenic pathways. Thalidomide was found to be a potent antiangiogenic (likely a major reason for the induction of severe birth defects) and anti-inflammatory agent as well as to have a major modulating influence on immune responses. Then, in a very controversial decision, considering the drug’s potential for producing severe adverse events, the agency charged with protecting patients against these kinds of catastrophes approved the use of thalidomide as a treatment for the particularly devastating symptoms of leprosy (erythema nodosum laprosum).2 This was followed by landmark studies demonstrating the favorable effect of thalidomide on survival in multiple myeloma, which led to the subsequent development ®

McMahon Publishing is a 40-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications. Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2013 McMahon Publishing, New York, NY. All rights reserved. POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

of other, even more effective drugs in this same class that are now routinely employed in the treatment of myeloma and myelodysplastic syndrome.3,4 And reports of the utility of thalidomide in remarkably different clinical settings continue to appear in the medical literature. In a recent, very provocative study, thalidomide was highly effective in the management of distressing chronic cough in patients with the rare condition idiopathic pulmonary fibrosis.5 In this randomized trial involving 24 patients suffering from

EDITORIAL BOARD COMMENTARY

normal tissue. Today, for example, the FDA would appropriately require extensive preclinical testing before any novel pharmaceutical agent is permitted to enter human trials. The experience also demonstrates, however, that with appropriate laboratory testing before clinical use and the subsequent conduct of well-designed trials, it is possible to convert a potentially highly toxic agent into a very useful pharmaceutical. This experience is particularly relevant in cancer drug development, where it is recognized that essentially all anti-

The thalidomide experience demonstrates that with appropriate laboratory testing before clinical use and the subsequent conduct of well-designed trials, it is possible to convert a potentially highly toxic agent into a very useful pharmaceutical. this condition for a minimum of at least two months without relief before study entry, investigators demonstrated that not only did thalidomide improve the cough but also patients’ overall quality of life. Notably, this is the first pharmaceutical agent to demonstrate this outcome in a randomized trial of idiopathic pulmonary fibrosis. The “thalidomide story” is a truly powerful example of how any pharmaceutical agent developed to achieve one purpose, or “target” a particular pathway, may cause serious adverse events because of unrecognized “off-target effects” or unanticipated “on-target effects” within

neoplastics have the potential to produce serious side effects but also (hopefully) produce major clinical benefits. It is fitting to note that at approximately the same time that thalidomide’s impressive utility in the management of symptomatic idiopathic pulmonary fibrosis was appearing in a major peer-reviewed medical journal, thalidomide’s German manufacturer was publicly apologizing for the first time for the devastating results of aggressively marketing an inadequately tested agent for use during pregnancy.5,6 There are clearly critically important lessons to be learned here that should not be forgotten.

EDITORIAL STAFF

SALES STAFF

Kevin Horty, Group Publication Editor khorty@mcmahonmed.com

Julianna Dawson, Publication Director jdawson@mcmahonmed.com

Gabriel Miller, Managing Editor gmiller@mcmahonmed.com

David Nathanson, Account Manager dnathanson@mcmahonmed.com

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

ART AND PRODUCTION STAFF

James Prudden, Group Editorial Director

Michele McMahon Velle, Creative Director, MAX Graphics

Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

References 1. Stephen T, Bryner R. Dark Remedy. Cambridge, MA: Perseus Publishing; 2001. 2. Stolberg SG. Thalidomide approved to treat leprosy, with other uses seen. The New York Times. July 17, 1998. 3. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood. 2008; 111:3968-3977, PMID: 18245666. 4. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007; 357:2133-2142, PMID: 18032763. 5. Horton MR, Santopietro V, Mathew L, et al. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: A randomized trial. Ann Intern Med. 2012; 157:398-406, PMID: 22986377. 6. Burns JF. German drug maker apologizes to victims of thalidomide. The New York Times. September 2, 2012.

Comments or feedback on Dr. Markman’s column? Please write to Clinical Oncology News managing editor Gabriel Miller at

gmiller@mcmahonmed.com

Brandy Wilson, Circulation Coordinator Mark Neufeld, Associate Director, Project Management

MCMAHON PUBLISHING Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner

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If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

ONCOLOGYFellow S UPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS

oncologyfellowadvisor.com

advisor

ONCOLOGYFellow

Vol. 3, Issue 3

S UPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS

oncologyfellowadvisor.com Fellowship Training

Paths

A DAY IN THE LIFE

We highlight the work of fellowship director Timothy Gilligan, MD. 4 FELLOWSHIP TRAINING

Experts discuss what to expect in 6 the first year of fellowship. FELLOWSHIP TRAINING

Communication skills are crucial for oncology fellows.

is brought to you as a professional courtesy. This content is selected and controlled by McMahon Publishing and is funded by Lilly USA.

For the latest oncology fellow–related information, please visit www.oncologyfellowadvisor.com

advisor

Mentor Memos

Survey Says

Physician Finance

Top-Tier Centerss Share Tips

ospitals in the United States are anx xious to be included in the annual US News and World Rep port’s list of top hospitals. To make the 2011 to 2012 cut, cancer centers had to treat at least 254 inpatients with h highlevel expertise in 2007, 2008, and 2009 9.1 The following are the top 10 cancer centerss in US News and World Report, in ascending orrder of quality: University of Texas MD Anderson n Cancer Center, Memorial Sloan-Kettering Cancer Center (MSKCC), Johns Hopkins (JH), Mayo Clinic, Dana Farber Cancer Institute/Brig gham & Women’s Cancer Center, University of Washington Cancer Center in Seattle e, Massachusetts General Hospital, UCSF F Medical Center, Cleveland Clinic, and d Ronald Reagan UCLA Medical Center.1 Oncology Fellow Advisor spoke witth Daniel Spratt, radiation oncology trainee at Memorial Sloan-Kettering (No. 2 on the

Top-Tier page 5

Master Work–Life Balance

raining to be an oncologist can be rough. In the face of long hours, sleep deprivation, and patient suffering, young oncologists may sacrifice hobbies, interests, and even relationships. Many fellows find comfort in reminding themselves that better days are ahead but experts say that they may be setting themselves up for disappointment. Oncologists who cope by looking to the future may miss opportunities in the present to shape their career to meet their needs.1 “Putting aside one’s personal needs or personal wellness can eventually come back in a negative

or unhealthy way that can lead to burnout,” said Charles M. Balch, MD, FACS, professor of surgery in the Division of Surgical Oncology at University of Texas Southwestern Medical School in Dallas, Texas. “A successful medical career at the expense of personal wellbeing is not at all successful.” One in 3 oncologists will experience significant career burnout— described as emotional exhaustion, depersonalization, and a sense of low personal accomplishment that leads to decreased effectiveness at work.2 Some of its more tragic consequences see, Work–Life page 2

To obtain educational information for oncology fellows, please visit us online: www.oncologyfellowadvisor.com

CURRENT PRACTICE

VOGL, NY continued from page 1

afterlife and salvation of eternal souls has no place. We know that everyone will die, that death is neither pretty nor pleasant, and that most everything that happens before death is complex both in the experience and the interpretation. In nearly all that we as physicians do, we do not “save lives.” Instead, we define and resolve problems in a way that we hope may add years of good d life. For instance, if we detect on mammogram and remove a 5-mm breast cancer that is not bothering the patient, we cannot claim to have saved the life of the woman with the screen-detected breast cancer. Even if there are fewer deaths from metastatic disease 10 years later in a screened population, our single patient may well have survived anyway had her cancer been detected a year later as a palpable mass. I tried to conceive of a situation in which the “save a life” rhetoric would apply. I considered the situation of an infant falling from a high window in a moderately tall building. Catching the infant will prevent its immediate death, and if the catch is sufficiently gentle, then injury also will be prevented, and the rescued infant will presumably join the general population of similar infants enjoying the long and happy life to which most citizens of the United States like to think they are entitled. The situation is probably more complicated because someone neglected to adequately care for the infant, allowing it to fall out a window. If the rescued infant is returned to the same dangerous circumstances, then was its “life saved,” or did we just delay a tragic outcome by a few days or months? The argument is not meant to suggest that we not seek to aggressively treat curable infectious diseases or to prevent and treat trauma or bleeding. The argument suggests that many of the situations we encounter as internists treating adults and oncologists treating cancer patients are better considered in subtle quantitative terms than in terms of “lives saved.” In screening for cancer, we subject large numbers of asymptomatic subjects

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Do you have thoughts on Dr. Vogl’s commentary? Please send comments to gmiller@mcmahonmed.com

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

to some test or tests. We then evaluate the result in a subset (those with a positive test) with procedures that may be unpleasant, risky or both. We eventually decide that some radical treatment with the goal of “cure” is needed for some individuals, who have now become our patients. We hope that most of those subjected to the radical treatment actually needed it, though some raise questions like overdiagnosis by mammogram and overtreatment of most screen-detected prostate cancers. We are pleased if the patient lives a long time and dies of some other cause than the disease that we sought and treated. Superficial analyses neglect the costs in terms of money, inconvenience, loss of time and loss of function caused by the process of evaluation as well as the treatment, the morbidity and mortali-

accept the burden of comparing varying risks of impairing function and creating symptoms whose relative weight will often be unclear. Computed tomography (CT) screening for lung cancer in long-time heavy smokers reduces all-cause mortality by 7% (a substantial benefit), and begins to do so after only two to three years. This is the only cancer-screening test so far that has been shown to affect all-cause mortality in a prospective, randomized clinical trial. Although evaluating and resecting possible lung cancers causes some morbidity and mortality, the substantially greater early and large decrease in the overall death rate for the entire screened population makes this the cancer-screening test I recommend with the fewest reservations to my patients.

EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, New York City

will approach the number entered. Also, although it removes bias in assignment, it does not guarantee that another committee working on another population at a different time would assign the cause of death the same way. Looking at cancer-specific mortality as the sole end point ignores the impairment of quality of life as a result of treatment of the discovered cancer. Although

In medicine and public health, grounded in the practical and the empirical, the afterlife and salvation of eternal souls has no place. We know that everyone will die, that death is neither pretty nor pleasant, and that most everything that happens before death is complex both in the experience and the interpretation.

ty from overtreatment (some subjects with positive tests would never develop the symptomatic illness), the inaccuracy and the imprecision in attributing the cause of death, and the difficulty in determining the number of years of life added versus subtracted. More sophisticated analyses are hard to follow and very dependent on baseline assumptions. For example, when the U.S. Public Health Service Task Force on mammography wanted to decide if the test is worthwhile in women between the ages of 40 and 49 years, it commissioned six different mathematical models to determine the possible benefits. That each one showed only a tiny benefit for women younger than age 50 added to the validity of the conclusions. Our goals as physicians are to relieve and prevent suffering, to add years of functioning and years of life. This is far more subtle and nuanced than “saving lives,” and makes evaluation of cancer-screening programs more difficult and more quantitative. We are forced to

I never tell my patients who smoke heavily that a CT scan will save their lives, only that finding and treating a small lung cancer may prevent their imminent death. Smoking produces so many cancers and so much vascular disease, that a return to the general population of heavy smokers after “cure” of a screen-detected lung cancer can be considered a life prolonged, but not “saved.” Other cancer-screening tests have been judged only on “cancer-specific” mortality. Assignment of cause of death is arbitrary and inherently not reproducible. This was recognized in the American Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) Trial, in which the chart of each dead patient was analyzed by a committee blinded to screening assignment to assign a cause of death. Such review is fair and reasonable, and removes many unknown biases in the comparison of the screened and unscreened subjects, but is not practical for large trials with long follow-up because the number of dead participants

only one of two studies of prostatectomy versus observation for prostate cancer shows a modest benefit in prostate cancer–specific survival (and that appears only after 10 years), large numbers of treated patients have lifelong difficulties with potency and urinary continence as a result of radical prostatectomy or irradiation. Because of the small and uncertain benefits from detection and treatment of asymptomatic prostate cancer, and the major risks of impotence and urinary incontinence from its treatment, I routinely discourage my asymptomatic male patients from PSA testing. They usually take my advice. I always couch these discussions not in terms of finding a cancer and “saving a life,” but in terms of finding a problem where none may develop in the patient’s lifetime, of a small probable (“causespecific”) treatment benefit many years away, and in terms of the invasive nature of the evaluation and the immediate, prolonged and substantial toxicities of the treatments commonly employed.

Now Available... in Non-Hodgkin’s Lymphoma

Evolving Treatment Paradigms To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MM111” Release Date: August 22, 2012

Expiration Date: August 22, 2013

Chair

Learning Objectives

Julie M. Vose, MD, MBA

Review optimal therapy for the management of newly diagnosed and relapsed/refractory follicular lymphoma (FL) and diﬀuse large B-cell lymphoma (DLBCL), taking into consideration the heterogeneity of patient and tumor characteristics.

Neumann M. and Mildred E. Harris Professor Chief, Division of Hematology/Oncology Professor of Medicine

1 Identify the most recent data pertaining to emerging single and combination therapies for the treatment of relapsed/refractory NHL.

Nebraska Medical Center Omaha, Nebraska

Faculty

John P. Leonard, MD

2 Explain the most signiﬁcant new data on consolidation and maintenance strategies in NHL.

Myeloma

3 Describe current and emerging prognostic clinical and molecular markers to aid in treatment decision making for NHL.

Professor of Medicine

Intended Audiences

Weill Medical College of Cornell University

The intended audiences for this educational activity are hematologists, community oncologists, oncology nurses, pharmacists, and other hematology/oncology health care professionals. These professionals constitute the core audience for this initiative as they direct treatment for patients with NHL.

Clinical Director, Center for Lymphoma and

NewYork-Presbyterian Hospital New York, New York

Jonathan W. Friedberg, MD Professor of Medicine and Oncology Chief, Hematology/Oncology Division James P. Wilmot Cancer Center University of Rochester Medical Center Rochester, New York

challenges for clinicians, who must stay abreast of the new data and be prepared to incorporate emerging therapeutic strategies into their practice.

Course Format Interactive Web-based monograph

Estimated Time for Completion: 60 minutes Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Statement of Need

Method of Preparation

The incidence of NHL is increasing steadily, and new therapeutic strategies are needed; FL remains incurable, and 30% to 40% of patients with DLBCL still die from their disease. The abundance of ongoing research into therapeutic strategies for these conditions presents opportunities for improved patient outcomes as well as

To receive CME credit, participants should read the preamble, complete the pre-test, read the monograph, and complete the post-test and evaluation. A score of at least 75% (in 3 attempts) is required to complete this activity successfully. CME certiﬁcates will be issued immediately upon successful completion.

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

This activity is supported by educational grants from Genentec

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MM111”

HEMATOLOGIC DISEASE

IBRUTINIB continued from page 1

University in Columbus, who presented one of the studies. He pointed out that there are no curative therapies for CLL. “The therapies, particularly for older patients, are unacceptable and not good, due to low response, short remissions and significant toxicity, particularly with chemotherapy,” said Dr. Byrd. “Even our treatments in younger patients are associated with considerable immune suppression, so new therapies are needed.” Ibrutinib could meet this need. The drug targets Bruton tyrosine kinase, a protein crucial for allowing CLL cells to survive and grow; the majority of B-cell tumors also are dependent on Bruton for proliferation.

Ibrutinib Monotherapy The Phase Ib/II PCYC-1102-CA trial, presented by Dr. Byrd, involved 116 patients with previously untreated or relapsed/refractory CLL or small lymphocytic lymphoma. Patients were divided into three groups: treatment-naive patients aged 65 years or older (n=31), relapsed/ refractory patients (n=61) or high-risk relapsed/refractory patients (n=24). The high-risk group was defined as those having disease that progressed within 24 months of initiation of a regimen containing at least a nucleoside analog or bendamustine (Treanda, Cephalon) in combination with a mono-

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

persistent lymphocytosis. “Generally, patients felt good and didn’t care about that lymphocytosis,” said Dr. Byrd. In the relapsed/refractory group, including high-risk patients (n=85), the ORR was 71%, with 2% achieving a CR. Another 18% of patients had PRs except for persistent lymphocytosis. Dr. Byrd provided progression-free survival (PFS) and overall survival data at 26 months. The PFS was 96% in the treatment-naive group, and Dr. Byrd pointed out that the PFS in the group of patients receiving standard chemotherapy would be expected to be 50% or less. The PFS was 76% in relapsed/refractory patients and 55% in the del(17p) subset of patients. Overall survival was 96% in previously untreated patients and 85% in relapsed/refractory patients.

toxicities and 13% for grade 4 toxicities. There were no grade 4 nonhematologic toxicities, and grade 3 nonhematologic toxicities were infrequent (Table). Grade 3/4 infections were seen in 10% of treatment-naive patients and 40% of the relapsed/refractory group. “Unlike many drugs that have been used in CLL where myelosuppression and immune suppression is problematic, this was not a common toxicity seen with this medicine,” said Dr. Byrd. “Most of the side effects were grade 1

‘Most of the side effects were grade 1 or 2, were modest enough that patients could live with them and often went away after the first couple of cycles of oral therapy.’

—John Byrd, MD

Table. Grade 3 Nonhematologic Toxicities in the PCYC-1102-CA Trial Treatment-Naive, %

Relapsed/Refractory, %

Diarrhea

Hyponatremia

Enterocolitis hemorrhagic

Pneumonia

Dehydration

Cellulitis

Hypertension

Sinusitis

‘Ibrutinib in combination with rituximab or even as a single agent should rapidly be developed in high-risk CLL.’

—Jan Burger, MD, PhD

or 2, were modest enough that patients could live with them and often went away after the first couple of cycles of oral therapy.”

Rituximab Plus Ibrutinib clonal antibody, or failure to respond to such a regimen. In the treatment-naïve patients, aged 65 years or older, the overall response rate (ORR) was 68%, including 10% with a complete response (CR) and 58% with a partial response (PR). Another 13% of patients had lymph node reductions, but

Grade 3/4 hematologic toxicities, including neutropenia, anemia and thrombocytopenia, were infrequent. In the treatment-naive patients, 6% experienced grade 3 hematologic toxicities and 6% experienced grade 4 toxicities. In the relapsed/refractory and high-risk groups, these rates jumped to 13% for grade 3

In a second study, Jan Burger, MD, PhD, an associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, presented data from a Phase II study combining ibrutinib with rituximab in 40 high-risk CLL patients. Highrisk was defined as patients who had a

Expert Commentary: The Future of Ibrutinib If early promise holds, BTK inhibitor could have broad applications in CLL

he data presented at ASH 2012 suggest that the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Pharmacyclics) has profound activity in both treatment-naïve and relapsed, refractory chronic lymphocytic leukemia (CLL). Registration trials have been initiated, led by the RESONATE study, which is a randomized, open-label, Phase III study

comparing ibrutinib 420 mg per day with ofatumumab (Arzerra, GSK), given at its labeled dose and schedule (weekly for eight weeks with a 300 mg first dose and then 2,000 mg weekly, followed by 2,000 mg monthly for four months). Eligibility for this study includes previously treated CLL patients who are in need of therapy and not appropriate for

del 17p/TP53 mutation, a del11q deletion, or less than three years remission after first-line chemoimmunotherapy. With three or six months of follow-up, the ORR was 83%, with 80% achieving a PR and 3% achieving a CR. Another 8% achieved a PR with lymphocytosis. It was too early to do a response assessment in 5% of patients and 5% had no response. Similar to the monotherapy study, the toxicity profile of the combination was favorable compared with other current

purine analog–based therapy because of one of the following features: relapse within three years of the start of prior purine analog–based chemoimmunotherapy, age over 70 or 65 with comorbidities, 17p deletion, or a history of purine analog–associated autoimmune cytopenias. The estimated enrollment is 350 CLL patients. The eligibility for

therapeutic options. Dr. Burger said further study was needed to evaluate the durability of remissions and identify any long-term side effects. “Ibrutinib in combination with rituximab or even as a single agent should rapidly be developed in high-risk CLL,” said Dr. Burger. According to Claire Dearden, MD, the head of the CLL Unit at the Royal Marsden Hospital in London, who was not involved with the studies, ibrutinib is a promising agent. She said that Dr. Byrd’s study “suggests that this investigational therapy may be an effective and safe targeted treatment option for previously untreated CLL, for hard-totreat patients and for relapsed patients with CLL.” According to Dr. Dearden, the study combining rituximab and ibrutinib shows the combination is “a safe and effective option for CLL, which may be used as an alternative to current chemoimmunotherapy treatments.” —Kate O’Rourke Both studies were funded by Pharmacyclics, which is developing ibrutinib. Dr. Byrd disclosed research funding from Pharmacyclics. Dr. Burger reported consulting and research funding from Pharmacyclics. Dr. Dearden had no relevant disclosures.

EDITORIAL BOARD COMMENTARY Jennifer R. Brown, MD, PhD Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

this study suggests that, if positive, ibrutinib could receive a fairly broad label for high-risk relapsed CLL, where the

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ FEBRUARY 2013

data presented at ASH indicate significant efficacy, with a 26-month progression-free survival (PFS) of 76%. Given, however, that based on current data ibrutinib appears to be one of the most active single agents for CLL, it would seem reasonable to start testing its use much earlier in the course of the disease, perhaps for up-front therapy. The results reported at ASH from 31 treatment-naĂŻve older patients are excellent, even given that the patient population was not particularly high risk, and certainly in this patient subgroup single-agent therapy or combination therapy with an antibody is likely to be highly effective. A Phase III study has in fact been initiated to compare ibrutinib with chlorambucil in this patient population. In addition, the US cooperative groups led by the Alliance for Clinical Trials in Oncology are currently planning a randomized study of initial therapy in older patients comparing ibrutinib alone with ibrutinib plus rituximab and bendamustine plus rituximab (BR). For younger patients in whom FCR (fludarabine, cyclophosphamide and rituximab) is the current standard of care, the US cooperative groups led by the Eastern Cooperative Oncology Group (ECOG), as well as the UK group, are planning separate studies that will compare ibrutinib plus rituximab with standard FCR. These studies may demonstrate that ibrutinib with rituximab is as or more effective than chemoimmunotherapy, which may displace the latter from its current position as standard of care. To date, study designs have been primarily interested in exploring opportunities to avoid the toxicity of chemoimmunotherapy, but the possibility of combining ibrutinib with chemoimmunotherapy is also of interest given non-overlapping toxicity. A Phase 1b study reported last year at the American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) meetings has combined ibrutinib with BR and with FCR in relapsed patients, with high efficacy and good tolerability. Combinations like these may warrant further investigation in younger patients, in whom very prolonged remissions may result. The results of these studies are likely to define the eventual use of ibrutinib in clinical practice, which may well be in the up-front setting. Many other effective novel agents are also currently in development, including the PI3 kinase delta inhibitor idelalisib (formerly CAL101 or GS1101, Gilead), the antiCD20 antibody GA101 (obinutuzumab, Roche) and the BCL2 inhibitor ABT199 (Abbott), but the development of these drugs is generally a bit behind, such that studies that could be practice-changing in an up-front clinical setting have not yet been planned. The exception to this is GA101, which is being tested in the German CLL Study Group CLL11

trial comparing chlorambucil with chlorambucil plus rituximab and with chlorambucil plus GA101. This study has

this elderly patient population, however, chlorambucil will likely be displaced. Studies would then need to assess

and ongoing trials, the future landscape of CLL therapy is evolving rapidly and remains a bit unpredictable, but certain-

With all these novel therapies and ongoing trials, the future landscape of CLL therapy is evolving rapidly and remains a bit unpredictable, but certainly the explosion of new, highly effective drugs, currently led by ibrutinib, heralds very exciting developments over the next several years. the potential to demonstrate superiority for chlorambucil plus GA101 in elderly untreated patients. Given the high efficacy and tolerability of ibrutinib in

whether GA101 added substantially to ibrutinib as a single agent or improved upon rituximab in combination with ibrutinib. With all these novel therapies

ly the explosion of new highly effective drugs, currently led by ibrutinib, heralds very exciting developments over the next several years.

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

MUTATIONS Figure originally appeared in “Taking Aim at Melanoma,” The Scientist, April 2011. Reprinted with permission.

continued from page 1

Early efforts to target specific mutations in tumors have shown preliminary success. For instance, in an open-label, randomized multicenter trial, researchers showed that the KIT kinase inhibitor imatinib (Gleevec, Novartis) prompted a partial response in just over 50% of patients with a KIT mutation-positive gastrointestinal stromal tumor ((N Engl J Med d 2002;347:472-480, PMID: 12181401). More recently, a Phase I, dose-escalation trial found that the majority of patients with BRAF mutation-positive melanoma who carried the BRAF F mutation, V600E, had a partial or full response to the study drug, vemurafenib (Zelboraf, Roche), designed to target mutated BRAF (N ( Engl J Med 2010;363:809-819, PMID: 20818844). However, common solid tumors such as breast, lung and colorectal cancer

The same tumor type may behave differently in different people, which explains why a drug may be effective against breast cancer in one patient but not in another. remain difficult to treat because they may be caused by several different pathways and molecular abnormalities, not just a single aberration ((Mol Cancer Ther 2007;6:1175-1179, PMID: 17431100; Sci Transl Med 2012:4:127ps10, PMID: 22461637). In other words, the same tumor type may behave differently in different people, which explains why a drug may be effective against breast cancer in one patient but not in another. In the session, the panelists discussed efforts to uncover the abnormalities that dictate the success or failure of existing drugs, allowing clinicians to personalize treatment, as well as efforts to determine what aberrations drive tumor progression in cancers with no available drugs, allowing investigators to develop highly targeted therapies. “We’re shifting our focus to a patientbased approach, which means we want a molecular definition of an individual patient’s disease,” said Susan Galbraith, PhD, the vice president and head of Oncology Innovative Medicines at AstraZeneca in Macclesfield, England, who introduced the session. Dr. Galbraith noted that having a better molecular understanding of patients will make it possible to identify new targets for drugs, develop better preclinical disease models and personalize

treatments to patients based on who is most likely to respond. “We’re seeing that cancer is not one disease, 10 diseases or even 100 diseases; it’s thousands of diseases, and that is going to take a long time to sort out,” said Maurie Markman, MD, the senior vice president of clinical affairs and the national director for medical oncology at Cancer Treatment Centers of America in Philadelphia, who was not on the panel. “However, there’s been tremendous progress so far. The advances we’ve seen in the past five years are greater than those we’ve seen in the past 200.”

Mutations Predict Response to Therapy Understanding the mutations that sensitize patients to a particular drug is critical to improving patient care. Panelist Nigel Brooks, PhD, a senior project director of Cancer and Infection Research at AstraZeneca in Cheshire, England, discussed challenges in translating preclinical hypotheses to the clinic by comparing

that express or overexpress EGFR would make an effective therapy, and in 1995, the first selective inhibitor of EGFR, called gefitinib (Iressa, AstraZeneca and Teva), was developed to treat advanced NSCLC. However, in two Phase II IDEAL (Iressa Dose Evaluation in Advanced Lung Cancer) trials, only 19% of patients with recurrent NSCLC showed a dramatic clinical response to the drug in IDEAL 1 and 10% in IDEAL 2 ((J Clin Oncol 2003;21:2237-2246, PMID: 12748244; JAMA 2003;290:2149-2158, PMID: 14570950). However, it was striking that some specific patient subgroups responded to the drug, including women, Asians, nonsmokers and patients with adenocarcinomas ((J Clin Oncoll 2004;22:1103-1109, PMID: 15020612). To understand why the drug only helped certain patients, researchers at Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston analyzed EGFR mutations in patients with NSCLC ((N Engl J Med 2004;350:2129-2139, PMID: 15118073).

adenocarcinoma, women and nonsmokers with NSCLC. The authors concluded that mutations in EGFR predicted sensitivity to gefitinib. In the Phase III, open-label IPASS (Iressa Pan-Asia Study) trial, investigators demonstrated that East Asians with advanced lung adenocarcinoma who were either light or never-smokers derived a greater benefit from gefitinib than from standard chemotherapy if they had EGFR mutations ((N Engl J Med 2009;361:947-957, PMID: 19692680). Patients with EGFR mutations who were treated with gefitinib 250 mg daily had a higher objective response rate (71.2%) than did those who received carboplatin-paclitaxel (47.3%; P<0.001), and better progression-free survival at 12 months (hazard ratio [HR] with gefitinib, 0.48; P<0.001). In patients without EGFR mutations, the objective response rate with gefitinib was low (1.1%), and progression-free survival favored the chemotherapy group (HR with gefitinib, 2.85; P<0.001).

‘We need to dramatically change the paradigm for drug development. The idea that we should continue to do clinical trials to help a few [who] we don’t understand is not sustainable or rational and it’s got to stop. This strategy costs tens of millions of dollars per trial to give a benefit of a few weeks, maybe months.’ —Maurie Markman, MD and contrasting efforts to target epidermal growth factor receptor (EGFR), a kinase that is mutated or overexpressed in various cancers, including non-small cell lung cancer (NSCLC), and fibroblast growth factor (FGFR), which is genetically dysregulated in tumor types, including squamous NSCLC and breast cancer. Several decades ago, researchers hypothesized that targeting solid tumors

The investigators found that specific mutations in EGFR (exon 19 deletions and exon 20 mutations) were associated with clinical response to gefitinib. In particular, eight of nine patients with NSCLC who responded to gefitinib had these EGFR mutations, compared with none of the seven patients who did not respond to the drug. The mutations were observed more frequently in

The study helped confirm that ““EGFR mutations are a strong predictor of gefitinib benefit versus double chemotherapy,” concluded Dr. Brooks, who was not involved in this study. “From this evidence, we were able to develop predictive biomarkers after clinical trials. In the future, however, having predictive biomarkers before clinical trials is the ultimate goal. That way we can prospectively select

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

patients that will benefit from therapy.” Dr. Brooks then used the development of AZD4547 (AstraZeneca), a potent and selective inhibitor of FGFR1, 2 and 3, to illustrate how a compelling preclinical hypothesis that links drug response to a predictive marker (in this case, FGFR gene amplification), allowed prospective selection of patients at a much earlier stage in the drug development process. Using this logic, researchers at the University of Texas MD Anderson Cancer Center devised a hypothesis based on compelling preclinical data that suggested mutations in the PIK3CA gene predicted response to inhibitors of the phosphatidylinositol 3 kinase (PI3K)/ AKT/mammalian target of rapamycin (mTOR) pathway, which is overactive in a range of cancers ((Nat Rev Cancer 2009;9:550-562, PMID: 19629070). In a Phase I trial, PIK3CA mutations were detected in 11.5% of patients (25 of 217) with diverse solid tumors (Mol ( Cancer Ther 2011;10:558-565, PMID: 21216929). Of the 25 patients with PIK3CA mutations, 17 (68%) were treated with a PI3K/ AKT/mTOR pathway inhibitor and six (35%) achieved a partial response compared with 15 of 241 patients (6%) without PIK3CA mutations treated with the same protocols ((P=0.001). “Usually, we’re begging to find one patient who will respond in a Phase I trial, but this is remarkable. More than 30% of patients demonstrated a benefit,” said Dr. Mills. “The study shows that matching aberrations to drugs works. We see endometrial cancer shrinking, ovarian cancer shrinking.”

Nontargetable Aberrations: Drivers and Passengers Investigators also are working to identify aberrations that drive cancer but that don’t yet have drugs to target them. In his talk at NCRI, Dr. Mills focused on abnormalities along the PI3K pathway— the most common activating aberration in cancer—to determine which ones are drivers and which are passengers. To this end, Dr. Mills’ team is conducting a clearinghouse study, which encompasses nearly 30,000 new patients a year, in which all participants undergo tumor biopsies. The investigators have demonstrated that fewer than half of the patients characterized so far had actionable events, but “for the 50% of patients with no targetable aberration, we don’t know what the aberrations mean,” Dr. Mills said. Dr. Mills’ team is now conducting deep characterization of the tumors, using DNA/RNA sequencing proteomics, to find drivers. Many of the aberrations his group has characterized are turning on unpredicted pathways, which is why “we are going to have to look at life in a mutation-specific event, not a gene-specific event to have a better way to handle patients going forward,” Dr. Mills said. For instance, in a recent study, the

small cell lung cancer (SCLC), which was sensitive to standard SCLC treatments. Additionally, three patients overcame their acquired resistance once treatment ceased, and became sensitive to another round of treatment with EGFR inhibitors. The results highlighted the importance of continuing to assess cancers throughout the course of the disease. “Much research is now focused on strategies to combat secondary resistance to targeted agents,” said Timothy Yap, MBBS, a clinical research fellow at the Royal Marsden Hospital and The Institute of Cancer Research in Sutton, England. “Such approaches are likely to include the use of different combination regimens to decrease the opportunities for acquired drug resistance. The key challenge will be to establish how such novel molecular agents should be combined, and which drugs they should be given with, bearing in mind issues of toxicities and pharmacokinetic interactions.”

Future Challenges

Oncogenes and tumor suppressor genes investigators examined 243 endometrial carcinomas—a PI3K kinase–driven disease—and found that two mutations, PIK3R1 and PIK3R2, were critical drivers of endometrial cancer pathogenesis.

signaling circuitry—for instance, taking advantage of pathway redundancies—and develop acquired resistance (Cancer Biol Therr 2011;11:793-800, PMID: 21307659). “If we understand what’s driving resis-

‘For patients with a particular biomarker, only subpopulations benefit and the responses are usually short. I think that’s one of the things we forget to emphasize—we’re seeing remarkable steps forward, but they’re usually measured in months, not years and certainly not in cures.’ —Gordon Mills, MD, PhD PIK3R1 mutations occurred at a higher rate in endometrial cancer than in any other tumor lineage (20% of endometrial cancers), and PIK3R2, not previously demonstrated to be a cancer gene, was mutated in 5% of endometrial cancers (Cancer Discov 2011;1:170-185, PMID: 21984976).

Drug Resistance Understanding resistance, both intrinsic and acquired, also remains a challenge. Despite the initial response to inhibitors, such as gefitinib, most NSCLC patients relapse and develop acquired resistance, with the underlying mechanism unclear. After being exposed to chronic drug treatment, cancer cells often adapt their

tance to these pathways, we might be able to develop the right combinations of drugs to take into the clinic,” Dr. Mills said. To determine the mechanisms underlying acquired drug resistance in NSCLC, researchers from Massachusetts General Hospital Cancer Center performed systematic genetic and histologic analyses of tumor biopsies from 37 patients with drug-resistant NSCLC who carried EGFR mutations ((Sci Transl Med 2011;3:75ra26, PMID: 21430269). The investigators found that 55% of tumors developed known mechanisms of resistance. Unexpected genetic changes, such as mutations in the PIK3CA gene, occurred in 10% to 20% of tumors, and five resistant tumors (14%) turned into

As investigators embrace a personalized medicine approach to cancer care, they can glean a fuller picture of what aberrations drive cancer and how to combat them. “We can characterize the patient, tumor and tumor environment in a way we’ve never been able to do before,” Dr. Mills said. However, there are still major challenges in this area. Even after identifying relevant aberrations and useful biomarkers, the scope of this knowledge remains limited. “For patients with a particular biomarker, only subpopulations benefit and the responses are usually short,” Dr. Mills said. “I think that’s one of the things we forget to emphasize—we’re seeing remarkable steps forward, but they’re usually measured in months, not years and certainly not in cures.” Dr. Markman stressed, “We need to dramatically change the paradigm for drug development. The idea that we should continue to do clinical trials to help a few we don’t understand is not sustainable or rational and it’s got to stop. This strategy costs tens of millions of dollars per trial to give a benefit of a few weeks, maybe months.” He added: “The future of research is looking at individual patients, collecting data in these patients worldwide, making info available to doctors and insurers, and figuring out how to do this quickly and less expensively. Although there’s been lots of talk of change, I’ve seen no action yet.” —Victoria Stern Dr. Mills reported consulting for AstraZeneca and Novartis, among others; stock ownership in Catena Pharmaceuticals and Spindle Top Ventures; and research sponsored by AstraZeneca and Roche, among others.

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Expert Insights From the U.S. Oncology Network Each month, Clinical Oncology News highlights key studies from the most important journals and provides perspectives from guest clinicians at a top cancer center. Every four months, Clinical Oncology News features clinicians from a different U.S. center. We hope you find our Reviews & Commentaries section a valuable tool.

Genomic Variants Used To Further Stratify Risk in Breast Cancer From the Journal of Clinical Oncology

igh-penetrance breast cancer genes like BRCA1 or BRCA2 account for less than 25% of the incidence of familial breast cancer. Recent large genome-wide association studies (GWAS) have sought to identify variants of single nucleotide polymorphisms (SNPs) associated with the onset of breast cancer. In the general population, identification of these variants has produced only a modest increase in the discernment of breast cancer risk.

In this Australian study, 1,143 highrisk women from the Victorian Familial Breast Cancer Cohort were compared with a randomized control group of 892 women. The study participants all had high familial risk, had at least one breast cancer, and had undergone BRCA1 or BRCA2 determinations. The principal author was Sarah Sawyer of the Peter MacCallum Cancer Centre in East Melbourne. All study participants received genotyping for 22 variants. The presence or absence of these variants was noted and the results fashioned into a polygenic

EXPERT INSIGHT

Medical Oncologist and Hematologist, Virginia Cancer Specialists, Affiliate of The US Oncology Network

atients who are considered high risk based on family history or age at diagnosis currently are referred for genetic testing looking for BRCA mutations. These uncommon high-penetrance mutations represent only a fraction of all heritable breast cancer cases. Of those tested, 80% do not harbor BRCA-1 or -2 and get no useful information concerning their real risk. Considerable interest exists in trying to more fully identify individuals who are at increased risk but do not carry a BRCA mutation. Large GWA studies have been used to

controls, and BRCA and PRS were inversely correlated (P ( =2.3 × 10-6). Women with high or top-quartile PRS scores were more likely to have had early-onset breast cancer (age <30 years; odds ratio [OR], 3.37; P=0.03) and were more likely to have a second breast cancer (OR, 1.96; P=0.02). The study supports an important complement to testing for the BRCA mutation; genetic testing for specific SNPs within the subgroup of women at high risk for familial breast cancer is indicated and may well inform the clinical management of such cases.

This information could prove practically relevant to the approximately 80% of patients who are deemed high enough risk to undergo genetic testing but don’t carry a BRCA mutation.

Anne Favret, MD

risk score (PRS), differentiated into a low (bottom 25%), medium (middle 50%) or high (top 25%) score. These parameters were compared among themselves and with a control group. Results were published in the Journal of Clinical Oncology (2012;30:43304336, PMID: 23109704). Of the 1,143 high-risk participants, 142 had BRCA1 and 116 had BRCA2 mutations. These women had a highly significant excess of risk alleles compared with the unaffected controls ( =1 × 10-16). Women with BRCA muta(P tions had a low PRS compared with

identify common variants in the genome associated with increased risk for breast cancer. Unfortunately, studies performed with these common variants in the general population have failed to generate meaningful information to date. Sawyer et al. have attempted to narrow the pool by finding 1,143 index cases from individuals who attended four familial cancer clinics in Victoria, Australia, between 1997 and 2010. They proceeded to genotype 22 breast cancer–associated genomic variants on the index patients with cancer. The authors

calculated a PRS, which is the sum of the log odds ratio for each allele, and compared them in 892 control patients. They found that the PRS was predictably greater in the patients with familial breast cancer than in the controls. Interestingly, the PRS was higher in those who tested BRCA-negative. Those with a higher PRS had an earlier age of onset of their breast cancer (age <30 years), an increased risk for contralateral breast cancer and no excess in risk for ovarian cancer. This information could prove practically relevant to the approximately 80% of patients who are deemed high

enough risk to undergo genetic testing but don’t carry a BRCA mutation. These women may consider risk management options such as increased surveillance and possible bilateral mastectomies. Using breast cancer–associated common variants in patients already deemed high risk by genetic counseling may provide invaluable, useful information for those women who have strong family histories but who do not carry BRCA mutations. This is an area worth additional exploration. Dr. Favret reported no relevant financial disclosures.

Let Us Visit Your Practice Please consider inviting the staff of Clinical Oncology News s to visit your practice. We want to meet you and your colleagues, listen to your concerns and observe the physical site of your practice. You can help us improve Clinical Oncology News s and fulfill our mission—to provide evidencebased, clinically relevant information that you can use to benefit your patients and practice.

If you are interested, please contact managing editor Gabriel Miller at (212) 957-5300 ext. 265 or via email at gmiller@mcmahonmed.com

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

New TKI Ponatinib Effective in Resistant CML From The New England Journal of Medicine

utations in the BCR-ABL kinase domain have been shown to cause resistance to tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph-positive) acute lymphoblastic leukemia (ALL). Now, however, a novel oral TKI that blocks both native and mutated BCR-ABL—including T315I— has shown promising results in a Phase I clinical trial involving patients with

resistant hematologic cancers. The drug—ponatinib (Inclusig, ARIAD)—has already received FDA approval as second-line therapy for the treatment of adult patients with TKIresistant (or intolerant) chronic (CP)-, accelerated- or blast-phase CML or Phpositive ALL. The results of this important Phase I dose-escalation study were published in the November issue of The New England Journal of Medicine (2012;367:2075-2088, PMID: 23190221). For the study, a team of researchers from cancer centers across the country enrolled 81 patients with resistant

EXPERT INSIGHT Nicholas J. DiBella, MD Co-Chair, The US Oncology Network Hematology Research Committee Medical Oncologist, Rocky Mountain Cancer Centers

orge Cortes et al reported in the present study on the results of treating refractory Ph-positive leukemias with ponatinib, a new TKI that appears to be more potent and, to date, effective in TKI-resistant CML. On Dec. 14, 2012, this agent received accelerated FDA approval for the treatment of adult patients with chronic-phase, accelerated-phase or blast-phase CML that is resistant or intolerant to prior TKI therapy or for Ph-positive ALL. This is indeed welcome news for patients with CML. None of the currently available TKIs (imatinib, nilotinib, dasatinib or bosutinib) are effective

against the T315I mutation, whereas ponatinib was specifically engineered to overcome this resistance. All 12 patients with this mutation experienced a CHR, 82% experienced an MCyR and 50% had an MMR, according to updated information provided in a poster at the recent American Society of Hematology meeting in December.1 Furthermore, all patients with six other mutations had a good response to ponatinib. This agent provides another option for patients who become resistant to standard TKIs, where the only other options include interferon or allogeneic bone marrow transplantation.

hematologic cancers, including 60 with CML and five with Ph-positive ALL. The researchers, led by Jorge E. Cortes, MD, at MD Anderson Cancer Center, administered ponatinib once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks. Among the 43 patients with CMLCP, 98% had a complete hematologic response (CHR), 72% had a major cytogenetic response (MCyR), and 44% had a major molecular response (MMR). Importantly, in the 12 patients who had CML-CP with the T315I mutation, the CHR rate was 100% and the MCyR

rate was 92%. Additionally, in the 13 patients with CML-CP with no detectable mutations, the CHR rate was also 100%, whereas the MCyR rate was 62%. Finally, among the 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, the major hematologic response and MCyR rates were 36% and 32%, respectively. There were dose-limiting toxic effects associated with ponatinib therapy—most notably elevated lipase or amylase levels and pancreatitis—and common adverse events included rash, myelosuppression and constitutional symptoms.

This agent provides another option for patients who become resistant to standard TKIs, where the only other options include interferon or allogeneic bone marrow transplantation. The side effects of this new agent are similar to the other TKIs, including rash, arthralgias and thrombocytopenia. However, these patients also experienced a higher incidence of abdominal pain, pancreatitis and lipase elevation compared with other TKIs. Pancreatitis developed in 11 of 81 patients and was reported as a serious event in eight patients. Elevated levels of lipase or amylase also were noted in seven additional patients. Pancreatitis typically developed in the first two months of therapy and resolved with discontinuation of the drug in 13 of 15 patients. Rechallenge of these patients at a lower dose did not result in a recurrence of pancreatitis. Thus, the patient and the physician should be aware of this potential

complication, and the drug withheld until pancreatitis has been ruled out. At this time, ponatinib is only approved for CML following resistance or intolerance to prior TKIs, but ARIAD is now sponsoring a Phase III trial in newly diagnosed CML patients comparing this drug with imatinib. Stay tuned for these results.

Reference 1. Deininger M, Cortes J, Kantarjian H, et al. Long-term anti-leukemic activity of ponatinib in patients with Philadelphia chromosome-positive leukemia: updated results from an ongoing phase 1 study. American Society of Hematology, abstract 3743, Dec. 10, 2012. Dr. DiBella reported no relevant financial disclosures.

CURRENT PRACTICE

Tracking System Improves Care for Cancer Patients

ancer centers that participated in a performance tracking system significantly improved their adherence to key quality measures in oncologic care, according to a new study. Developed by the Commission on Cancer of the American College of Surgeons (ACS), the system also helps hospitals to track their patients’ information, which prevents medical records from getting lost, the researchers said. “Cancer care is unique in that it requires extensive coordination with providers across disciplines to ensure patients receive all of their treatments.

Patients are not only getting surgical treatment but also chemotherapy, radiation and possibly hormone therapy,” said Erica McNamara, MPH, the lead study author and a quality improvement analyst at the ACS. “Our system is built to provide an extra layer of support in the coordination of that care.” Ms. McNamara presented the findings at the American Society of Clinical Oncology’s inaugural Quality Care Symposium in December (abstract 286). The ACS’ Rapid Quality Reporting System (RQRS) provides feedback to cancer centers on individual patient

care while the patient is still undergoing oncologic treatment. Accredited cancer centers submit data about their current breast or colorectal cancer cases on a monthly or quarterly basis. The RQRS system tracks the data for adherence to five quality measures for breast and colon cancer that are endorsed by the National Quality Forum, a not-for-profit organization whose mission is to “improve the quality of American health care.” These measures, which are considered the standard of care, include radiation therapy following breast-conserving

surgery; multiadjuvant chemotherapy for hormone receptor–negative breast cancer patients; hormone therapy for hormone receptor–positive breast cancer patients; adjuvant therapy for lymph node–positive colon cancer patients; and the removal and pathologic examination of at least 12 regional lymph nodes for resected cancer. The RQRS system will send an alert to the cancer center when patients are scheduled to enter the next stage of treatment. Physicians, cancer registrars and cancer program administrators have access to the feedback. For example, a hospital will receive a color-coded alert to indicate that staff should check on a patient’s treatment status when the

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Lifestyle Affects Colon Cancer Recurrence, Progression Risk From the Journal of the National Cancer Institute

ew evidence confirms that recurrence or progression of colon cancer is affected by daily dietary choices. A Western pattern diet, characterized by high intakes of meat, fat, refined grains and sugar, has been implicated as a risk factor for colon cancer, but little is known about its role in recurrence and survival of colon cancer. Jeffrey Meyerhardt, MD, MPH, and colleagues from the Dana-Farber Cancer Institute in Boston, analyzed food intake among colon cancer patients; results were published in the Journal of the National Cancer Institute (2012;104:1702-1711,

PMID 23136358). Data was obtained by abstracting survival results and analyzing food frequency questionnaires (FFQs) completed by patients enrolled in the NCI-sponsored Cancer and Leukemia Group B (CALGB) 89803 trial. All participants in this multicenter study had stage III colon cancer with positive regional lymph nodes. Subjects had undergone a resection of the primary tumor within 56 days of completing the initial FFQ and were enrolled in chemotherapy treatment. The final sample size of 1,011 participants completed two surveys (the first upon enrollment and the second six months after completion of adjuvant therapy) that self-reported

Thomas H. Cartwright, MD Medical Oncologist and Hematologist, Ocala Oncology, an affiliate of The US Oncology Network

his study indicates that a diet with a higher glycemic load and a higher intake of carbohydrates is associated with higher risk for relapse and mortality in stage III colon cancer patients. It has been known for some time that the risk for recurrence in early-stage colorectal cancer is associated with lifestyle. The same group at Dana-Farber Cancer Institute previously reported a higher risk for cancer relapse in patients who follow a Western diet, are overweight, lack

carbohydrate intake affect colon cancer recurrence and survival. Stage III colon cancer patients in the highest quintile of glycemic load had a hazard ratio for disease-free survival of 1.79 (95% confidence interval, 1.29 to 2.48) compared with the lowest quintile (P ( <0.001). The deleterious association between diet and a disease-free state was heightened among those who were overweight or obese (body mass index ≥25 kg/m2). Similar results were seen in patients with increased glycemic load and increased total carbohydrate intake. This study offers further evidence that dietary choices may affect colon cancer recurrence or progression.

This study is consistent with the growing body of evidence suggesting that lifestyle choices are important in the risk for recurrence.

EXPERT INSIGHT

lifestyle habits and diet, in which they noted how often they consumed portions of specific foods. Researchers computed a glycemic load by multiplying the frequency and nature of carbohydrate consumption by glycemic index. The study end points were diseasefree survival, occurrence of a new primary colon tumor or death from any cause. To avoid potential bias due to declining health, results from patients with a cancer recurrence or death within 90 days of completing the FFQ were excluded. Researchers sought to determine if certain dietary features, including high glycemic load, fructose intake and

exercise and have lower vitamin D levels.1-5 This study suggested that patients with early-stage colon cancer who consumed a diet with a high carbohydrate load and high dietary glycemic load had an 80% increase in recurrence. The patients with the highest body mass index had the worst disease-free survival. This study is certainly consistent with the growing body of evidence that lifestyle choices are important, not only in the development of colon cancer,

but the risk for recurrence after diagnosis. It is now important that oncologists discuss lifestyle changes with their patients and how these may result in lower risk for colon cancer and its recurrence.

References 1. Meyerhardt JA, Heseltine D, Niedzwiecki D, et al. Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Clin Oncol. 2006;24:35353541, PMID: 16822843. 2. Meyerhardt JA, Giovannucci EL, Ogino S, et al. Physical activity and male colorectal cancer survival. Arch Intern Med. 2009;169:2102-2108, PMID: 20008694. 3. Meyerhardt JA, Giovannucci EL, Holmes MD, et al. Physical activity and

survival after colorectal cancer diagnosis. J Clin Oncol. 2006;24:3527-3534, PMID: 16822844. 4. Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA. 2007;298(7):754-764, PMID: 17699009. 5. Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: findings from Cancer and Leukemia Group B 89803. J Clin Oncol. 2008;26:4109-4115, PMID: 18757324. Dr. Cartwright reported that he is on advisory boards at Sanofi and Genentech, and is on the speakers’ bureau for Genentech.

CURRENT PRACTICE

Participants in the program said that they regularly “catch” patients who otherwise would have been missed, when the system issues an alert that the patient should have received adjuvant therapy.

RQRS does not receive a timely report confirming that a treatment decision or adjuvant therapy has been completed. Furthermore, the RQRS system provides performance rates and comparisons to other centers, based on current patients and clinical practice. Study researchers examined data from 64,129 breast and colorectal cancer patients treated between 2006 and 2010 at 64 RQRS-participating cancer programs nationally. The investigators assessed how well the cancer programs adhered to the five quality measures before and after participation in the program. Analysis of the data showed that all see RQRS TRACKING, G page 16

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Utility of Adjuvant Aspirin in CRC Now Has Biomarker From The New England Journal of Medicine

recent study points to a useful biomarker for patients with colorectal cancer who might benefit from adjuvant aspirin therapy. Previous published studies have confirmed anecdotal observations of the benefit of aspirin therapy in improving outcomes in certain cancers. Researchers in Boston and Japan analyzed data obtained from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) to determine if the regular use of aspirin had a significant effect on survival among patients with colorectal cancer.

Xiauyun Liao, PhD, and colleagues at the Dana-Farber Cancer Institute in Boston, selected 964 patients who had been diagnosed with rectal or colon cancer, reviewing data on survival, aspirin use before and after diagnosis, and tumor tissue data, including the presence of the PIK3CA mutation, present in 15%-20% of colorectal cancers. Biomarkers also were examined, including PTGS2 (i.e., cyclooxygenase-2), phosphorylated AKT, KRAS, BRAF F and microsatellite instability. Results were published in The New England Journal of Medicine (2012;367:1596-1606, PMID 23094721). Researchers hypothesized that regular aspirin use (defined as a standard

EXPERT INSIGHT Thomas H. Cartwright, MD Medical Oncologist and Hematologist, Ocala Oncology, an affiliate of The US Oncology Network

he article published by Liao, et al suggests that the regular use of aspirin after the diagnosis of colon cancer was associated with a longer survival in patients with mutated PIK3CA colon cancer. The authors hypothesized that acquired mutations of the gene

PIK3CA may influence the effect of aspirin in the adjuvant setting. There is evidence that PIK3CA mutations are frequent in colorectal cancer and that these mutations may inhibit apoptosis in colorectal cancer by activation of PTGS2 activity. The analysis found that the regular use of aspirin among

dose taken two or more times a week during most weeks) may inhibit cancer cell growth and induce apoptosis by blocking the PI3K pathway. The results showed patients with the PIK3CA mutation who took regular aspirin had an increased survival rate compared with patients with wild-type PIK3CA, regardless of whether the aspirin therapy began before or after diagnosis. In patients with the mutated PIK3CA gene who did not use aspirin, 23 of 90 died within five years of diagnosis, whereas only two of 62 died who had used aspirin ((P<0.001). These patients had significantly increased cancer-specific survival (multivariate hazard ratio [HR] for death, 0.18; 95% confidence

interval [CI], 0.06-0.61; P<0.001) and superior overall survival. Regular use of aspirin after diagnosis in patients with wild-type PIK3CA was not associated with cancer-specific survival (multivariate HR, 0.96; 95% CI; 0.691.32; P=0.076) or overall survival. The authors noted the exact mechanism that causes these results needs to be clarified and that the heterogeneous nature of colon cancers may also affect outcomes. They conclude that colorectal cancer patients with the PIK3CA mutation would derive a benefit from aspirin as an adjuvant therapy, and that the mutation might provide a useful biomarker for such therapy.

patients with mutated PIK3CA was associated with a clinically significant reduction in the overall mortality and a reduction in colorectal-specific mortality. The patients with wild-type PIK3CA did not benefit. This study is certainly interesting, especially since we have made very little progress in the adjuvant treatment in early-stage colon cancer beyond 5-fluorouracil and oxaliplatin. On the other hand, the study looked at 964 patients and only 66 patients (6.8%) with mutated PIK3CA tumors used aspirin and three of these patients (4.5%) died from colorectal cancer during the follow-up. I certainly agree that this looks promising and exciting. PIK3CA

mutations may become a useful marker in the future to guide adjuvant therapy for colorectal cancer. However, there are still unanswered questions, such as “How long should patients take aspirin for the optimum effect?” and “What is the best dose?” As we all know, there are clinically significant, but small, bleeding risks associated with aspirin use. Hopefully, these preliminary findings will be confirmed in larger prospective studies, as one in six patients with primary colorectal cancer has PIK3CA mutations. Dr. Cartwright reported that he is on advisory boards at Sanofi and Genentech, and is on the speakers’ bureau for Genentech.

CURRENT PRACTICE

RQRS TRACKING continued from page 15

five compliance rates rose considerably after hospitals joined RQRS. The greatest increase was in the number of patients who received hormone therapy for breast cancer, which grew from 47% in 2006 to 85% to 2010. Delivery of adjuvant chemotherapy for colon cancer increased 18%, from 68% to 86%, and the percentage of patients from whom 12 or more lymph nodes were retrieved rose from 70% to 90%. “This study is really noteworthy in that the development of this database significantly improved cancer care within a very short period of time,” said Jyoti Patel, MD, a thoracic oncologist and associate professor of medicine at the Feinberg School of Medicine at Northwestern University in

Chicago. “This sort of innovative feedback can provide real-time improvement in care, so it’s very exciting.” Investigators also reported that performance rates differed by patient age, race and payer status (private insurance versus Medicare), but the relative number and size of the disparities were reduced in participating programs two years after implementing the RQRS system. “The results from this analysis suggest that those differences may actually have been more of a reflection of incomplete data and information in the registries than a reflection of differences in care delivery to subpopulations of patients,” said Andrew Stewart, MA, a study coauthor and the National Cancer Database senior manager at the ACS. These measures have been the focus of significant public awareness campaigns, led by professional organizations and

the National Quality Forum, and they frequently are discussed at surgical and oncologic meetings. Officials familiar with RQRS said that the system boosts compliance with quality measures because it improves the coordination of evidence-based care among different disciplines, and it requires more complete reporting of adjuvant therapy data. Participants in the program said that they regularly “catch” patients who otherwise would have been missed, when the system issues an alert that the patient should have received adjuvant therapy. “We find that after about six to nine months of using RQRS, one-third of program participants report that they have prevented RQRS patients from slipping through the cracks or not receiving timely adjuvant care,” Ms. McNamara said.

An anonymous RQRS participant said, “We have prevented at least two patients from slipping through the cracks. The oncology providers now ask for the reports to be given to them monthly so that they can review the yellow and orange alert cases and prevent any red alerts.” The RQRS system is the only known disease-specific treatment monitoring system in the country. The program was launched nationally in September 2011, in 66 test sites that are accredited by the Commission on Cancer. Currently, there are about 400 centers using the system. The researchers are developing additional clinical measures to expand the use of RQRS to encompass adherence to quality measures for lung, stomach and esophagus cancers. —Christina Frangou

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Lapatinib Tested as Adjuvant Therapy in HER2+ Breast Cancer From The Lancet Oncology

n instances where women with HER2-positive early-stage breast cancer do not receive trastuzumab as adjuvant therapy, lapatinib might possibly be a replacement. Researchers participating in the international TEACH (Tykerb Evaluation After CHemotherapy) clinical trial compared and evaluated results of a daily dose of lapatinib, a dual tyrosine kinase inhibitor, versus placebo in women with breast cancer. Patients in this study, for a variety of reasons, did not receive a course of trastuzumab as adjuvant therapy. From 2006 to 2008, 3,147 patients

from 33 countries were assigned to either the lapatinib (n=1,571) or placebo (n=1,576) arms of the study. Participants in both groups were matched for age, ethnic origin, time since initial diagnosis, menopausal status, primary tumor stage and hormone receptor status. At enrollment, all were believed to be HER2-positive. Preliminary findings from this ongoing study were published recently in The Lancet Oncology (2013;14:88-96, PMID: 23234763); Paul E. Goss, MD, of Massachusetts General Hospital in Boston, was the principal investigator. The median follow-up in the lapatinib group was 47.4 months (range, 0.4–60.0) and in the placebo group

EXPERT INSIGHT Neelima Denduluri, MD Oncologist, Virginia Cancer Specialists, an affiliate of The US Oncology Network

he addition of trastuzumab (a monoclonal antibody targeting the HER2 receptor) to chemotherapy clearly improves disease-free and overall survival in HER2-positive early-stage breast cancer. Therefore, adjuvant chemotherapy with one year of trastuzumab is the current standard of care for HER2-positive earlystage breast cancer. Lapatinib, an oral HER1 and HER2 tyrosine kinase inhibitor, has been shown to be effective with capecitabine or trastuzumab in the advanced breast cancer setting, and is FDA-approved for advanced breast cancer. Goss et al studied the efficacy

of lapatinib in an adjuvant HER2positive early breast cancer population that did not receive trastuzumab in addition to chemotherapy. They reported that there was no significant disease-free survival benefit with the addition of lapatinib in the intent-totreat arm, but there was the suggestion of benefit in the population positive by central HER2 testing. While the study’s primary end point was negative, this study highlights three major points. Proper selection of patients for adjuvant breast cancer trials is imperative and we have moved away from the one-size-fits-all approach, highlighted by the possible

was 48.3 months (0.7–61.3). Few valid statistical associations were found in the original enrollment cohort. The authors confirmed previous reports of adverse effects: Mostly mild to moderate reactions were reported in 77 (5%) of patients taking placebo and 99 (6%) of patients taking lapatinib. Serious adverse events included grade 3-4 diarrhea in nine patients (<1%) given placebo and 97 patients (6%) given lapatinib; rash in three (<1%) versus 72 patients (5%); and hepatobiliary complications in one (<1%) versus 36 (2%) patients, respectively. Results from a quality of life survey did not differ significantly between the two groups. Overall, 97 patients (6%) in the placebo group and

92 patients (6%) in the lapatinib group died. As the study progressed, only 2,490 (79%) of all the patients in the study were confirmed as HER2-positive: 1,230 in the lapatinib group and 1,260 in the placebo group. Similar concordance discrepancies have been reported in other international, multicenter studies. The authors observed that when the subgroup of confirmed HER2-positive subjects was evaluated, there appeared to be a modest benefit in disease-free survival—especially if treatment had started within one year of diagnosis— suggesting a role for lapatinib when trastuzumab is either unavailable or impractical.

Our challenge within the breast cancer community will be to ascertain predictive markers to guide which agent should be used in which HER2-positive tumor and to determine the appropriate sequence and combination of targeted agents. disease-free survival benefit in the HER2-amplified subgroup by central review. Standardization of HER2 testing by recent ASCO-CAP guidelines has also helped us adequately select a truly HER2-positive population. Additionally, the median time to enrollment from initial diagnosis was 2.7 years, with approximately 28%29% randomized over four years since time of diagnosis. This trial may have been negative due to the time to randomization, as it could have potentially selected out those patients who already recurred and would have benefitted from adjuvant HER2-targeted

therapy. Finally, another monoclonal antibody directed against HER2, pertuzumab, has recently been approved by the FDA, and TDM1, an antibodydrug conjugate, is currently under review. Our challenge within the breast cancer community will be to ascertain predictive markers to guide which agent should be used in which HER2-positive tumor and to determine the appropriate sequence and combination of targeted agents.

Dr. Denduluri reported no financial disclosures relevant to this study.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Small Benefit for Some Metastatic CRC Patients With Regorafenib From The Lancet Oncology

here is a critical and urgent need for new colorectal cancer treatments. More than 600,000 patients worldwide die each year from the disease, and 1.25 million new cases are diagnosed annually. Despite the available chemotherapeutic and surgical treatments, a sizeable pool of patients exhausts all therapeutic options while the cancer metastasizes. The CORRECT trial was initiated to evaluate the efficacy of regorafenib (Stivarga, Bayer) in extending the lives of these patients. Regorafenib is

an oral multikinase inhibitor that has shown promise with other cancers; it affects the regulation of tumor angiogenesis (VEGFR 1, 2 and 3), oncogenesis (KIT, RAF and BRAF) and the tumor microenvironment (PDGFR and FGFR). Between April 2010 and March 2011, a multinational Phase III trial was launched in which eligible patients were randomized 2:1 into regorafenib and placebo groups. To be eligible, patients required cytologic or histologic proof of adenocarcinoma of the colon or rectum and must have completed standard therapy but

Thomas H. Cartwright, MD Medical Oncologist and Hematologist, Ocala Oncology, an affiliate of The US Oncology Network

he FDA approved regorafenib on Feb. 27, 2012, based on the CORRECT trial. This was a large, international, multicenter, randomized, placebo-controlled, Phase III trial looking at regorafenib as monotherapy versus placebo in heavily pretreated metastatic colorectal cancer. There is certainly an unmet therapeutic need

that led to dose interruption or modification; some treatment-related adverse effects were noted in 93% of the regorafenib group and 61% of the placebo group. The regorafenib group had a median overall survival of 6.4 months versus 5.0 in the placebo group (hazard ratio, 0.77; 95% confidence interval, 0.64-0.94; P=0.0052). This was a small but significant result. Further analyses of the data and subject biomarkers may identify subgroups for which this therapy may lead to a life-extending option following completion of standard treatments.

Hopefully, in the next few years, biomarkers will help identify the subset of patients who are most likely to benefit from regorafenib monotherapy.

EXPERT INSIGHT

progressed within three months after the last administration (or to have stopped standard therapy because of adverse toxic effects). Patients had an ECOG performance score of 0 or 1, life expectancy of 3 or more months, and adequate clinical parameters. The regorafenib group was comprised of 500 patients and the placebo group of 253. The primary end point was overall survival. Results of this trial, published in The Lancet Oncology (2013;381:303312), revealed that 67% of patients in the regorafenib group and 23% in the placebo group suffered adverse effects

for patients who have failed standard chemotherapy regimens for colorectal cancer, as this rapidly accruing trial demonstrated. The improvement in overall survival was modest, at just 1.4 months. The progression-free survival only increased from 1.7 to 1.9 months; however, the hazard ratio was 0.49 for

progression-free survival, indicating a 51% reduction in the risk for progression. This likely is the result of a subset of patients achieving a significant benefit from the drug. Many patients in the regorafenib group required dose reductions or delays due to adverse events. The main adverse events were: fatigue, diarrhea, hypertension and elevated liver enzymes. These adverse events are similar to what is seen with sorafenib. Sorafenib has been approved for some time and many GI oncologists have learned to use this drug successfully.

Hopefully, in the next few years, biomarkers will help identify the subset of patients who are most likely to benefit from regorafenib monotherapy. This will allow us to better select patients who will benefit from this new therapy and also possibly to incorporate the drug in combination therapy and in earlier lines of therapy. Dr. Cartwright reported that he is on advisory boards at Sanofi and Genentech, and is on the speakers’ bureau for Genentech.

CURRENT PRACTICE

Memantine Alleviates Cognitive Dysfunction From Radiation Boston—Memantine can help minimize cognitive dysfunction associated with whole-brain radiotherapy (WBRT), according to a Phase III, randomized, double-blind, placebo-controlled trial by the Radiation Therapy Oncology Group (RTOG). Based on this study, some clinicians are now recommending memantine for their patients. According to Nadia Laack, MD, a radiation oncologist at the Mayo Clinic in Rochester, Minn., 60% of patients undergoing WBRT experience declines in more than one cognitive domain four months after therapy. Dr. Laack presented the study at the annual meeting of the American Society for Radiation Oncology (abstract 2). Memantine, an open blocker of the N-methyl-D-aspartic acid, or NMDA, receptor, is FDA-approved to improve

cognition in patients with mild to moderate vascular and Alzheimer’s dementia. The RTOG 0614 trial randomized 508 patients with brain metastases to receive a 24-week course of place-

cognitive decline at 24 weeks ((P=0.01), as assessed by the Hopkins Verbal Learning Test, which was the primary end point. This improvement was sustained even after memantine was

Some clinicians are now recommending memantine, an NMDA receptor antagonist, for radiotherapyassociated cognitive dysfunction. bo or 20 mg memantine daily, started within three days of initiating WBRT of 37.5 Gy in 15 fractions. Patient characteristics were well balanced in the two arms, and 70% had non-small cell lung cancer. Compared with patients in the placebo group, patients receiving memantine experienced a 17% relative reduction in

stopped. Results of the Controlled Oral Word Association test at eight and 16 weeks and the Trail Making Test Part A at 24 weeks also demonstrated that fewer patients in the memantine group experienced cognitive decline. Furthermore, there were reduced declines in memory, cognitive executive and global function as well as processing speed

( <0.01). There were no differences in (P toxicities or survival between the two treatment arms. “The effect, although modest, demonstrates that cognitive deterioration in brain metastases patients can be prevented,” said Vinai Gondi, MD, the associate director of research at the CDH Proton Center in Warrenville, Ill., and a clinical assistant professor at the University of Wisconsin in Madison. “Should we be recommending memantine for our brain metastases patients? I would say yes. [This trial] 0614 clearly demonstrates that memantine is well tolerated and associated with a modest cognitive benefit.” —Kate O’Rourke Drs. Laack and Gondi have no relevant disclosures.

Now Available...

Individualizing Therapy in Metastatic Breast Cancer To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MM112” Release Date: October 22, 2012

Expiration Date: October 22, 2013

Chair

Learning Objectives

Linda T. Vahdat, MD

1 Appraise recent studies that may have clinically important therapy implications for patients with locally recurrent breast cancer or metastatic breast cancer (MBC).

Associate Professor of Clinical Medicine NewYork Presbyterian Hospital Weill Cornell Medical Center New York, New York

Faculty

Adam Brufsky, MD, PhD Assistant Professor of Medicine University of Pittsburgh School of Medicine Co-Director, Comprehensive Breast Cancer Center Medical Director, Women’s Cancer Center Magee Womens Hospital/UPCI Pittsburgh, Pennsylvania

William J. Gradishar, MD Professor of Medicine Division of Hematology and Medical Oncology Department of Medicine Feinberg School of Medicine Northwestern University Chicago, Illinois

in integrating this potentially practice-changing data. For these reasons, oncologists require education on clinically relevant recent studies, against a backdrop of evidence- and consensus-based treatment recommendations.

2 Describe a treatment algorithm that reﬂects evidence-based management of advanced HER2-negative and HER2-positive breast tumors and novel strategies for circumventing treatment resistance.

Course Format

3 Explain core guideline-recommended approaches to MBC management that take into consideration the heterogeneity of patient and tumor characteristics.

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

4 Compare the mechanisms, synergies, and evolving roles of current and emerging targeted therapies with activity in MBC, particularly in terms of novel combinations and sequences.

Intended Audiences Oncologists

Statement of Need Complexities in the management of MBC are substantial, and the optimal approach to therapy remains unclear. Toxicity, resistance, and hypersensitivity reactions limit the use of cytotoxic drugs in mainstay treatment regimens, and improved therapeutic options are needed for this heterogeneous disease. There are encouraging data on novel treatment approaches, including combinations and sequencing regimens, but clinicians face challenges

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

Interactive Web-based monograph

Estimated Time for Completion: 60 minutes Accreditation Statement

Method of Preparation To receive CME credit, participants should read the preamble, complete the pre-test, view the program, and complete the post-test and evaluation. A score of at least 75% is required to complete this activity successfully. CME certiﬁcates will be issued immediately upon successful completion. This activity is supported by educational grants from Genentech, Inc

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MM112”

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Nationwide Cancer Programs Begin To Take Effect Montreal—Nearly 15 years ago, in 1998, the Tobacco Master Settlement Agreement sounded what anti-tobacco activists hoped would be the death knell for Big Tobacco in the United States. Over four decades, more than 800 claims had been brought against tobacco companies in state courts throughout the country. Overwhelmingly, they did not result in change. The 1998 settlement, between the four largest U.S. tobacco companies and the attorneys general of 46 states, not only systematically began to dismantle Big Tobacco’s influence in government, but also ordered the payment of a minimum of $206 billion to state governments over the first 25 years of the agreement. The payments, many of them directed to tobacco-farming states with high smoking rates, are now beginning to have a local impact. For example, in Indiana, smoking among adults decreased by 23% from 2001 to 2010 and per capita cigarette consumption decreased by 41% between 2000 and 2010, from 121.4 to 71.7 packs per year. Similarly, smoking rates among high school students decreased by 45%, falling from 31.6% to 17.5%, over the same 10-year period. These grassroots anticancer efforts are part of the much larger Centers for Disease Control and Prevention’s (CDC) National Comprehensive Cancer Control Program (NCCCP), which seeks to organize state anticancer efforts. Now,

cancer control plans exist in n every state in the nation— many of them either started or given new life with tobacco money—and 13 states have moved on to creating cancer policy plans that will set the stage for continuous improvements in the years to come. At a symposium on national cancer control strategies at the 2012 World Cancer Congress, Marcus Plescia, MD, MPH, director of the CDC’s Division of Cancer Prevention and Control, described the progress in creating coalitions of national, state and local groups to make significant progress in combating cancer. “There are a lot of things that we look to other countries for, like cancer screening. But I would say that development of these cancer coalitions and use of a large organizational framework to affect policy—there’s not a lot of international examples that I’m aware of,” Dr. Plescia said. “The CDC is uniquely situated in the U.S. to manage such a program because its mission and strategies are multidimensional—science/research to implementation, program to policy development, data collection to analysis to prioritization, and public health advice

to services,” said epidemiologgist Norma Kanarek, PhD, MPH, an associate professor of environmenttal health sciences and oncology at Johns Hopkins University, in Baltimore, in an email to Clinical Oncology News. Dr. Kanarek added that collection of cancer incidence data across the country was an early and central part of the NCCCP. “Statelevel and sometimes local data are now leveraged to raise awareness, program effectively, create efficacious policies and track changes in population health. Local data seem to be more relevant to every audience.”

State Cancer Control Programs And Policy Plans The NCCCP was established in 1998, and by 2010 every area of the country had implemented a cancer control plan. Statewide coalitions are brought together under the guidance of the NCCCP to create, implement and evaluate these data-driven cancer control plans, which cover every aspect of cancer from prevention to survivorship. “Creating a state cancer plan is a major accomplishment, and it’s based on a significant infrastructure that’s created in

‘Creating a state cancer plan is a major accomplishment and it’s based on a significant infrastructure that’s created in each state. The next step is for each state to actually implement these plans—that’s where the real challenge comes in, because these plans are very ambitious.’ —Marcus Plescia, MD, MPH

1 Measure

2 Plan

3 Act

4 Measure

Registry data Other data

Health care provider data Community data

Health care provider data Other data

Registry data Other data

Figure. The Kentucky Cancer Program’s four-step model for reducing morbidity and mortality from cancer. Source: Redmond J. Kentucky Cancer Consortium. Using cancer epidemiology data for comprehensive cancer control planning, implementation, and evaluation. http://www.kycancerc.org/docsandpubs/Redmond_KCC%20poster_CDC%20Ca%20Conference_Final.pdf.

each state,” said Dr. Plescia. “The next step is for each state to actually implement these plans. That’s where the real challenge comes in, because these plans are very ambitious.” Results already are coming in from the cancer control plans that are in place. For example, data presented at the recent 2012 CDC Cancer Conference indicated that colon cancer screening rates in Kentucky are now 63.7% of people over age 50 years; colon cancer mortality had fallen to 57.1 per 100,000 people by 2006; and mortality dropped to 18.9%. Thirteen states received grants in 2010 from the CDC to take the next step: Develop a five-year strategy focusing on primary, secondary or tertiary prevention. Most state programs are focusing on risk factors for two of the most common cancers in the country: lung and colorectal. Program success will be evaluated next year, with the goal of taking lessons learned from these state programs and disseminating them at low cost across the entire United States. In Utah, for example, the CDC-supported cancer control coalition is looking at policy approaches to reduce radon exposure in homes. Coalitions in Massachusetts and Kentucky are moving toward making their states smoke-free. “What we find is a lot of people do not realize that we now know there’s no safe level of secondhand smoke,” said Jennifer Redmond, DrPH, an assistant professor of public health at the University of Kentucky, Lexington, and the program director of the Kentucky Cancer Consortium, the state’s comprehensive cancer control coalition (Figure). “We do not advocate for specific policy changes because our funding comes from the CDC; [instead] we focus on educating communities, organizations, businesses and others on the scientific evidence related to the negative health effects and increased cancer risk associated with exposure to secondhand smoke.” “We have already almost completed implementation of the first two policy agenda items that are tobacco-related, which are support and education around banning the sale of tobacco products in local pharmacies and implementing smoke-free perimeters in the largest hospital system in southeast Massachusetts,” said Cheryl Bartlett, RN, the director of the Bureau of Community Health and Prevention at the Massachusetts Department of Public Health, and the director of the Massachusetts Comprehensive Cancer Prevention and Control Program. —Rosemary Frei, MSc None of the sources have relevant conflicts of interest to disclose.

Now Available... on Breast and Ovarian Cancers

Integrating Data, Improving Outcomes To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN122” Release Date: October 22, 2012

Chair

Stefan Glück, MD, PhD, FRCPS Sylvester Professor, Department of Medicine Division of Hematology/Oncology Sylvester Comprehensive Cancer Center Leonard M. Miller School of Medicine University of Miami Miami, Florida

Expiration Date: October 22, 2013

Faculty

Learning Objectives

Course Format

Ruth O’Regan, MD

1 Identify recent major findings in breast and ovarian cancer research. 2 Describe how recent findings may affect screening, diagnosis, and the use of biomarkers in breast and ovarian cancer. 3 Discuss the implications of recent research for clinical practice in treating breast and ovarian cancer.

Interactive Web-based monograph

Professor and Vice Chair for Education Department of Hematology/Medical Oncology Chief of Hematology/Medical Oncology Georgia Cancer Center for Excellence Grady Memorial Hospital Director, Hematology Oncology Fellowship Emory University Chair, Louisa and Rand Glenn Family Breast Cancer Research Director, Emory Breast Center Atlanta, Georgia

Robert A. Burger, MD Professor of Medicine and Oncology Professor, Surgical Oncology Section of Gynecologic Oncology Director, Women’s Cancer Center Fox Chase Cancer Center Philadelphia, Pennsylvania

Samer I. Schuman, MD, FACS, FACOG Assistant Professor, Obstetrics and Gynecology Associate Director, Gynecologic Oncology Fellowship Sylvester Comprehensive Cancer Center Leonard M. Miller School of Medicine University of Miami Miami, Florida

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

Intended Audiences Oncologists

Statement of Need Cancer is the second leading cause of death. Among women, breast and ovarian cancers are particularly common and have high mortality rates. Clinical needs have been identified in the management of patients with these conditions, including the difficulty of translating the constant flow of newly presented data into daily physician practice; the quantity of information being released each year is considerably greater than the clinician can readily absorb. To close these gaps, education is needed in reviewing the most important research in breast and ovarian cancers and clarifying how the new findings may improve screening, diagnosis, and treatment.

Estimated Time for Completion 90 minutes

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this enduring activity for a maximum of 1.5 AMA PRA Category 1 Credits™. s Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Method of Preparation To receive CME credit, participants should read the preamble, complete the pre-test, read the monograph, and complete the post-test and evaluation. A score of at least 75% is required to complete this activity successfully. CME certiﬁcates will be issued immediately upon successful completion.

This activity is supported by educational grants from Genentech, Inc.

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN122”

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Combining MEK, BRAF Inhibitors in Melanoma For metastatic disease, combo could be future standard of care Vienna, Austria—Mounting evidence shows that combining a MEK inhibitor and a BRAF inhibitor could be the future standard of care for metastatic melanoma. The dual-blockade strategy was supported by two studies that tested two different combinations, both reported at the annual meeting of the European Society for Medical Oncology (ESMO). “I think we are now convinced that the combination of a BRAF inhibitor plus a MEK inhibitor will be the first choice for BRAF-mutated patients in the near future,” said melanoma expert Reinhard Dummer, MD, an oncologist with the Department of Dermatology at University Hospital in Zurich, Switzerland, who was not involved with either study. Approximately 50% of melanoma patients have a BRAF F mutation. In August 2011, the FDA approved the BRAF inhibitor vemurafenib (Zelboraf, HoffmanLa Roche) for patients with unresectable or metastatic melanoma with the BRAF V600 mutation. Although the oral drug has provided a new therapeutic option, the majority of patients develop resistance within five to seven months. Because MEK inhibitors interfere with the same MAP kinase pathway as BRAF inhibition, but later in the pathway, researchers decided to test the effectiveness of dual blockade. In a Phase II study (LBA27), investigators randomized 162 BRAF V600-mutant metastatic melanoma patients in a 1:1:1 fashion to receive dabrafenib 150 mg twice daily, dabrafenib plus once-daily 1-mg trametinib, or dabrafenib plus oncedaily 2-mg trametinib. Progression-free survival (PFS), the primary end point, was 5.8 months in the monotherapy arm, 9.2 months in patients receiving 1-mg trametinib (P ( =0.005), and 9.4 months in patients receiving 2-mg trametinib ( <0.0001). The response rate was 76% (P in the full-dose trametinib arm and 54% in the monotherapy arm (P ( =0.026). No patients in the full-dose combination arm had progressive disease compared with 6% in the monotherapy arm. “The landmark 12-month overall survival in the full combination group was 79%. We have never, ever seen a 12-month survival of that level in metastatic melanoma to date,” said Georgina Long, MD,

Table. Comparison of Selected Adverse Events Dabrafenib Monotherapy, %

Dabrafenib + 2 mg Trametinib, %

Skin papilloma

Hyperkeratosis

Squamous cell carcinoma/ keratoacanthoma

Acneiform rash

Peripheral edema

Reduced ejection fraction

Alopecia

Clinicians will have to wait to see if the early data pans out in Phase III trials and how much this dual therapy is going to cost.

Phase II results presented at the European Society for Medical Oncology (ESMO) 2012 Congress showed a 3.6-month improvement in progression-free survival for patients receiving both the BRAF inhibitor dabrafenib and trametinib, a MEK inhibitor, compared with those receiving dabrafenib alone.

‘The landmark 12-month overall survival in the full combination group was 79%. We have never, ever seen a 12-month survival of that level in metastatic melanoma to date.’ —Georgina Long, MD a medical oncologist at Westmead Hospital and Melanoma Institute Australia at the University of Sydney in Australia, who presented the study.

The most common grade 3/4 adverse event (AE) in the full-dose combination group was neutropenia (11%), with one patient developing febrile neutropenia.

Several AEs, such as alopecia and squamous cell carcinoma, were decreased in the combination arm compared with the monotherapy arm (Table). Dr. Long said a biological rationale supports these reductions. The full-dose combination arm had higher rates of pyrexia (67% vs. 23%), nausea (33% vs. 17%), vomiting (35% vs. 11%), fatigue (45% vs. 34%) and diarrhea (31% vs. 23%). The study results were published simultaneously online in The New England Journal of Medicine [Epub ahead of print, PMID: 23020132]. In August, GlaxoSmithKline submitted new drug applications seeking approval of each drug for use as a single agent in patients with BRAF-mutant metastatic melanoma. In a Phase IB study presented at the ESMO meeting (LBA28), the combination of vemurafenib (Zelboraf, Hoffman-LaRoche) and GDC-0973 (Exelixis) shrank melanoma tumors from 25% to 60%. PFS data was not yet mature. All patients in the study, all of whom had unresectable or metastatic BRAF V600 melanoma mutations, responded to the drug. “Every patient responded. I have never seen something like this,” said Dr. Dummer. Clinicians will have to wait to see if the early data pans out in Phase III trials and how much this dual therapy is going to cost. Two Phase III trials testing combination dabrafenib and trametinib are currently recruiting patients with BRAF V600-mutant metastatic cutaneous melanoma. COMBI-d (Combination of MEK and BRAF Inhibitors versus dabrafenib) will continue to evaluate whether trametinib plus dabrafenib is better than dabrafenib alone. COMBI-v (Combination of MEK and BRAF Inhibitors versus vemurafenib) will compare dabrafenib plus trametinib with vemurafenib. —Kate O’Rourke

Dr. Long is a consultant advisor to Amgen, Bristol-Myers Squibb (BMS), GlaxoSmithKline (GSK) and Roche, and her institution received research support from Roche. Dr. Dummer has received consulting fees and research grants from AstraZeneca, Bayer, BMS, Cephalon, Genta, GSK, Merck, Novartis, Roche, Spirig and Transgene.

Send us your news Clinical Oncology News appreciates news tips and suggestions for coverage from readers. All submissions will be considered for publication. Write to managing editor Gabriel Miller at

gmiller@mcmahonmed.com

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

New Antiandrogen Drug ODM-201 Promising Very early data; unclear whether ODM-201 will be superior to other drugs in class Vienna, Austria—Twelve weeks after receiving the investigational agent ODM-201 (Orion), all patients with metastatic castration-resistant prostate cancer (mCRPC) in a Phase I/II trial had a partial response or stable disease. The drug is a second-generation androgen receptor antagonist. “These results are better than the historical data with enzalutamide [Xtandi, Medivation] or abiraterone [Zytiga, Janssen],” said Christophe Massard, MD, PhD, of Gustave Roussy Institute in Villejuif, France. He reported the findings at the annual meeting of the European Society for Medical Oncology (abstract LBA25). The ARADES trial was a nonrandomized, uncontrolled multiple-dose escalation study with a randomized Phase II expansion component. The study accrued 21 patients with progressive mCRPC. Of the 18 patients evaluable for response at 12 weeks, researchers identified partial response or stable disease in soft tissue

by RECIST (Response Evaluation Criteria in Solid Tumors) in all patients, and stable disease in bone in 90%. There was a 50% decrease in prostate-specific antigen (PSA) in 90% of chemotherapy-naive patients and a 75% decrease in patients who had received chemotherapy. The study planned to enroll three to six patients per dose-escalation cohort on the preplanned doses of 100, 200, 300, 500, 700 and 900 mg twice daily. Once the safety of an administered dose was established, the next dose level was given, and patients at the previous dose level were allowed to continue treatment until progression or an intolerable adverse event occurred. At press time, the dose-escalation portion of the study was still ongoing at 700 mg twice daily. Dr. Massard said that unlike conventional antiandrogens such as bicalutamide, ODM-201 does not cross the blood–brain barrier or lead to increases in testosterone in animal models.

by the

Figure. Approval speed: FDA vs. European Medicines Agency, 2011-2012.

numbers

Source: Courtesy of Jean-Charles Soria, MD, PhD, the Institut Gustave-Roussy

‘These results are better than the historical data with enzalutamide or abiraterone.’ —Christophe Massard, MD, PhD According to Oliver Sartor, MD, the medical director of Tulane Cancer Center in New Orleans, who was not involved with the study, more research is needed and it is unclear whether ODM201 is superior to drugs already available. “I am impressed with the data but

Patients in the United States have faster access to new oncology drugs than patients in Europe. In the past two years, the FDA has consistently approved cancer drugs earlier than the European Medicines Agency, with only two exceptions: everolimus for breast cancer

cannot say it is better than expected for this class of drugs,” he said. Dr. Sartor pointed out that enzalutamide, recently FDA-approved, and ARN-509 (Aragon) block the androgen receptor with little or no agonist activity. “Much more data will be needed to ensure the safety of this interesting compound,” said Dr. Sartor. “In addition to safety, we will need to determine how much cross-resistance occurs between this new drug, and others in this class, to assess the potential added value of ODM-201.” —Kate O’Rourke Dr. Massard disclosed relationships with Orion and Endo. Dr. Sartor has consulted for and received grant/research support from Algeta ASA, Bayer, Exelixis, Johnson & Johnson, Sanofi and Takeda; consulted for Amgen, Bellicum, Bristol-Myers Squibb, Celgene, Dendreon, GlaxoSmithKline, Medivation and OncoGenex; and received grant/research support from AstraZeneca and Cougar Biotechnology, Inc.

and sunitinib for pancreatic neuroendocrine tumors. This chart was created by Jean-Charles Soria, MD, PhD, a medical oncologist at Gustave Roussy Cancer Institute, in Villejuif, France. He presented it at the European Society for Medical Oncology meeting.

Ipilimumab Vandetanib Abiraterone Everolimus Sunitinib Vemurafenib Cancer Type Crizotinib*

Thyroid

Denosumab*

Primitive Neuroectodermal Tumors Lung

Axitinib

Bone

Vismodegib*

Skin

Pazopanib

Sarcoma

Pertuzumab*

Breast

Everolimus

Genitourinary

Aflibercept*

Months

Early EMA approval

* Pending

Early FDA approval

Months

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Radiation Boosts Survival in Elderly Breast Cancer Patients Boston—An analysis of data from roughly 30,000 elderly women with early-stage breast cancer has concluded that adding radiation to lumpectomy improves breast cancer–specific survival by roughly 2% at 10 years. “The improvement in cause-specific breast cancer survival with the addition of radiation suggests that in healthy, elderly women, adjuvant radiation should be strongly considered as part of their breast cancer treatment,” said Randi Cohen, MD, an assistant professor at the University of Maryland School of Medicine, Baltimore. She presented the study at the annual meeting of the American Society for Radiation Oncology (abstract 82). In 2004, the Cancer and Leukemia Group B 9343 trial of 636 women, aged 70 and older, with early breast cancer showed that adding radiation to lumpectomy and tamoxifen reduced the risk for cancer returning in the breast but did not affect survival ((N Engl J Med 2004;351:971-977, PMID: 15342805). Another randomized trial of 769 women, aged 50 years or older, with early breast cancer assigned to

receive tamoxifen with or without radiation came to a similar conclusion ((N Engl J Med 2004;351:963-970, PMID: 15342804). Based on these studies, the National Comprehensive Cancer Network (NCCN) amended its clinical practice guidelines to reflect that omitting radiation is a reasonable alternative in elderly patients with early-stage breast cancer. In the new study, researchers

evaluated the records of 29,949 women from the Surveillance, Epidemiology and End Results database between 1990 and 2008, aged 70 to 84 years, who were diagnosed with clinical stage I, estrogen receptor–positive breast cancer who underwent lumpectomy with or without adjuvant radiotherapy. In the study, 76% received radiation. Patients who received radiation had improved breast cancer–specific survival at five years

AT A GLANCE Adding radiation improves breast cancer–specific survival for elderly women with early-stage breast cancer The SEER database study challenges two smaller, prospective randomized trials Fewer of these women have been receiving radiation since the NCCN altered treatment guidelines in 2004 The 2% increase in cancer-specific survival at 10 years may be considered clinically significant

(98.3% vs. 97.4%) and at 10 years (95.5% vs. 93.3%; hazard ratio, 1.41; P<0.0001). Mariam Korah, MD, a radiation oncologist at the University of Southern California Keck School of Medicine in Los Angeles, who was not involved with the study, pointed out that after the 2004 clinical trials that spurred the NCCN to change its guidelines, the proportion of elderly patients with early-stage breast cancer receiving radiation declined. The percentage of women receiving radiation declined from 72.1% in 2000-2004 to 66.6% in 2005-2009. “The randomized controlled trials [in 2004] with the small absolute numbers of deaths or deaths due to breast cancer were underpowered to detect significant differences in these end points,” said Dr. Korah. “The large number of patients and breast cancer–specific events in the current trial were able to highlight clinically meaningful survival differences between treatment groups.” —Kate O’Rourke Drs. Cohen and Korah have no relevant disclosures.

Doxepin Reduces Mucositis Pain Boston—A large clinical trial has shown that doxepin rinse reduces mucositis pain in patients with head and neck cancer who are receiving radiotherapy. Robert Miller, MD, a professor of radiation oncology at Mayo Clinic in Rochester, Minn., said the study provides a new standard for treatment of radiotherapy-induced oral mucositis. He presented the study at the annual meeting of the American Society for Radiation Oncology (abstract LBA2). Doxepin is a tricyclic antidepressant approved for depression/anxiety and moderate pruritus. The Alliance for Clinical Trials in Oncology launched the N09C6 trial, a double-blind, Phase III randomized controlled trial, after a small study suggested doxepin reduces mucositis pain in patients with cancer ((J Pain Symptom Manage 2007;33:111-114, PMID: 17280915). The study enrolled 155 adults with head and neck cancer from 26 institutions. Patients were eligible if they had received radiation therapy, in which at least 30% of the oral cavity was treated, and had developed mucositis pain of at least a 4 on a scale of 0 to 10. Patients received a single dose of doxepin, 25 mg of the drug in 5 mL of water, or a placebo of water on day 1 of the study. On day 2, patients crossed over to receive the

opposite agent. Roughly 80% of patients received concurrent chemotherapy and baseline patient characteristics were balanced in the two arms. Pain was assessed on a scale of 1 to 10 via a questionnaire that was completed at baseline and then at five, 10, 30, 60, 120, and 240 minutes post-baseline. The primary study end point was total pain reduction as calculated by average patient reported mouth and throat pain over time on day 1, measured over the four-hour period after drug administration. Doxepin was more effective at reducing pain (area under the curve reduction –9.1 vs. –4.7; P=0.0003). On average, over time doxepin reduced a

patient’s pain score by 2 points, whereas placebo only reduced the score by 1 point. Patients receiving doxepin reported a temporary burning and stinging, an unpleasant taste and a mild increase in drowsiness, but the agent was Mucositis is commonly seen in high-dose well tolerated. After the chemotherapy protocols. double-blind, crossover portion of the study, 64% Oncology at the University of Wisconof patients opted to continue using dox- sin, who was not involved with the study, said, “There are many institutional reciepin ((P=0.002). Paul Harari, MD, the Jack Fowl- pes for head and neck cancer symptom er Professor and Chairman of Human treatment, but relatively limited rigorous clinical trial data.” Before calling doxepin a new standard of care, however, he said further study AT A GLANCE was warranted to evaluate whether Doxepin is a tricyclic antidepressant used to treat depression the transient 1-point reduction in pain score over placebo (on a 10-point scale) and anxiety justified the introduction of a new class The drug likely reduces mucositis pain by interacting locally of agent for these patients or whether with nerves in the oral cavity a slight adjustment in pain medication or numbing rinse might achieve the A high percentage of head and neck cancer patients treated same effect. with radiation develop oral mucositis; however, options are —Kate O’Rourke

limited beyond narcotics and lidocaine

Investigators recommend doxepin as a new standard of care

Dr. Miller disclosed scientific advisory board involvement with Tekcapital Limited. Dr. Harari had no relevant disclosures.

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Second-Line mRCC: mTOR Inhibitor or Another TKI? Fleshing out the treatment algorithm for mRCC Vienna, Austria—After patients with metastatic renal cell carcinoma (mRCC) fail first-line therapy with a tyrosine kinase inhibitor (TKI), should clinicians switch to an mTOR inhibitor or try another TKI? This is one of the major questions facing oncologists who treat kidney cancer. New data presented at the annual meeting of the European Society for Medical Oncology (abstract 794) is prompting some clinicians to choose another TKI. The Phase III INTORSECT (Investigation of Torisel and Avastin Combination Therapy) trial demonstrated that second-line use of sorafenib (Nexavar, Bayer), a vascular endothelial growth factor (VEGF) TKI, improved survival in mRCC compared with temsirolimus (Torisel, Pfizer), an mTOR (mammalian target of rapamycin) inhibitor. “In second-line, the Phase III trial on temsirolimus versus sorafenib supports the sequence of a TKI followed by a TKI, rather than TKI followed by an mTOR inhibitor,” said Manuela Schmidinger, MD, a senior physician in the Clinical Division of Oncology at the Medical University of Vienna, who was not involved with the study.

Guidelines from the National Comprehensive Cancer Network list two agents supported by level 1 evidence for patients progressing after a first-line VEGF TKI. The first is everolimus (Afinitor, Novartis), an mTOR inhibitor, and the second is axitinib (Inlyta, Pfizer), a TKI that inhibits VEGF, platelet-derived growth factor receptor and cKIT. To date, there is no head-to-head comparison between the two agents in this setting. According to Christian Kollmannsberger, MD, a medical oncologist at BC Cancer Agency in Vancouver, Canada, and an investigator in INTORSECT, the choice for second-line therapy is “largely arbitrary.” “Due to the lack of direct comparisons, [choice] is based on individual physician knowledge and experience with the drugs, the availability of these drugs, and for a minority of patients, patient-specific issues such as comorbidities or preexisting toxicities,” said Dr. Kollmannsberger. The mTOR signaling pathway regulates cell proliferation and metabolism in response to environmental factors, linking cell growth factor receptor signaling via phosphoinositide-3-kinase

(PI3K) to cell growth, proliferation and angiogenesis. VEGF TKIs, such as sunitinib (Sutent, Pfizer), sorafenib and axitinib, inhibit VEGF signaling by targeting the intracellular domain of its receptor. In the INTORSECT trial, 512 patients with mRCC who had progressed on firstline therapy with sunitinib were randomized to receive temsirolimus or sorafenib and treated until disease progression or unacceptable toxicity. Progressionfree survival, the primary end point, was identical in the two arms from a statistical standpoint. However, overall survival, a secondary end point, was longer in patients receiving sorafenib than in those receiving temsirolimus (median 16.6 vs. 12.3 months; P=0.014). At the time INTORSECT was designed, axitinib was not available. Dr. Schmidinger pointed out that since then, axitinib has demonstrated superior progression-free survival over sorafenib in the second-line treatment of mRCC ((Lancett 2011;378:1931-1939, PMID: 22056247) and thus clinicians should choose axitinib over sorafenib in this setting. According to Dr. Kollmannsberger, INTORSECT is only the second study

Metastatic renal cell carcinoma.

that has shown a survival benefit in second-line treatment of mRCC. Although overall survival was only a secondary end point, the difference is not something to dismiss, and doesn’t seem to be explained by subsequent therapy or other factors. “It is too large a difference to be ignored and until we have really proven it, we cannot automatically assume it is a false positive,” Dr. Kollmannsberger said. —Kate O’Rourke Dr. Schmidinger disclosed a consultant or advisory role with Astellas, GlaxoSmithKline, Novartis, Pfizer and Roche, and research funding from Pfizer and Roche. Dr. Kollmannsberger disclosed an advisory role with GlaxoSmithKline, Novartis and Pfizer, and has received meeting travel support from these companies.

Sorafenib Falls Short in Phase III Lung Cancer Trial EGFR-positive subset benefits in exploratory analysis Vienna, Austria—Sorafenib monotherapy does not improve overall survival as third- or fourth-line therapy in patients with advanced non-small cell lung cancer (NSCLC), according to a Phase III trial. A subset analysis, however, showed that patients with epidermal growth factor receptor (EGFR) mutations may benefit from this drug. Researchers launched the international, randomized, double-blind, placebocontrolled MISSION trial because Phase II trials have shown that second- or third-line therapy with sorafenib (Nexavar, Onyx) monotherapy can improve outcomes in patients with advanced NSCLC. The study of 703 patients compared sorafenib plus best supportive care (BSC) with BSC alone in patients with relapsed or refractory advanced NSCLC who had disease progression after two or three prior treatment regimens. Patients had predominantly nonsquamous histology. Treatment was continued until disease progression. Presenting the study results at the annual meeting of the European Society for Medical Oncology (abstract

LBA33_PR), Luis Paz-Ares, MD, PhD, the chair of oncology at Seville University Hospital in Seville, Spain, said that there was no difference in overall survival, the primary end point (hazard ratio, 0.9934; P=0.4687). However, sorafenib improved

Lung cancer expert Cesare Gridelli, MD, the chief of medical oncology at S.G. Moscati Hospital in Avellino, Italy, pointed to a slew of negative lung cancer trials involving the antiangiogenic agent sorafenib, including NEXUS and

There has been a slew of negative lung cancer trials involving the antiangiogenic agent sorafenib, but the EGFR subanalysis suggests an opportunity for patient selection for the drug. secondary end points, including progression-free survival (PFS; median, 2.8 vs. 1.4 months; P<0.0001) and overall response rate (17% vs. 3%; P<0.000001). Fewer patients in the sorafenib arm went on to receive additional lines of therapy after discontinuing the study protocol (Table), which could have confounded the data. An exploratory analysis showed that sorafenib improved median overall survival (13.9 vs. 6.5 months; P=0.002) and PFS (2.7 vs. 1.4 months; P=0.001) in patients who had an EGFR mutation in tumor or plasma.

ESCAPE, as well as other antiangiogenic agents including motesanib (Takeda) ((J Clin Oncoll 2012;30:3084-3092, PMID: 22851564; J Clin Oncol 2010;28:18351842, PMID: 20212250; J Clin Oncol 2012;30:2829-2836, PMID: 22753922). “The leading target [in these trials] is angiogenesis, VEGF [vascular endothelial growth factor], but to date we have no predictive factors for efficacy and no opportunity for patient selection for this kind of drug in our patients,” said Dr. Gridelli. For this reason, he found the EGFR subanalysis “very provocative,” and said that

Table. Post-Progression Therapy in the MISSION Trial Number of Additional Regimens

Sorafenib

Placebo

1 or more

43.1%

56.1%

2 or more

17.7%

22.1%

3 or more

7.7%

8.8%

further investigation of the EGFR pathway and angiogenesis is needed. Dr. Paz-Ares said that researchers were hoping to move forward in this area. “The biomarker analysis reveals a hypothesis that needs to be tested, first in the lab, but maybe further in the clinic [to investigate] the potential role of this drug in the subpopulation of EGFR mutants,” said Dr. Paz-Ares. —Kate O’Rourke Dr. Paz-Ares disclosed honoraria from Bayer HealthCare, Eli Lilly, Hoffmann-LaRoche and Pfizer. Dr. Gridelli disclosed a consultant or advisory role for and honoraria from Roche.

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Breakthrough Study Catalogs Breast Cancer Types Genetic Makeup of Tumors More Important Than Location

n a finding that is expected to revolutionize future approaches to the treatment of breast cancer, researchers have confirmed the presence of four distinct subtypes of breast cancer, each with a unique heterogeneous mix of genetic and molecular abnormalities. The findings, published online Sept. 23 in Nature, add to the growing body of evidence suggesting that tumors should be catalogued and treated based on the genes that are disrupted, rather than the tumor location in the body. As well, the researchers reported a breakthrough finding about triple-negative breast cancers: These breast cancers more closely resemble ovarian cancer than other breast cancers. Basal-like breast tumors and ovarian tumors could potentially be treated with the same therapeutic approaches, said the investigators. “With this study, we’re one giant step closer to understanding the genetic origins of the four major subtypes of breast cancer,” said Matthew J. Ellis, MD, PhD, the Anheuser-Busch Chair in Medical Oncology at Washington University School of Medicine in St. Louis, in a statement. “Now, we can investigate which drugs work best for patients based on the genetic profiles of their tumors. For basal-like breast tumors, it’s clear they are genetically more similar to ovarian tumors than to other breast cancers. Whether they can be treated the same way is an intriguing possibility that needs to be explored.” Surgeons, oncologists and other physicians who treat patients with breast cancer say the study adds significantly

to knowledge of breast cancer, and will shift the traditional way of thinking about cancer, in which tumors are classified by body part, to a more modern system that relies on a tumor’s genetic signature. “I believe that this study is highly significant because it confirms what many of us have predicted for some time: Our current breast cancer phenotypes are far more complex than the current classification system suggests, and the genetic abnormalities extend to primary tumors in other organ systems,” said Richard J. Bleicher, MD, the director of the Breast Fellowship Program and an associate professor of surgical oncology at Fox Chase Cancer Center in Philadelphia. “Data of this type will be what reshapes our understanding of cancer, how we classify it and how we tailor therapy.” The new research is part of The Cancer Genome Atlas Project, which brings together the country’s leading genetic sequencing centers to identify and catalogue mutations involved in many common cancers. The effort is funded by the National Institutes of Health. A nationwide consortium of researchers analyzed tumors from 825 women with breast cancer. The scientists used six different technologies to examine subsets of the tumors for defects in DNA, RNA and proteins. (In comparison, most other studies use one, perhaps two techniques to perform genetic analysis of cancer tumors.) The techniques included Agilent mRNA expression microarrays, Illumina Infinium DNA methylation chips, Affymetrix 6.0 single nucleotide polymorphism arrays,

miRNA sequencing, whole-exome sequencing and reverse-phase protein array data. Nearly 350 tumors were analyzed using all six techniques. By integrating information across platforms, researchers gained key insights into previously defined gene expression subtypes and confirmed the existence of four main breast cancer classes: luminal A, luminal B, HER2enriched and basal-like.

‘Now, we’re much closer to understanding the true origins of the different types of breast cancer.’ —Matthew J. Ellis, MD, PhD Charles Perou, MD, co-author of the paper and the May Goldman Shaw Distinguished Professor of Molecular Oncology at the University of North Carolina at Chapel Hill School of Medicine, said researchers were able to collect “the most complete picture of breast cancer diversity ever.” “This study has now provided a near complete framework for the genetic causes of breast cancer, which will significantly impact clinical medicine in the coming years as these genetic markers are evaluated as possible markers of therapeutic responsiveness.” Across the four subtypes, mutations in only three genes—TP53, PIK3CA and GATA3—occurred in more than 10% of patients’ tumors. But, the scientists found unique genetic and molecular signatures within each of the subtypes. Compared with other subtypes, basal-like and HER2 tumors had the highest mutation rates but the shortest list

‘This study has now provided a near complete framework for the genetic causes of breast cancer, which will significantly impact clinical medicine in the coming years as these genetic markers are evaluated as possible markers of therapeutic responsiveness.’ —Charles Perou, MD

of significantly mutated genes. These genes are thought to be the major drivers of cancer progression. Eighty percent of basal-like tumors had mutations in the TP53 gene, a known marker for more aggressive disease and poorer overall survival. About 20% of the tumors also had inherited mutations in the BRCA1 or BRCA2 genes, which are known to increase the risks for breast and ovarian cancers.

“This suggests that it only takes a few hits to key genes that drive cancer growth,” said co-author Elaine Mardis, PhD, co-director of The Genome Institute at Washington University. Overall, the genetic profiles of basallike and ovarian tumors were strikingly similar, with widespread genomic instability and mutations occurring at similar frequencies and in similar genes. Among the similarities, both tumors have BRCA1 inactivation, RB1 loss and cyclin E1 amplification, high expression of AKT3, MYC amplification and high expression, along with the high frequency of TP53 mutations. “The common findings of TP53, RB1 and BRCA1 loss, with MYC amplification, strongly suggest that these are shared driving events for basal-like and serous ovarian carcinogenesis,” the authors reported. “This suggests that common therapeutic approaches should be considered, which is supported by the activity of platinum analogues and taxanes in breast basal-like and serous ovarian cancers.” Finding new drug targets for this group is critical, said the authors. Basal-like tumors account for about 10% of all breast cancers and disproportionately affect younger women and those who are African American. Another previous study from Dr. Ellis’ group showed that women with basallike tumors do not benefit from anthracycline-based chemotherapy, commonly used to treat breast cancers (Clin Cancer Res 2012;18:2402-2412, PMID: 22351696). The new data indicate that clinical trials should be designed to avoid the use of these drugs in basallike tumors. Instead, patients with mutations in the BRCA genes may benefit from poly (ADP-ribose) polymerase inhibitors or platinum-based chemotherapy, which already are used to treat breast cancer.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Clinical Hematologic Review: Highlights from ASH and NEJM, JCO and Blood QUESTIONS

1. True or False. The combination of

brentuximab vedotin (Adcetris, Seattle Genetics) and CHP (cyclophosphamide, doxorubicin, prednisone) showed poor tolerability in the front-line treatment of patients with CD30+ mature T- and NKcell lymphomas.

2. True or False. Brentuximab vedo-

tin is an antibody–drug conjugate consisting of an anti-CD30 monoclonal antibody (mAb) covalently attached to the cell wall membrane-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable link.

True or False. Investigators from the University of Texas MD Anderson Cancer Center in Houston reported that epigenetic therapy is associated with similar survival rates as intensive chemotherapy in older (age >65 years) adults with newly diagnosed acute myeloid leukemia (AML).

“It’s particularly exciting when research delivers important findings with an immediate impact on treatment,” said Marisa C. Weiss, the director of breast radiation oncology at Lankenau Hospital in Philadelphia, and founder of the nonprofit information website breastcancer.org. The study showed that luminal cancers had the lowest mutation frequencies and longer lists of significantly mutated genes, suggesting that defects in multiple genetic pathways lead to the development of luminal breast cancers. Luminal A tumors are the most common form of breast cancer in the United States and the primary cause of breast cancer deaths, accounting for 40%. The study provides a much better picture of the genetic causes of this subtype. The most common mutation in luminal A tumors occurred in PIK3CA, and was present in 45% of these tumors. TP53 mutations occurred only in 12%. Patients with luminal B tumors generally do well after treatment but many experience recurrence years after treatment. The study showed that the most common mutations in these tumors occurred in TP53 and PIK3CA, which

7. True

True or False. The Dutch-Belgian Cooperative Trial Group for Hematology-Oncology and the Swiss Group for Clinical Cancer Research reported, for the first time, reassuring response rates with the addition of bevacizumab to standard chemotherapy in older adults with AML.

5. True

or False. On behalf of the Groupe Francophone Des Myelodysplasies (GFM) Experience, Lionel Ades, MD, reported the relevance of the IPSSR in azacitidine-treated patients and found that the new IPSS-R has strong prognostic value for overall survival but not response rates.

Primum non nocere. (First, do no harm.)

or False. The current perioperative recommendation for patients taking warfarin is that it should be discontinued approximately five days before surgery to prevent bleeding complications.

6. True or False. The revised Inter-

national Prognostic Scoring System (IPSS-R) for myelodysplastic syndrome (MDS) defined five rather than four major prognostic risk categories.

8. True or False. A mul-

ticenter study in symptomatic patients with myelofibrosis (MF) showed no benefit with starting a lower daily dose of ruxolitinib (Jakafi; Incyte Pharmaceuticals and Novartis) in patients with platelet counts between 50 and 100×109/L.

9. True or False. The final results of

the GIMEMA MDS0306 prospective trial of deferasirox (Exjade, Novartis) showed that despite high rates of treatment discontinuation during one year of planned therapy, the probability of

‘Although this is interesting and fascinating research, it does not really change how we manage the patient with breast or ovarian cancer who is diagnosed today.’ —Deanna Attai, MD may explain the disparate results seen in patients with this subtype. “Now, we’re much closer to understanding the true origins of the different types of breast cancer,” said Dr. Ellis. “With this information, physicians and scientists can look at their own samples to correlate patients’ tumor profiles with treatment response and overall outcomes. That’s the challenge for the future: translating a patient’s genetic

profile into new treatment strategies.” For now, experts say that the findings are not changing clinical practice. “Although this is interesting and fascinating research, it does not really change how we manage the patient with breast or ovarian cancer who is diagnosed today,” said Deanna Attai, MD, a breast surgeon at the Center for Breast Care, Burbank, Calif. “We are able to get more information

Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

becoming red blood cell (RBC) transfusion–independent was 19.7% (95% confidence interval, 19.4%-20%) at 12 months.

10. True or False. The prospec-

tive study from the Groupe d’Etudes des Lymphomes de l’Adulte and GOELAMS (Groupe Ouest Est d’Etude des Leucémies et Autres Maladies du Sang) of follicular lymphoma (FL) did not demonstrate that positron emission tomography (PET) scan could predict response assessment.

11. True or False. In FL, several ret-

rospective studies have indicated that PET scan detects more lesions than computed tomography, with a potential to alter management through upstaging or changing the size of the radiotherapy field. for answers see CONUNDRUMS, S page 30

than ever before on the genetic makeup and biological behavior of an individual patient’s cancer, but we still are not at the point where we can offer truly individualized treatment. And the more we learn, the more questions remain.” The study offers “lots of promise and potential for future treatment, but no real changes today in how surgeons and medical oncologists approach patients with breast or ovarian cancer,” Dr. Attai said. But, physicians can use the report to help patients understand the complexity of breast cancer and the need for a multidisciplinary response, said Dr. Weiss. “The message here is quite clear: The constitution of a cancer is complex, heterogeneous; the cells are not all identical,” she said. “Each woman’s individual cancer is unique. It’s made up of a range of different cells that work in different ways. In order to get rid of them, you need to use different treatments that address different vulnerabilities of that cancer.” —Christina Frangou Drs. Ellis and Perou are inventors on the patent filing for PAM50 and have equity interest in Bioclassifier LLC.

CURRENT PRACTICE

CONUNDRUMS continued from page 29

ANSWERS

1. False. This study evaluated the

safety and activity of brentuximab vedotin at a recommended dose of 1.8 mg/kg in sequence with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or in combination with CHP for front-line treatment for patients with higher-risk (international prognostic index [IPI] score ≥2 or anaplastic lymphoma kinase-negative) anaplastic large-cell lymphoma (ALCL) and other CD30-positive mature T- and NK-cell lymphomas. A Phase III study that compared CHOP with brentuximab vedotin plus CHP in the front-line treatment of mature T-cell lymphomas is planned. Fanale MA, Shustov AR, Forero-Torres A, et al. Brentuximab vedotin administered concurrently with multi-agent chemotherapy as frontline treatment of ALCL and other CD30-positive mature T-cell and NK-cell lymphomas. ASH Annual Meeting Abstracts. Blood. 2012;120:60.

2. False. Brentuximab vedotin is an

anti-CD30 mAb covalently attached to the microtubule (not membrane)-disrupting agent MMAE via a proteasecleavable link. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30:2190-2196, PMID: 22614995.

3. True. In this retrospective study,

the complete response rates with chemotherapy and epigenetic therapy were 42% and 28%, respectively (P ( =0.001); but two-year relapse-free survival rates and median survival were similar between the two groups. This and a few other retrospective studies suggest a potential role for hypomethylating therapy among patients who cannot tolerate chemotherapy, in particular very old patients or those with adverse karyotypes. Quintás-Cardama A, Ravandi F, Liu-Dumlao T, et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood. 2012;120:4840-4845, PMID: 23071272. Lestag E, Ayari S, Chevallier P, et al. 5-azacytidine (AZA) compared with intensive chemotherapy in elderly acute myeloid leukemia (AML)

CLINICAL ONCOLOGY NEWS • FEBRUARY 2013

patients: results of a retrospective single-centre matched analysis. ASH Annual Meeting Abstracts. Blood. 2011;118:3620. Serrano J, de la Fuente A, Bergua J, et al. 5-azacytidine versus intensive chemotherapy or BSC in elderly (>60 years) acute myeloid leukemia patients. a retrospective analysis. ASH Annual Meeting Abstracts. Blood. 2011;118:2612.

4. False. There is an urgent need

for new treatment modalities in elderly patients with AML. The results of this multicenter Phase II study showed that the addition of bevacizumab to standard chemotherapy did not improve the therapeutic outcome of older patients with AML. Ossenkoppele GJ, Stussi G, Maertens J, et al. Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK). Blood. 2012 120:4706-4711, PMID: 23047822.

True. The elimination half-life of warfarin is 36 to 42 hours and withholding warfarin for five days would allow sufficient time for the regeneration of functional vitamin K–dependent coagulation factors to achieve normal hemostasis, assuming normal diet and an international normalized ratio that was not markedly supratherapeutic on the day warfarin was stopped. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e326S-50S, PMID: 22315266. Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Blood. 2012;120:4699-4705, PMID: 22855600.

6. True. To refine the IPSS, MDS

patient databases from international institutions (11 countries) were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], N=7,012; IPSS, N=816) for analysis. The novel components obtained in the current analysis included: five rather than three cytogenetic prognostic subgroups with specific classification of a number of less common cytogenetic subsets and alteration of others; the less than 5% marrow blast category was split between 0% and 2% and greater than 2% and less than 5%, whereas all patients with greater than

10% blasts were grouped in the same category; the depth of cytopenias at clinically and statistically relevant cut points was established rather than merely the number of these abnormalities; and modification of the absolute neutrophil count cut point to 0.8×109/L was finalized. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454-2465, PMID: 22740453.

7. True. This multicenter retrospec-

tive study used IPSS-R to evaluate the outcome of higher-risk MDS patients (n=264) treated in a previously published study on behalf of GFM. Ades L, Lamarque M, Raynaud S, et al. RevisedIPSS (IPSS-R) is a powerful tool to evaluate the outcome of MDS patient treated with azacitidine (AZA): The Groupe Francophone Des Myelodysplasies (GFM) Experience. ASH Annual Meeting Abstracts. Blood. 2012;120:422. Itzykson R, Thépot S, Quesnel B, et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood. 2011;117:403-411, PMID: 20940414.

8. False. Ruxolitinib has demonstrat-

ed clinical benefit in patients with MF with or without the JAK2V617F F mutation at starting doses of 15 or 20 mg orally twice a day. The preliminary findings in this study suggest that a dosing strategy with a low starting dose of ruxolitinib and escalation to 10 mg twice a day may be appropriate in patients with MF who have low platelet counts between 50 and 100×109/L. An increase in platelet counts was observed in approximately one-fourth of patients who completed 24 weeks of this drug. Escalation to, and subsequent maintenance of, a 10 mg twicea-day dose of ruxolitinib also preserves both hemoglobin and platelet count, which may be beneficial for patients with MF patients who also have anemia or thrombocytopenia. Talpaz M, Paquette R, Afrin L, et al. Efficacy, hematologic effects, and dose of ruxolitinib in myelofibrosis patients with low starting platelet counts (50–100 x 109/L): a comparison to patients with normal or high starting platelet counts. ASH Annual Meeting Abstracts. Blood. 2012;120:176.

9. True. The patients in this study

were RBC transfusion–dependent (minimum transfusion history, 20 units received) with IPSS scores of low (n=60) or intermediate-1 (n=90) and serum

ferritin level of no less than 1,000 ng/mL. Transfusion–independence was defined as three consecutive months without packed RBC requirement with a minimum stable hemoglobin level of 9 g/dL. Serum ferritin significantly decreased during the study from a median starting value of 1,966 ng/mL (1,416-2,998 ng/ mL) to a median final value of 1,475 ng/ ml (915–2,010 ng/mL; P<0.0001). Angelucci E, Santini V, Di Tucci AA, et al. Deferasirox chelation therapy in transfusion dependent MDS patients. Final report from the GIMEMA MDS0306 prospective trial. Program and abstracts of the 54th American Society of Hematology Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 425.

10. False. In patients (n=121) with

advanced (high tumor burden) FL who were treated with six cycles of R-CHOP with two additional cycles of rituximab, the two-year progression-free survival rates were 86% for interim PET–negative versus 61% for interim PET–positive patients (P ( =0.0046); and 87% for final PET–negative versus 51% for final PET– positive patients (P ( <0.001), respectively. Of note, the effect of up-front bendamustine with rituximab and maintenance therapy on the prognostic value of endof-therapy PET requires investigation. Dupuis J, Berriolo-Riedinger A, Julian A, et al. Impact of [18F]fluorodeoxyglucose positron emission tomography response evaluation in patients with high–tumor burden follicular lymphoma treated with immunochemotherapy: a prospective study from the Groupe d’Etudes des Lymphomes de l’Adulte and GOELAMS. J Clin Oncol. 2012;30:43174322, PMID: 23109699. Barrington SF, Mikhaeel NG. Imaging follicular lymphoma using positron emission tomography with [18F]fluorodeoxyglucose: to what purpose? J Clin Oncol. 2012;30:4285-4287, PMID: 23109690.

11. True. There might be a ratio-

nale for performing PET scan for imaging of patients with limited-stage FL to avoid futile involved-field radiotherapy (IFRT). However, the outcome of IFRT for localized FL staged by PET has not yet been reported; therefore, it is not known whether the improved staging accuracy will result in improved outcome. Barrington SF, Mikhaeel NG. Imaging follicular lymphoma using positron emission tomography with [18F]fluorodeoxyglucose: to what purpose? J Clin Oncol. 2012;30:4285-4287, PMID: 23109690.

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