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  • Paths of Progress Fall/Winter 2011

    Frontier of Discovery

    Dana-Farber and Brigham and Women's Hospital join for genetic research
    By Robert Levy

    Whenever someone is treated successfully for cancer, the credit belongs not only to health care providers and scientists, but also to the generations of patients who came before. Their willingness to donate tissue for study and to try new, unproven therapies in clinical trials has been part of virtually every advance against cancer during the past half-century.

    As cancer medicine becomes more genomic – increasingly directed at the specific disobedient genes and discordant proteins in tumor cells – today's patients have a distinct opportunity to benefit those who will come tomorrow. Advanced technology has enabled scientists and physicians to survey vast regions of tumor cells' DNA for gene mutations involved in cancer.

    Now the challenge is to determine how those abnormalities affect the course of the disease: Which mutations cause tumors to be aggressive or metastatic? Which treatments work best against tumors with particular mutations? Answering such questions requires vast amounts of high-quality information. The kaleidoscopic nature of cancer – the astonishingly diverse patterns of mutations in cancer cells – dictates that data be collected from as many patients and tumor samples as possible, and that it be analyzed in a highly meticulous manner.

    Top: Barret Rollins and Janina Longtine; bottom: Monica Bertagnoli and Phillip KantoffKey leaders of the new genetic-screening research program include Dana-Farber's Barrett Rollins, MD, PhD, and Janina Longtine, MD, of Brigham and Women's Hospital, (top photo) as well as Monica Bertagnolli, MD, also of Brigham and Women's, and Philip Kantoff, MD, from Dana-Farber (bottom photo).

    That is the inspiration for a groundbreaking research effort by Dana-Farber and Brigham and Women's Hospital (BWH). The program, which debuted earlier this year, gives all adult cancer patients at Dana-Farber/ Brigham and Women's Cancer Center (DF/BWCC) the option of having their tumor tissue scanned for genetic mutations that are known or suspected of being linked to cancer. Researchers will use the database in studies that seek to improve the effectiveness, safety, and precision of future cancer treatments.

    A second aspect of the program focuses on familial cancer risk. Patients will be asked if they wish to donate normal cells – from their blood or the inside of their cheek, for example – for studies of inherited gene mutations that increase people's risk of developing certain cancers at a young age.

    "The explosion of genomics research means that every patient has something to contribute to the defeat of cancer," says Barrett Rollins, MD, PhD, Dana-Farber's chief scientific officer and one of the program's architects. "Ultimately, our goal is to bring cancer treatment fully into the era of personalized medicine, in which treatment addresses the specific genetic composition of each patient's tumor."

    With a patient's consent, investigators will be able to link genetic information about each tumor with data from the individual's medical records to track how the disease responds to treatment, whether the cancer recurs, the type and severity of side effects, and other health-related issues. Researchers will use such information to determine which therapies are most effective against certain tumor types, and which doses and treatment schedules produce the best results.

    Such research also will reveal which drugs don't work for particular types of tumors, sparing future patients the prospect of unnecessary and ineffectual treatments, while also making therapy more cost-effective.

    "In the past several years, we've learned a great deal about the role of specific mutated genes in cancer, and we now have technology for testing large numbers of tumor samples for those mutations," says Janina Longtine, MD, director of Molecular Diagnostics at BWH and a key leader of the new genetic-screening research program. "For the first time, we have the opportunity to build a critical mass of genomic data that can be used to bring better treatments to patients."

    While other cancer centers have instituted genetic screening programs for tumor samples, the effort at Dana-Farber and BWH is the first to be available to every adult cancer patient who comes for treatment or evaluation.

    Here is how it works: A few days before their first appointment, patients receive a short brochure explaining the program. They can consent to participate in the protocol or, if they have further questions, opt to talk with their physician before making a decision.

    Participation is completely voluntary, involves no additional procedures, other than a blood draw or cheek swab (in some cases), and patients can decline to continue at any time. The consent form describes three genetic research procedures patients can consent to:

    • Offering their leftover tumor tissue for use in research tests, and linking the results to information on the course of patients' disease and treatment. Such cross-referencing will enable investigators to study, among other topics, the effectiveness of drugs that target particular mutated genes.
    • Letting clinicians collect a small sample of normal cells – by taking a blood sample, for example, or by swabbing the inside of a patient's cheek. These cells will be used for "germline" studies that explore whether inherited mutations predispose people to developing certain cancers.
    • Allowing their DF/BWCC physician to receive the results of genetic tests on their tumor tissue. If the results show that a patient's tumor carries a mutated gene that might be blocked by a potential new drug, the patient could be told about a related clinical trial.
    Illustration: Patient Groups

    "As with all consenting procedures, the aim is to ensure that patients have a clear understanding of what the program entails," Rollins remarks. "We want them to know how it will affect them, and how their participation can help us advance research. As in all medical research, patients can be assured that the confidentiality of their information will be protected."

    Tumor tissue from consenting patients will be scanned for nearly 500 mutations in 41 genes that are known to be involved, directly or indirectly, in cancer. The scans will be performed in the BWH Pathology Department using a system called OncoMap, which looks for "point mutations" – errors in a single digit of the genetic code that indicate faulty genes.

    Devised by a team of scientists at Dana-Farber and the Broad Institute of MIT and Harvard, and led by Levi Garraway, MD, PhD, OncoMap is one of the first tools to enable high-quality, large-scale screening for cancer-related mutations.

    This "genotyping" of each tumor sample – assigning it an identity based on its assemblage of cancer mutations – takes about four weeks. Patients are not billed for the tests. The testing results flow into a database that classifies tumors by the organ or tissue where they arose and the set of mutations within them.

    This information can be linked to a database of clinical data, allowing researchers to match the effectiveness of therapies to individual types of tumors and mutations. If a patient consents, his or her physician can receive a report on the mutations found in that patient's tumor tissue.

    The mutations fall into three categories: those known to make tumors susceptible to some drugs and unyielding to others; those which might affect a tumor's response to therapy, but for which there is insufficient scientific evidence to be certain; and those whose connection to a particular cancer is still unclear.

    To reach its potential, the genetic testing program needs the participation of large numbers of patients.

    "In cancer, we can't afford to overlook any source of information," says Monica Bertagnolli, MD, chief of Surgical Oncology at BWH, and a key architect of the program. "Early on, we realized that this project wouldn't work as a small-scale, 'boutique' effort. Without a global approach – analyzing the tumors of every patient who consents – we would be limiting our ability to make major breakthroughs."

    As the amount of data expands – researchers hope to ultimately collect information on tens of thousands of tumors – it will be a boon for clinical research, says Dana-Farber's Chief Clinical Research Officer Philip Kantoff, MD, who was also pivotal in the program's creation. He likens it to a Nurses' Health Study for the genomic age. (Since 1976, the nurses' study has tracked the health of more than 200,000 registered nurses, fueling discoveries about everything from diet and nutrition to heart disease.)

    "The data will allow us to analyze the links between specific mutations and tumor behavior to an extent that has never before been possible," Kantoff remarks. "We'll have the opportunity to make observations that can spark a whole new array of clinical trials."

    The genetic database is only as valuable as OncoMap's ability to detect bona fide cancer-causing mutations in tumor cells. To minimize the chance of error – that a tissue sample tests positive for a mutation that isn't really there, for example – OncoMap adheres to the most rigorous standards for tissue-handling and quality control, Longtine notes.

    The program would not have happened without intensive cooperation between Dana-Farber and BWH. For nearly two years, a team of Dana-Farber and Brigham and Women's physicians, laboratory scientists, translational researchers (who bridge the realms of laboratory and clinical science), information technology experts, and clinical service providers from both hospitals worked to assemble and implement the program, tackling everything from patient access issues, to financing, to procedures for preparing and analyzing tumor tissue.

    Helping lead the effort is William Hahn, MD, PhD, deputy chief scientific officer at Dana-Farber. Even though the program is brand-new, researchers and institutional leaders are already working to improve it. New cancer-related gene mutations will be added as they are discovered. In the future, OncoMap itself is expected to be replaced by next-generation technologies that can simultaneously recognize an enormous number of mutations and determine which genes are missing or overabundant in tumor tissue samples.

    Over the next year, the tumor testing program is slated to expand to Boston Children's Hospital, Dana-Farber's partner in pediatric cancer treatment.

    "What we're creating with our current plan is less a permanent fixture than an infrastructure that allows us to install new technologies as they become relevant," Rollins says. "The state of the art in gene-screening technology is always advancing. To remain useful, our program will advance with it."

    Paths of Progress Fall/Winter 2011 Table of Contents

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