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  • Turning Point 2012

    Research Roundup

    Anti-angiogenesis drugs may work in ovarian cancer subtype

    Dana-Farber scientists have identified a subtype of ovarian cancer able to grow its own blood vessels, suggesting that such tumors might be especially susceptible to "anti-angiogenic" drugs that block blood vessel formation.

    In a study published earlier this year, investigators estimate the subtype may account for a third of all serous ovarian cancers, a common cancer of the surface of the ovaries. The discovery may spur clinical trials to see if patients with the subtype can benefit from anti-angiogenic therapies now being tested in other cancers.

    "We've shown that serous ovarian cancer exists in at least one distinct subtype at the molecular level, raising the possibility that it will be vulnerable to therapies directed at its molecular weaknesses," says John Quackenbush, PhD, who, along with his Dana-Farber colleague Ursula Matulonis, MD, served as the study's co-senior author.

    Researchers scanned the activity of thousands of genes in high-grade serous ovarian cancers, taken from 129 patients with an advanced stage of the disease, then sifted the data with a specially designed algorithm. They identified a subtype in which genes involved in blood vessel growth were highly expressed, and confirmed their findings by drawing on other published studies involving more than 1,500 patients.

    Advocates measure value of reporting results

    A group of advocates who provide a patient perspective to clinical investigators in the Susan F. Smith Center for Women's Cancers have now become researchers in their own right.

    The Breast Cancer Advocacy Group (BCAG), composed chiefly of breast cancer patients and survivors, has begun a pilot study to measure the value of reporting clinical trial results to participants.

    "Patients are, understandably, focused on their own outcomes when they join clinical trials, but, in most cases, they never find out the overall result of the study," says Elizabeth Frank, lead patient advocate for the BCAG. Ann Partridge, MD, director of Dana-Farber's Adult Survivorship Program, and Eric Winer, MD, director of the SSC's Breast Oncology Center, are co-investigators.

    The study will develop a protocol for returning results to participants, evaluate the process and materials, and survey two sets of patients: those who receive results and those who do not. Key among the study's goals is one very simple intervention: a thank-you to participants.

    Although BCAG members are called "patient advocates," Frank explains that their roles are different from traditional advocates, who tend to support patient rights.

    "We work solely on the research side, reviewing concepts and protocols for clinical trials from a patient's perspective," says Frank, who has a background in market research and program evaluation. "It can be very hard work." For example, the advocates might recommend revisions to research questions so they more closely reflect the concerns of patients.

    Other duties include helping investigators develop grant proposals for a Breast SPORE (Specialized Program of Research Excellence) from the National Cancer Institute, reviewing applications for SPORE-funded Career Development Awards, and working hand-in-hand with investigators to design research studies.

    "Liz and the other advocates have played an instrumental role in research design that I think is stimulating and productive," says Nancy Lin, MD, clinical director of the Breast Oncology Center in the SSC.

    In emphasizing the importance of examining the way participants receive clinical trial results, Dr. Lin adds that the new study will help researchers understand the impact of delivering such results and identify the best approach for doing so.

    "In addition, the study will help us develop standard guidelines that investigators can turn to in the future."

    Exploring how cells specialize

    Parents often share household responsibilities, one handling a chore while the other relaxes. Something quite similar happens within the human genome: although we all inherit two copies of each gene – one from our mother and one from our father – both copies are not always active at the same time.

    Such single-gene activation plays a key role during the development of many nerve cells, helping map their connections within the brain. The process is also at work in the immune system, where it leads to the creation of slight variations in certain disease-fighting cells, enabling the body to counter a wide range of infectious agents.

    At Dana-Farber, Alexander Gimelbrant, PhD, is exploring why some genes consistently favor the expression of DNA from one parent or the other. He and his colleagues have found that this kind of preferential treatment is hardly a rare event, but occurs in many hundreds of human genes.

    Dr. Gimelbrant is currently building a map of gene activation, showing which genes are likely to have one copy on and one copy off in different types of cells in both humans and mice.

    "We're particularly interested in how this uneven activation contributes to the progression of cancer," Dr. Gimelbrant says. "The more we understand the process, the better we'll be able to intervene in a way that impairs the development of cancer."

    Scientists identify breast cancer features in rare disorder

    Breast cancer in women with Li Fraumeni Syndrome (LFS) – a rare, inherited cancer-susceptibility disorder – is likely to have certain characteristics that can be used to guide treatment, new research by Dana-Farber scientists and an international consortium of associates has found.

    The investigators learned that breast tumor cells in women with the syndrome tend to have two specific attributes – hormone receptors and an overabundance of receptors known as HER2 – suggesting that treatments targeted at those receptors can be especially effective in these patients.

    People with LFS inherit a mutation in a tumor-suppressor gene known as TP53, placing them at increased risk for cancers of the breast, bone, brain, blood, and other tissues, predominantly in childhood and early adulthood. The risk of breast cancer in women with LFS is approximately 49 percent by age 60, with a significant risk before age 40.

    "Recent studies have suggested that breast cancers in women with LFS are positive for hormone receptors and HER2, but the number of tumors analyzed in those studies was relatively small," says the new study's senior author, Judy Garber, MD, MPH, director of the Center for Cancer Genetics and Prevention at Dana-Farber.

    "By working with an international group of colleagues, we were able to extend that analysis to additional samples. The results will help us more closely match treatment to the specifics of each patient's disease."

    Setting standards for cancer care

    There's still room for improvement in national efforts to produce guidelines for high-quality cancer care. Look no further than a study in the February 2012 issue of the Journal of the American Medical Association, which showed that nearly half of women who had lumpectomies for breast cancer underwent second operations they may not have needed – all because surgeons don't yet agree on guidelines for the most common operation for breast cancer. The study was based on the medical records of more than 2,000 women treated at four hospitals nationwide.

    At Dana-Farber, Michael Hassett, MD, MPH, is working with colleagues to develop quality measures based on evidence-based practices, and optimize the delivery of cancer care. A breast oncologist in the Susan F. Smith Center for Women's Cancers, Dr. Hassett conducts research and serves on a number of advisory panels.

    "Whenever you're measuring quality, you want to identify the best treatment options for a particular group of people and see how often these recommended treatments are given," says Dr. Hassett.

    "For example, if evidence shows that breast cancer patients who have a lumpectomy have better outcomes if they get follow-up radiation therapy, our quality measure should be to see how many women are getting radiation. If we find that 20 percent of patients at a certain organization don't get radiation therapy, that's low quality care."

    Dr. Hassett works with colleagues at Dana-Farber and other experts to develop measures that can be used by hospitals, clinics, and health systems to help reduce the gap between ideal and actual care – that is, the difference between what evidence identifies as recommended care and what patients actually receive.

    "The concept of meaningful use, which encourages health care organizations to use electronic health records in ways that help us measure successes and quality, is becoming part of health care reform," Dr. Hassett says. "To get incentive payments from Medicare and Medicaid, doctors and hospitals will need to show that they are meeting certain quality guidelines."

    This same idea applies to other endeavors, Dr. Hassett says, such as 'pay for performance,' where private insurers provide incentives to health care providers who meet certain quality or performance targets. Organizations such as the Joint Commission and governmental agencies are exploring how quality measures can be used to ensure patients are getting the best possible care, without unduly raising costs.

    How male hormone can fuel breast tumors

    Androgen, the hormone responsible for producing male sexual characteristics, also fuels the growth of some breast tumors in women. Dana-Farber scientists recently became the first to trace a molecular circuit by which the hormone accomplishes this, revealing several points where the circuit could potentially be cut short – and tumor growth stopped – by new therapies.

    "We identified a special subtype of breast cancer that grows in response to androgen instead of estrogen, and have mapped the signaling pathways involved in its growth," says Dana-Farber's Myles Brown, MD, who led the research. "We've also demonstrated that drugs capable of blocking these pathways can inhibit tumor growth."

    The research began when Dr. Brown and his colleagues investigated a distinctive group of breast tumor cells, found in 5 to 10 percent of patients with the disease. Unlike other varieties of breast tumor cells, these had many receptors for androgen, none for estrogen, and an overabundance of a protein called HER2. When the cells were exposed to androgen, they proliferated.

    Analysis of the tumor cells' genetic material showed that the androgen receptor activates two "transmission lines" for growth signals. The pathways, named for important proteins within them (WNT and HER2), play central roles in cell division and proliferation.

    When researchers used drug molecules to handcuff the androgen receptor or the WNT or HER2 proteins in these cells, tumor growth stopped, both in laboratory cell cultures and in mice grafted with the cells.

    "Therapies that shut down proteins in the androgen receptor, WNT, and HER2 pathways have the potential to be effective anti-tumor agents for women with this variety of breast cancer," Dr. Brown says. "We hope combination therapies that target proteins at different points in these pathways will have the greatest chance for success."

    Two programs collect tissue for research

    Dana-Farber continues to advance the fields of genetic analysis and cancer research with two programs launched last year. First, the Susan F. Smith Center for Women's Cancers (SSC) created the Tissue Resource for Research (TRR), a state-of-the-art system to collect and store tissues used for research in breast and gynecologic cancers.

    In a similar effort, Dana-Farber and Brigham and Women's Hospital announced the launch of Profile, a large-scale research program for all types of cancer in adults. It will establish an extensive genomic database for studies that seek to improve the effectiveness, safety, and precision of future cancer treatments.

    While both programs aim to strengthen cancer research, they each have a different focus. The TRR, which was made possible by a $5 million initiative from the SSC Executive Council, collects samples from consenting patients with breast or gynecologic cancers, and scientists use those samples to pursue a diverse range of research into women's cancers.

    Profile has a more defined goal: scanning samples from consenting Dana-Farber adult patients for a specific set of genetic mutations that are known or suspected of being linked to cancer.

    "While Profile is an effort to build an unprecedented genomic database, it is a very targeted initiative," says J. Dirk Iglehart, MD, director of the SSC. "The TRR is much more of a discovery tool, providing researchers with tissue that can be used in many different research efforts and tests – genetic and otherwise."

    Patients who donate their tissue to the TRR can also participate in Profile, Dr. Iglehart says. The TRR samples, which are typically gathered during a biopsy or surgery, are preserved and protected for researchers seeking to find better ways to diagnose, prevent, and treat cancer in the future.

    "The TRR is an incredibly helpful research tool that not many other facilities have," Dr. Iglehart says.

    "Many people assume that tumor tissue automatically gets saved for research, but in fact, it is destroyed at most hospitals. There are significant costs associated with storing it, obtaining patients' consent, and maintaining quality. Thanks to the Executive Council's initiative, we can save this tissue and ensure that it will be used for discovery."

    Turning Point 2012 

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