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Genomic Studies Reveal a Tumor’s Secrets

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Nikhil Wagle, MDBy Robert Levy

One day, the genome of a tumor will be as revealing as a tell-all memoir. Doctors will obtain a full report on each tumor’s genomic quirks – its vulnerabilities, defenses, survival strategies, even its history of advance and retreat. The revelations will help physicians decide which therapies, in which order and at what doses, are most likely to work.

At Dana-Farber and other centers around the world, the effort to understand tumors at such an intimate  level is well under way. Advances in DNA sequencing are enabling scientists to catalog the full extent of genomic abnormalities in many types of cancer. (The field of cancer genomics studies changes in tumor DNA.) The Profi   research project at Dana-Farber, Brigham and Women’s Hospital, and Boston Children’s Hospital has analyzed thousands of tumor tissue samples to identify the cancer-related mutations within them.

“Genomic research is key to our progress in women’s cancers,” says Eric Winer, MD, director of the Breast Oncology Program for the Susan F. Smith Center for Women’s Cancers at Dana-Farber.

Biology Influences Therapy

Breast cancer was the first solid tumor for which an understanding of the biologic features of the cancer had a major impact on therapy.  Finding that many breast cancer cells carry the estrogen receptor – an antenna for growth messages from estrogen – led to the discovery that tamoxifen and similar drugs could halt the growth of these cells by standing in estrogen’s way. For almost 40 years, tamoxifen has been a standard treatment for women whose breast cancer is fueled by estrogen.

Similarly, learning that some breast cancers have a surplus of the growth-promoting protein HER2 led to the development of agents that block HER2, most notably the drug trastuzumab (Herceptin).

“Today, diagnosing breast cancer by its molecular subtype, and selecting the appropriate targeted treatments, has become routine,” says Dr. Winer. “As we gain more insights into the molecular make-up of breast cancer, we are refining treatment even further.”

At the Susan F. Smith Center, for example, when hormone-sensitive breast tumors are removed during surgery, they’re often sent for genomic analysis by a  test called OncotypeDX. “Each tumor is assigned a score that helps us gauge how aggressive the cancer is and how likely it is to respond to chemotherapy,” says Erica Mayer, MD, MPH, a senior physician and breast oncologist in the Susan F. Smith Center. “The test helps provide assurance that chemotherapy is prescribed only for patients who are likely to benefit  from it.”

Genomic information is also opening treatment opportunities in other areas. “When breast cancer arises in women who carry mutations in the genes BRCA1 or BRCA2, the tumor cells’ capacity to repair their DNA is reduced,” says Judy Garber, MD, MPH, director of the Center for Cancer Genetics and Prevention at the Susan F. Smith Center. (Normally, BRCA1 and BRCA2 are involved in repairing damaged DNA; when they’re idled because of a mutation, DNA repair is hampered.) “If you know a tumor can’t repair DNA errors as easily, then part of your treatment strategy could be to exploit that weakness. Drugs capable of doing so include platinum- based chemotherapy agents and PARP inhibitors.”

Dana-Farber investigators were among the first to study the potential of platinum agents in breast tumors with BRCA mutations. With colleagues at Beth Israel Deaconess Medical Center, they’re leading a clinical trial of standard chemotherapy versus platinum chemotherapy in breast cancer patients who carry a BRCA mutation.

How a Tumor’s Genome Changes

Tumors evolve over time, acquiring new mutations as they grow and spread and encounter drug treatment. A newly diagnosed tumor may look markedly different, genomically speaking, from a tumor that has been wounded by multiple drug attacks.

Nikhil Wagle, MD

Nikhil Wagle, MD

Nikhil Wagle, MD, of the Breast Oncology Program at the Susan F. Smith Center, is exploring how, or if, a breast tumor’s genome changes when it becomes metastatic. In a project run by the Center for Cancer Precision Medicine (a joint effort of Dana-Farber, Brigham and Women’s Hospital, and the Broad Institute of Harvard and MIT), patients can agree to have a tumor sample analyzed when their cancer becomes metastatic or begins resisting the original drug. By comparing the genomes of these tumors with samples obtained before resistance developed, researchers hope to find explanations for drug resistance and metastasis – and provide a blueprint for new therapies.

In another project, Dr. Wagle is using social media to enlist metastatic breast cancer patients around the country to share their medical records, saliva, and tumor samples with his team. The project has a variety of research goals, including the identification of “exceptional responders” – patients who derive the greatest benefit from treatments that may not be effective for others. It has enrolled 1,500 patients in its first four months, a sizable number of whom qualify as exceptional responders. Researchers hope to learn what drives these tumors and why certain drugs are effective against them.

“We view this project as patient empowerment – a way for patients to participate in cutting-edge cancer research, no matter where they may live,” Dr. Wagle says.

Making Connections in Gynecologic Cancers

Scientists have made an impressive start in tracking the genomic irregularities in ovarian and other gynecologic cancers. They have discovered, for example, four common mutations in high-grade serous endometrial cancer.

From a molecular standpoint, gynecologic cancers are quite complex. “Every gynecologic cancer has a unique genomic composition,” Dr. Matulonis says. “High-grade serous ovarian cancers [HGSCs], for example, have few genetic mutations, but they have many copy number alterations – instances in which certain genes are deleted or amplified.”

Patterns are emerging amid the diversity. The Cancer Genome Atlas – a national effort to map the key genomic changes in several major forms of cancer – found that approximately 50 percent of HGSCs have alterations that hinder their ability to repair damaged DNA. As in breast cancer, researchers found that patients with HGSC whose tumors have mutations in the BRCA1 or BRCA2 DNA-repair genes often benefit from PARP inhibitors. Intriguingly, studies have shown that non-serous ovarian cancers, too, often have mutations in DNA-repair genes.

“The discovery of BRCA1 and BRCA2 mutations as indicators of a good response to PARP inhibitors represents one of the most important steps in personalized treatment for ovarian cancer,” Dr. Matulonis says. “As we learn more about HGSC, high-grade serous cancer of the endometrium, and triple-negative breast cancer, we’re finding they have a great deal in common at the molecular level.”

Researchers have also learned that ovarian tumors with an oversupply of the cyclin-E1 protein tend to have a poor prognosis. One reason is that, unlike other ovarian cancers, tumors with extra cycline-E1 can promptly repair the damage caused by chemo- therapy agents. They also don’t respond well to PARP inhibitors or existing targeted therapies.

Panos Konstantinopoulos, MD, PhD, of the Gynecologic Oncology Program at the Susan F. Smith Center, has received a large grant from the U.S. Department of Defense to explore three new strategies for disrupting the growth of this type of ovarian tumor. One involves drugs targeting a protein that helps cells respond to stress; another seeks to block the interaction of two key proteins in tumor cells; and the third involves molecules called microRNAs that may have a powerful anti-cancer effect when combined with other drugs.

Courtesy of Dana-Farber Cancer Institute

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