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Tackling DNA Repair, Brain Metastases, and Disparities in Breast Cancer

An investigational MRI-based approach shows abnormal blood vessels (in red) entering a breast cancer brain metastasis (in gray) in a patient treated on a clinical trial. Researchers are able to quantify the degree of blood vessel abnormality and to image changes in blood vessels in patients over time. Credit: Bullitt E, Lin N U, Smith J K, et al. Blood vessel morphologic changes depicted with MR angiography during treatment of brain metastases: a feasibility study. Radiology 2007; 245:824-830. Figure 1c.

October 3, 2013 | eNews


The DF/HCC Breast Cancer Program received a Specialized Program of Research Excellence (SPORE) Grant in 2013, one of only five Breast Cancer SPOREs in the country. Eric Winer, MD (DFCI), director of the Program and principle investigator for the grant, attributes the SPORE award to the breadth and depth of the Program, which focuses on building bridges linking breast cancer investigators across institutions—Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Boston Children’s Hospital, Mass General Hospital, Harvard Medical School, and the Harvard School of Public Health—and facilitating their work with core resources. “Our hope is that laboratory research will result in an improved understanding of breast cancer biology. In turn, this understanding will give rise to preclinical and clinical investigations that can ultimately have a significant clinical impact,” says Winer. 

Translating Discoveries Into Therapies

As an example of how laboratory research progresses towards clinical impact, Winer points to the Program’s work on the hereditary breast and ovarian cancer predisposition genes, BRCA1 and BRCA2. In the mid 1990s, Ralph Scully, MBBS, PhD (BIDMC), was a postdoctoral researcher in the lab of David Livingston, MD (DFCI), studying the then recently identified BRCA1. A woman who inherits one defective germ line copy of BRCA1 has a greatly elevated risk of breast or ovarian cancer, and researchers sought to understand how these genes normally work to suppress cancer. Scully discovered that BRCA1 associates with the key double strand break (DSB) repair/homologous recombination (HR) enzyme, Rad51, suggesting that BRCA1 suppresses cancer by preventing genome instability, which includes large-scale rearrangements of the chromosomes that enable oncogenic mutations to accumulate. Soon thereafter, BRCA2 was also shown to function on the same pathway. Scully hypothesized that BRCA1 and BRCA2 act during DNA replication to enforce error-free repair of replication-associated DSBs, and more than a decade of research supports this model. “It was an exciting discovery,” Scully recalls, “but it wasn’t clear at the time how we could translate this into therapy for women with BRCA1- and BRCA2-linked breast cancers.”

DF/HCC researchers, however, realized that properties that make BRCA1 and BRCA2 mutations dangerous also make them vulnerable therapeutically. The chemotherapy agent cisplatin, for example, causes DNA damage that requires a functional BRCA pathway to provide optimal cellular repair. Thus, BRCA mutant cancer cells, in which this pathway is disabled, are disproportionately sensitive to cisplatin, making it a potentially promising therapy for patients with BRCA-associated cancers. “It was a rational connection between what the basic science told us about the BRCA genes and what we knew about how cisplatin works,” Scully says of this clinically important insight. “These connections are fostered by basic scientists interested in translational research and clinicians interested in basic science here at DF/HCC.”

Building on a more recent discovery that inhibitors of the enzyme poly(ADP-ribose) polymerase (PARP) dramatically sensitize BRCA mutant cells to killing, PARP inhibitors have moved rapidly into clinical trials at DF/HCC and elsewhere. DF/HCC investigators have spearheaded the search for synergistic combinations of therapies with PARP inhibitors and, using genetically defined mouse models of breast cancer, they identified PI3 kinase inhibition as a promising candidate. They are now leading a clinical trial testing the effectiveness and tolerability of a combination of PI3K and PARP inhibitors in BRCA-linked breast cancers and triple negative breast cancers and ovarian cancer.

“It’s satisfying to see how basic research in DNA repair is being translated into clinical cancer therapy,” says Scully, who is also investigating another, DSB repair mechanism, non-homologous end joining, as a potential therapeutic target. (See accompanying story on NHEJ research.)

Risk Prediction and Breast Cancer Prevention

The Breast Cancer Program also integrates basic and translational research with population science in the area of risk prediction and prevention. Women who learn that they carry risk factor genes before they develop cancer can undergo more aggressive screening to detect cancer at an early stage, or they may opt for prophylactic surgery. To make this difficult decision, a woman needs clear certainty of her elevated risks. While many known cancer-associated BRCA1 and BRCA2 alleles occur so frequently in the population that there is statistical certainty about the risk of cancer for carriers of these alleles, other alleles occur so infrequently that this risk is undetermined.

To better define the risks associated with rare alleles, Scully is developing laboratory assays to interrogate the DNA repair function of rare BRCA1 variants identified in the human population. He isolates the effect of different BRCA1 alleles from the effect of other cancerous mutations by using primary (non-cancerous) cells and manipulating only the BRCA1 gene. By comparing the quality of HR supported by each BRCA1 allele, he hopes to identify where each allele lies on the spectrum DNA repair and tumor suppression functions. “It’s not proof that an allele is safe or dangerous,” he admits, but it is a lead for further investigation with an end goal of providing women with BRCA1 mutations with enough information to make tough decisions about cancer prevention.

Treating and Preventing HER2+ Breast Cancer Brain Metastases

Breast cancers caused by overexpression of the Human Epidermal Growth Factor Receptor 2 (HER2) are particularly aggressive, and historically had high mortality rates. “The field has made truly remarkable progress in the last ten to fifteen years in the development of targeted therapies for HER2 positive (HER2+) breast cancers. We can now prevent a greater number of recurrences in early stage disease, and can extend survival of patients with more advanced cancers,” says Winer. His colleague, Ian Krop, MD, PhD (DFCI) played a pivotal role in the development of ado-trastuzumab emtansine (Kradcyla), an antibody-drug conjugate of trastuzumab (Herceptin) and a cytotoxic agent (DM1), which was approved in 2006 for metastatic HER2+ breast cancer.

Still, a major hurdle remains. Metastatic HER2+ breast cancer preferentially spreads to the brain, and brain metastases are notoriously hard to treat, at least partially because the protective blood brain barrier (BBB) prevents therapeutics that may control cancer elsewhere in the body from entering the brain. Also, the cancer cells may co-opt the brain’s guardian glial cells to further protect against cancer treatments. Although patients with HER2+ breast cancer brain metastases can be treated successfully with surgery and/or radiation, the majority will develop disease progression, and the treatments themselves can cause cognitive deficits and other side effects.

The problem has been understudied, but with more HER2+ patients living longer, brain metastases have become more common. According to Winer, the Program has a unique emphasis on HER2+ brain metastasis, led by Nancy Lin, MD (DFCI), and has launched clinical trials of investigational drugs and combinations at DF/HCC for treating these metastases. One trial involves AERRY380, a tyrosine kinase inhibitor that in animal studies can penetrate that brain and prolong survival. Another trial, led by Rachel Freedman, MD, MPH (DFCI), is testing neratinib with the chemotherapeutic capecitabine (Xeloda). Lin is also planning a randomized trial of carboplatin plus the angiogenesis blocker bevacizumab (Avastin) to see if the high response rate seen in an initial study of the combination might translate into improved survival. Also, collaborators at MGH and UNC Chapel Hill are determining if a brain MRI performed shortly after the first dose of a therapy can predict whether an individual will respond to the drug or should be switched to a different one.

The ultimate goal, however, is to prevent brain metastases. If a first line therapy could target cancer in the brain as well as in the body, then fewer patients would require brain surgery and/or whole brain radiation. “The challenge is that we can’t test every promising drug candidate and combination in people. The trials are costly and long-term, and they require many patients,” explains Lin.

As a shortcut for discovering which drug candidate will be most effective, Lin and colleagues Jean Zhao PhD (DFCI) and Keith Ligon, MD, PhD (DFCI) are developing mouse models of patient-derived breast cancer brain metastasis. Working with surgeons, they are collecting brain cancer and primary breast cancer tissue from patient volunteers with breast cancer brain metastasis. When implanted into mice, these tissues form tumors that closely replicate human tumors. Then the researchers can ask: if a tumor does not respond to a therapy, what about the cancer explains it? If it responds but becomes resistant, what other drugs can overcome the resistance? “We’re building a bridge from the clinic to the lab,” says Lin, “so we can go back to the clinic with new drugs that treat or prevent brain metastasis.”

Overcoming Racial Disparities in Breast Cancer Care

The Breast Cancer Program also has extensive epidemiological expertise and benefits from the large databases of the Nurses Health Study, which contribute to efforts to predict and prevent breast cancer. Rulla Tamimi, ScD (BWH), who co-leads of one of the SPORE projects, is one of many Nurses Health Study investigators who have played a key role in the Program over the years.

In other population science research, Nancy Keating, MD, MPH (HMS), uses databases from the National Cancer Institute, including the Surveillance, Epidemiology and End Results (SEER) Program, to understand breast cancer diagnosis and treatment provided to breast cancer patients. Working with Rachel Freedman, MD, MPH (DFCI), she has discovered distressing disparities in the care provided to black women, and to some extent Hispanic women, compared to white women.

“We know that early diagnosis of early stage tumors gives women the best outcome, with less progression and recurrence, a lower rate of metastasis, and better long-term survival,” Keating explains. Also, women do best when they receive the recommended treatment of breast conserving surgery (BCS) plus radiation, or mastectomy. Black women are diagnosed later, with cancers at more advanced stages. They are less likely to receive the recommended treatment, and more likely to experience treatment delays. Overall, black women are 40 percent more likely to die of breast cancer once diagnosed than their white peers. Although these disparities have been documented for years, the situation has not improved.

Keating wants to understand the reasons for these disparities, which genetic differences can only partially explain, and how to ameliorate the social and cultural factors that contribute to them. Her research indicates that the hospitals where women go for treatment contribute to disparities. Black women more often go to lower-quality hospitals, often hospitals that are Medicaid providers and that treat uninsured patients, regardless of whether the women themselves have health insurance or Medicare, or whether they live closer to a hospital that provides better care. She wants to understand what influences the women’s choices, and she is currently surveying breast cancer patients about how they chose their surgeon and hospital for their breast cancer treatment. She hopes this work will help to identify whether strategies are needed to steer black women toward hospitals that provide better care, or whether more resources to these lower-quality hospitals may help them improve their breast cancer treatment programs.

“Black women, especially those with children and/or jobs with limited flexibility, may face different challenges that hospitals could address,” she adds. For example, if a patient cannot get time off or transportation for daily radiation therapy, or if she does not understand the reason for radiotherapy, the hospital could provide a patient navigator or targeted educational services.

Disparities also occur among Hispanic women, particularly those who are foreign born. Keating is looking at cultural issues that may influence a woman’s adoption of cancer screening, acceptance of chemotherapy and surgery, or language barriers in communicate with healthcare providers.

“If we did nothing other than eliminate disparities in breast cancer care in the United States, without offering any new drugs or new screening programs, we could eliminate a significant portion of all breast cancer deaths,” says Winer. “Addressing disparities in breast cancer care is one of the DF/HCC Breast Cancer Program’s most important goals.”

Research detailed in this article was funded in part by NIH grants, including CA065164, CA095175 and GM073894, and the DF/HCC SPORE In Breast Cancer.

— Cathryn Delude