PHILADELPHIA—New findings from researchers in the Perelman School of Medicine at the University of Pennsylvania provide clues about immune response of tumors in patients with BRCA 1/2-related breast cancers. The research, published in the journal Clinical Cancer Research, could shape treatment strategies and clinical trial design for these patients, who make up about two percent of newly diagnosed cases of breast cancer.
“This study helps to highlight the immune characteristics of BRCA1/2 breast cancers and to identify the molecular features that may predict immunogenicity,” said the study’s senior author Katherine L. Nathanson, MD, Pearl Basser Professor for BRCA-Related Research at the Abramson Cancer Center of the University of Pennsylvania. “These data provide a strong building block for our work in uncovering the biological mechanisms that may inform treatment response for patients with BRCA1/2-related breast cancers. Each time we uncover new information that could help tailor the most effective treatments for each patient, we see it as a positive step forward.”
Checkpoint inhibitors are a popular immune therapy cancer treatment for some types of cancers and currently are being studied in clinical trials to test the efficacy in treating BRCA1/2 breast cancers.
Researchers sought to determine whether specific genomic markers could provide clues about the immune environment in BRCA1/2 mutation-associated breast cancers. To do so, the team analyzed genomic data from the Cancer Genome Atlas (TCGA) to compare breast cancers with (89) and without (770) either germline (inherited) or somatic (acquired) BRCA1/2 mutations. They also studied 35 breast cancers with germline BRCA1/2 mutations from Penn patients using whole exome sequencing (WES) and immunohistochemistry. It has been hypothesized that breast cancers with somatic or germline BRCA1/2 mutations may be more responsive to checkpoint blockade due to their relatively higher mutational burden. Nevertheless, in this study, researchers found that a higher frequency of mutations was associated with lower immune infiltration of tumors, suggesting that BRCA1/2 mutation status may not be directly predictive of response to checkpoint blockade.
The team found that higher levels of genomic instability, as measured by homologous recombination deficiency (HRD), were associated with lower immunogenicity and tumor infiltration by T cells. These results were unexpected and go against conventional clinical wisdom. “One aspect of the study that was particularly interesting was that it builds upon our prior studies. Previously we found that tumors in germline BRCA1/2 mutation carriers that did not lose the wild type allele were likely to be less sensitive to DNA damaging agents, and our new data suggests they may be more sensitive to checkpoint blockade,” Nathanson said.
“We had assumed that all BRCA1/2 cancers with the highest HRD scores were most likely have the strongest immune response,” said study author Susan Domchek, MD, the Basser Professor in Oncology and executive director of the Basser Center for BRCA at the Abramson Cancer Center at the University of Pennsylvania. “But with this data, we now know that these assumptions were incorrect.”
Although this study is one of the largest BRCA1/2 breast tumor analyses to date, authors suggest a larger sample size would help to further understand how the molecular features of BRCA1 and BRCA2 mutation associated breast cancers are linked to immune response.
Additional Penn authors on the study include Adam A. Kraya, Kara N. Maxwell, Bradley Wubbenhorst, Brandon M. Wenz, John Pluta, Andrew J. Rech, Liza M. Dorfman, Nicole Lunceford, Amanda Barrett, Nandita Mitra, Jennifer J.D. Morrissette, Michael Feldman, Anupma Nayak, and Robert H. Vonderheide.
This study was funded by the National Institutes of Health (P30 CA016520), Basser Center for BRCA at the University of Pennsylvania, Breast Cancer Research Foundation, Susan G Komen Foundation, Rooney Family Foundation, National Institutes of Health (K12-CA076931), Konner Family Foundation, the Parker Institute for Cancer Immunotherapy, the National Center for Advancing Translational Sciences of the National Institutes of Health (TL1TR001880) and the National Human Genome Research Institute of the National Institutes of Health (5T32HG009495 – 02).
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.6 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.
The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.
Penn Medicine is powered by a talented and dedicated workforce of more than 43,900 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2019, Penn Medicine provided more than $583 million to benefit our community.