Breast cancers with somatic or germline BRCA 1/2 mutations may not be as responsive to checkpoint inhibitors as previously thought.
BRCA 1/2 mutation status in patients with breast cancer may not be directly predictive of response to checkpoint inhibitor therapy, according to a new study published in Clinical Cancer Research.
For the study, the researchers examined whether specific genomic markers could help guide treatment strategies in BRCA 1/2 mutation-associated breast cancers. They analyzed genomic data from the Cancer Genome Atlas and compared breast cancer with and without either germline or somatic BRCA 1/2 mutations. Using whole exome sequencing and immunohistochemistry, the researchers also studied 35 breast cancers with germline BRCA 1/2 mutations.
According to the press release, the study is one of the largest BRCA 1/2 breast tumor analyses to date.
Prior studies have hypothesized that breast cancers with somatic or germline BRCA 1/2 mutations would be more responsive to checkpoint inhibitors; however, the results of the current study showed that this may not be the case.
“One aspect of the study that was particularly interesting was that it builds upon our prior studies,” senior study author Katherine L. Nathanson, MD, Pearl Basser Professor for BRCA-Related Research at the Abramson Cancer Center of the University of Pennsylvania, said in the release. “Previously we found that tumors in germline BRCA 1/2 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.”
In this study, higher levels of genomic instability, as measured by homologous recombination deficiency (HRD), were associated with lower immunogenicity and tumor infiltration in T cells. Despite being associated with a higher mutational burden in BRCA 1/2 mutant breast cancers, HRD scores were negatively associated with expression-based immune indices.
“We had assumed that all BRCA 1/2 cancers with the highest HRD scores were most likely to have the strongest immune response,” study author Susan Domchek, MD, the Basser Professor in Oncology, executive director of the Basser Center for BRCA at the Abramson Cancer Center at the University of Pennsylvania, said in a press release about the findings. “But with [these] data, we now know that these assumptions were incorrect.”
The findings will allow researchers to move forward with examining the biological mechanisms that may inform treatment response for patients with these cancers and could further shape treatment strategies and clinical trial design for these patients, according to the study authors.
Kraya AA, Maxwell KN, Wubbenhorst B, et al. Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer. Clinical Cancer Research. 2019. Doi: 10.1158/1078-0432.CCR-18-0468
Penn Research Provides Insight into Genetic Link to Potential Treatment Response Among BRCA1/2 Breast Cancer Patients [news release]. Penn Medicine. https://www.pennmedicine.org/news/news-releases/2019/may/research-provides-insight-genetic-link-to-potential-treatment-response-among-brca1-2-breast-cancer. Accessed June 4, 2019.