BRCA1/2 Mutation Status May Not Be Predictive of Checkpoint Inhibitor Response

Higher levels of genomic instability have been associated with lower immunogenicity, which means drugs are less effective, in patients with BRCA1/2-related breast cancers, according to research published in Clinical Cancer Research.

These findings, according to the authors, could help to shape treatment strategies and clinical trial designs for patients with this type of breast cancer. The findings may also help researchers understand whether checkpoint inhibitors may be effective in treating BRCA1/2 breast cancers.

“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,” Katherine L. Nathanson, MD, senior author and Pearl Basser Professor for BRCA-Related Research at the Abramson Cancer Center of the University of Pennsylvania, said in a statement. “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.”

The researchers used genomic data from the Cancer Genome Atlas and compared 89 breast cancers with germline or somatic BRCA1/2 mutations with 770 breast cancers without those mutations. Due to their higher mutation frequency, researchers have thought that breast cancers with somatic or germline BRCA1/2 mutations would be more responsive to checkpoint blockage. However, these researchers found the opposite.

They found that a higher frequency of mutations was associated with lower immune infiltration of tumors. Despite being associated with a higher mutational burden, homologous recombination deficiency scores were negatively associated with expression-based immune indices.

“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.”

Reference

Kraya AA, Maxwell KN, Wubbenhorst B, et al. Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer [published online March 26, 2019]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-18-0468.