More Women With BRCA Mutations May Respond to PARP Inhibitors Than Previously Thought

Inherited, somatic, and germline mutations in the BRCA1/2 genes are all responsible for cancer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors across various tumor types. New research published in Nature Medicine has identified a broader population of individuals with breast cancer (nearly 22%) who can have therapeutic sensitivity to PARP inhibitors.

About 252,710 women are estimated to be diagnosed with invasive breast cancer in 2017, and 12% of women in the United States will be diagnosed with the disease during their lifetime. Inherited mutations in the BRCA1/2 genes are the most common type of breast-cancer mutations—BRCA1 mutations increase the risk of developing breast cancer by 55% to 65%, while BRCA2 mutations increase the risk by 45%.

In their current study, the authors used a weighted computer model called HRDetect to identify mutation patterns. Their hypothesis that mutation in a single gene does not yield a single signature, rather, it gives rise to multiple gene signatures. This in turn expands the population of patients who would benefit from PARP inhibitors. HRDetect analyzed a cohort of 560 patients with breast cancer, 22 of whom had germline BRCA1 or BRCA2 mutation. But the broader scope of signatures being analyzed allowed the authors to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected.

The authors wrote that integrating the various classes of mutational signatures revealed a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%), as opposed to the 1% to 5% that are currently thought to have selective therapeutic sensitivity to PARP inhibition.

“In the past, clinical trials for PARP inhibitors have focused mainly on the 1 to 5 per cent of women with breast cancer. However, our study shows that there are many more people who have cancers that look like they have the same signatures and same weakness as patients with faulty BRCA1 and BRCA2 genes,” Serena Nik-Zainal, PhD, senior author on the study, from the Wellcome Trust Sanger Institute, United Kingdom, said in a statement.

“We should explore if they could also benefit from PARP inhibitors,” she added, recommending a change in design for future clinical trials that evaluate these drugs.

Reference

Davies H, Glodzik D, Morganella S, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures [published online March 13, 2017]. Nat Med. doi: 10.1038/nm.4292.