Blood Test Detects Resistance to BRCA-Targeting Drugs

Resistance to platinum-based chemotherapy or PARP inhibition in germline BRCA1 or BRCA2 mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function.

Scientists have assessed whether BRCA1/2 reversion mutations could be identified in circulating cell-free DNA (cfDNA) of patients with ovarian or breast cancer previously treated with platinum and/or Poly ADP ribose polymerase (PARP) inhibitors using a “liquid biopsy.”

An international team of scientists in conjunction with those at The Institute of Cancer Research (London, UK) collected cfDNA from blood samples of 24 prospectively accrued patients with germline BRCA1 or BRCA2 mutations, including 19 patients with platinum-resistant/refractory ovarian cancer and five patients with platinum and/or PARP inhibitor pretreated metastatic breast cancer. The cfDNA was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of BRCA1 and BRCA2. Functional studies were performed to assess the impact of the putative BRCA1/2 reversion mutations on BRCA1/2 function.

The investigators found diverse and often polyclonal putative BRCA1 or BRCA2 reversion mutations were identified in cfDNA from four patients with ovarian cancer (21%) and from two patients with breast cancer (40%). BRCA2 reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a patient with breast cancer who did not respond to treatment and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function.

Nicholas C. Turner, MD, PhD, a professor of Medical Oncology and senior author of the study, said, “With this new liquid biopsy, we picked up changes in tumor DNA that could give us early warning if a woman’s cancer is likely to stop responding to treatment. Next, we aim to further evaluate the blood test as part of a large clinical trial. In the future, this liquid biopsy could help us pick out those women with breast or ovarian cancer who are most likely to benefit from targeted therapy, and offer alternative treatment to women as soon as they develop drug resistance.” The study was published in the November 2017 issue of the journal Clinical Cancer Research.

Related Links:
The Institute of Cancer Research