BRCA Reversion Mutations in cfDNA Can Predict Response in Ovarian Cancer

A small study found that it is feasible to detect BRCA1/2 reversion mutations in circulating cell-free DNA (cfDNA) in patients with recurrent high-grade serous ovarian cancer (HGSC). Those reversion mutations can help predict poor response to therapy in these patients.

Patients with HGSC and germline BRCA1 or BRCA2 mutations have better response rates and longer progression-free intervals than those without the mutations. Among several mechanisms of acquired chemoresistance, though, is the development of reversion mutations. “Because knowledge of tumor reversion status, and, therefore, likely chemoresistance, may influence treatment planning, we sought to determine if BRCA1/2 reversion mutations could be identified in cfDNA as a noninvasive test in patients with primary or recurrent HGSC,” wrote study authors led by David Bowtell, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia.

The study included 14 patients who had not yet undergone primary debulking surgery and 16 patients at disease recurrence; all patients had germline BRCA1/2 mutations. Targeted amplicon next-generation sequencing was used to determine mutation status; matched tumor and plasma samples were available in 24 of the 30 patients. The results of the analysis were published online ahead of print in the Journal of Clinical Oncology.

In tumor samples, reversion mutations were detected in four patients, all with recurrent disease; another sample was included for analysis from a rapid autopsy of one patient. The cfDNA analysis was also able to detect these reversion mutations in some patients. The cfDNA assay had a specificity of 1.00, meaning there were no false positives, and a sensitivity of 0.60; it had a positive predictive value of 1.00 and a negative predictive value of 0.90.

The researchers also examined the clinical relevance of these reversion mutations. They found that any patient with the reversions detected in cfDNA had become resistant to platin- or PARP inhibitor–based chemotherapy.

“Our findings show that detection of BRCA1/2 reversion mutations in cfDNA by targeted amplicon sequencing is feasible and indicates poor response to platin-based therapy or PARP inhibition,” the authors concluded, adding that variation in detection of reversions across sequencing runs suggests that the sensitivity of the assay still needs improvement. “The use of a noninvasive biomarker to direct treatment in a clinical trial of patients with recurrent disease is attractive to demonstrate clinical benefits, such as improvement in survival and through detection of reversions early in recurrence, and thereby avoiding use of ineffective therapy.”