Reversion mutations may predict chemotherapy response in recurrent serous ovarian cancer
The detection of reversion BRCA1 or BRCA2 mutations among women with recurrent high-grade serous ovarian cancer predicted response to chemotherapy treatment, according to study results.
“This study demonstrates that analysis of circulating cell-free DNA (cfDNA) can detect reversion mutations in an unbiased manner and has the potential after further evaluation to be used to direct treatment in recurrent high-grade serous ovarian cancer,” David D.L. Bowtell, PhD, head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre in Victoria, Australia, and colleagues wrote.
There are no predictive markers of response used to guide drug selection in recurrent high-grade serous ovarian cancer, other than the length or remission after earlier therapy with platinum-based agents. Because knowledge of tumor reversion status and chemoresistance may impact treatment planning, Bowtell and colleagues sought to evaluate whether BRCA1/BRCA2 reversion mutations could be identified in cfDNA as a noninvasive test.
The researchers compared plasma and tumor samples isolated from 30 patients with BRCA1 or BRCA2 germline mutations, 14 of whom had a malignancy prior to undergoing primary debulking surgery and 16 of whom had recurring disease.
Using targeted amplicon, next-generation sequencing, researchers identified five patients with intragenic mutations predicted to restore BRCA1/BRCA2 open reading frames, including two patients with multiple independent reversion alleles. Reversion mutations were only found in tumor samples from patients with recurrent disease (n = 5 of 16) and only in cfDNA from patients with a tumor-detected reversion (n = 3 of 5).
The assay had a specificity of 1 — there were no false positives — and a sensitivity of 0.6, with a positive-predictive value of 1 and negative-predictive value of 0.9.
A rapid autopsy of a patient with multiple independent reversions showed that reversion-allele frequency in metastatic sites is vital to assay sensitivity. In addition, the abundance of tumor-derived DNA in total cfDNA also impacted assay sensitivity.
“Our findings encourage the development of assays with improved sensitivity and consistency, perhaps through use of molecular barcoding and methods to reduce polymerase chain reaction and sequencing error, followed by the evaluation of larger numbers of samples collected globally from patients with primary high-grade serous carcinoma after treatment of a prior malignancy, recurrent high-grade serous carcinoma and other malignancies associated with germline BRCA1/BRCA2 mutations,” the researchers wrote. – by Melinda Stevens
Disclosures: Bowtell reports research funding from AstraZeneca and Genentech, and travel accommodations and expenses from Genentech. Another researcher reports stock ownership in CLS Limited.