BRCA Reversion Mutations Detected in Ovarian Tumor cfDNA

BRCA Reversion Mutations Detected in Ovarian Tumor cfDNAAcquired reversion mutations in BRCA1/2 are detectable in circulating cell-free DNA (cfDNA) in women with high-grade serous ovarian cancer (HGSC), according to a study published in the Journal of Clinical Oncology.1

BRCA1/2 mutations are associated with better response rates and progression-free survival with platinum-based chemotherapy and poly ADP ribose polymerase (PARP) inhibitors compared with BRCA–wild-type variants. Responses are frequently not durable, however, due to acquired resistance to therapy.

Secondary mutations that restore functionality to BRCA proteins were demonstrated to confer acquired platinum resistance in previously sensitive samples.2 The purpose of this study was to determine if such secondary mutations could be detected in cfDNA, which could affect treatment decisions for women with ovarian cancer.

Plasma and tumor samples from 30 women with primary BRCA1/mutations were analyzed for acquired mutations. The sample included 2 cohorts: 14 women undergoing primary HGSC debulking surgery who had had a prior cancer and 16 women with ovarian cancer recurrence.

Reversion mutations were identified in 5 patients, all of whom had disease recurrence. In 1 of these samples, cfDNA prior to chemotherapy was available and did not harbor the reversion mutation.

All patients with BRCA reversion mutations demonstrated disease resistance to platinum- or PARP-inhibitor–based chemotherapy. One patient with a reversion mutation failed therapy with cisplatin and a PARP inhibitor, but responded to gemcitabine and bevacizumab.

The sequencing results from cfDNA were matched to those of tumor DNA and indicated that a cfDNA assay specificity of 1.00, sensitivity of 0.60, positive predictive value of 1.00, and a negative predictive value of 0.90.

According to the authors, these findings suggest that cfDNA can be used to detect BRCAreversion mutations and “has the potential after further evaluation to be used to direct treatment in recurrent HGSC.”

References

  1. Christie EL, Fereday S, Doig K, Pattnaik S, Dawson SJ, and Bowtell DD. Reversion of BRCA1/2 germline mutations detected in circulating tumor DNA from patients with high-grade serous ovarian cancer. J Clin Oncol. 2017 Feb 13. doi: 10.1200/JCO.2016.70.4627 [Epub ahead of print]
  2. Sakai W, Swisher EM, Karlan BY, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008;451:1116-20. doi: 10.1038/nature06633

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