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Rucaparib in Ovarian Cancer: Reversion Mutations in Predicting Treatment Resistance

By: Celeste L. Dixon
Posted: Wednesday, April 3, 2019

In some patients with high-grade ovarian carcinoma, testing circulating cell-free DNA prior to treatment with rucaparib may help to predict whether their disease will quickly become resistant to the drug, indicated the results of a study published in Cancer Discovery. Included in the trial were about 100 women with deleterious germline or somatic BRCA mutations.

Elizabeth M. Swisher, MD, of the University of Washington, Seattle, and colleagues performed targeted next-generation sequencing on samples of the patients’ pretreatment and postprogression circulating cell-free DNA. BRCA reversion mutations were identified in the pretreatment DNA of 18% of the women whose disease was later platinum-refractory (2 of 11) and 13% of those whose cancer was later platinum-resistant (5 of 38). Those mutations were seen in 2% of women who had platinum-sensitive cancers (1 of 48; P = .049). The samples were previously collected from enrollees in the phase II ARIEL2 trial.

The researchers noted that “BRCA reversion mutations…restore protein function, [providing] a key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers.” In this study, the progression-free survival of patients on the PARP inhibitor rucaparib who had BRCA reversion mutations in pretreatment cell-free DNA was significantly longer than that of those who had these mutations (median, 9.0 vs. 1.8 months; hazard ratio = 0.12; P < .0001).

The findings are relevant to clinical decision-making. Dr. Swisher and her team pointed out that in allof the cases they studied, “reversion mutations identified in cell-free DNA…[were] associat[ed] with concurrent or imminent progression.” In a similar patient scenario, a change in therapy would be warranted, the work indicated.

Disclosure: The study authors’ disclosure information may be found at aacrjournals.org.



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