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Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma

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University of Washington Seattle United States

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The breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 and BRCA12 are key components of the Fanconi anemia FAhomologous recombination HR pathway of DNA repair. Based on previous work in the Swisher and Kaufmann laboratories, we proposed to test the hypothesis that two different conditions must be met for ovarian cancer to be hypersensitive to platinum and PARP inhibitors The FAHR pathway must remain disabled and NHEJ must remain intact and functional. Although we proposed two aims, the aim in previously banked specimens was removed before the present grant was awarded, leaving us with the following aim Correlate biomarkers of HR deficiency and NHEJ pathway integrity in pre-treatment biopsies with response to a PARPi in a prospective single-agent PARPi phase 2 clinical trial in sporadic ovarian carcinoma. We obtained blood and tissue specimens from the phase 2 rucaparib trial ARIEL2, identifier NCT01891344 and completed sequencing of 75 DNA repair genes on blood and tumor samples fro ARIEL2. We found the HR mutations and methylation both predicted response to rucaparib and these findings are being prospectively followed up in the phase 3 trial ARIEL3.

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Technical Report,30 Sep 2013,29 Sep 2016



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Approved For Public Release;

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