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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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Technical Report,30 Sep 2014,29 Sep 2015

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University of Washington Seattle United States

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BRCA1 and BRCA2 BRCA12 are key components of the Fanconi anemia FAhomologous recombination HR pathway of DNA repair. Cancer cells with deleterious FAHR pathway mutations are hypersensitive to polyADP-ribose polymerasePARP inhibitors. However, only about half of the cancer patients with germline FAHR pathway mutations respond to PARPinhibitors, raising the question of why a substantial fraction of HR-deficient cancers are resistant to these agents in the clinic. 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. Our aim is to Correlate biomarkers of HR deficiency andNHEJ pathway integrity in pre-treatment biopsies with response to a PARPi in a prospective single-agent PARPiphase 2 clinical trial in recurrent ovarian carcinoma. Over the past 12 months we have i completed IRB and HRPO review of our project, ii developed sequencing and genomic scarring assay to assess large number of DNA repair genes on small core biopsy specimens iv begun accessioning samples from the phase 2 rucaparib trial Ariel 2, NCT01891344.

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