Precision medicine program for whole-exome sequencing (WES) provides new insight on platinum sensitivity in advanced prostate cancer (PCa).

158 Background: WES has provided insight into the genomic landscape of PCa. The next step for precision medicine requires prospective patient (pt) follow-up and clinical and functional validation of both common and low frequency mutations. We describe a precision medicine WES program and illustrate how this can be used to identify novel biomarkers associated with response. Methods: Metastatic PCa pts were prospectively enrolled. WES of metastatic biopsies or rapid autopsies and normal DNA were sequenced by Illumina HiSeq 2500. Results: Tumor-normal pairs from 71 pts with metastatic PCa (11 hormone naïve, 38 CRPC, 23 NEPC) were sequenced including 3 rapid autopsies, with a biopsy success rate of >95%, avg tumor purity 10-95%, avg coverage 85X. The spectrum of mutations across metastatic PCa and how serial biopsies and rapid autopsies were used to assess heterogeneity and clonal evolution will be presented. WES from a metastatic PCa pt (PM12) with exceptional response to platinum with complete remission of liver and lung metastases at 2 years follow-up, demonstrated a hypermutated genotype and hemizygous deletion of the DNA repair gene FANCA in both his primary and metastatic PCa. A loss of function germline variant was detected within the second allele, and only the mutated allele was expressed in his tumor. Genome editing of FANCA using CRISPR in PCa cell lines resulted in cisplatin hypersensitivity and a significant decrease in FANC complex formation. In patient derived xenograft (PDX) models, PM12’s PDX was significantly more sensitive to cisplatin compared to a control Pca PDX of similar morphology but lacking FANCA deletion. By screening larger cohorts, FANCA loss was detected by FISH in 16% of localized PCa (n= 69), 14% metastatic Pca (n= 29), and not detected in any benign prostate (n=69). Conclusions: Our study provides a proof of principle for developing a precision medicine approach to cancer care with the capability to identify potential biomarkers of response. Our findings suggest that a subset of PCa with FANCA loss may be particularly vulnerable to cytotoxic therapy and provides biologic rationale to help explain the exceptional response of pt PM12 to platinum chemotherapy.

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