SPOP mutated/ CHD1 deleted lethal prostate cancer and abiraterone sensitivity.

Purpose: CHD1 deletions and SPOP mutations frequently co-occur in prostate cancer (PCa) with lower frequencies reported in castration-resistant PCa (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of CHD1 deleted/ SPOP mutated metastatic CRPC (mCRPC). Experimental Design: We identified mCRPC 89 patients who had hormone naive and castration resistant tumor samples available: these were analyzed for CHD1, PTEN and ERG expression by immunohistochemistry (IHC). SPOP status was determined by targeted next generation sequencing (NGS). We studied the correlations between these biomarkers and a) overall survival from diagnosis; b) overall survival from CRPC; c) duration of abiraterone treatment and d) response to abiraterone. Relationship with outcome was analysed using Cox-regression and Log-Rank analyses. Results: CHD1 protein loss was detected in 11 (15%) and 13 (17%) of HSPC and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic SPOP mutations, with 6 of these mutations not reported previously in PCa. SPOP mutations and/ or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR=14.50 p=0.001; CHD1: OR=7.30, p=0.08) and a longer time on abiraterone (SPOP: HR=0.37, p=0.002, CHD1: HR=0.50, p=0.06). Conclusion:SPOP mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment.

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