Characterization of transcriptomic signature of primary prostate cancer analogous to prostatic small cell neuroendocrine carcinoma

Prostatic small cell neuroendocrine carcinoma (SC/NE) is well studied in metastatic castration‐resistant prostate cancer; however, it is not well characterized in the primary setting. Herein, we used gene expression profiling of SC/NE prostate cancer (PCa) to develop a 212 gene signature to identify treatment‐naïve primary prostatic tumors that are molecularly analogous to SC/NE (SC/NE‐like PCa). The 212 gene signature was tested in several cohorts confirming similar molecular profile between prostatic SC/NE and small cell lung carcinoma. The signature was then translated into a genomic score (SCGScore) using modularized logistic regression modeling and validated in four independent cohorts achieving an average AUC >0.95. The signature was evaluated in more than 25,000 primary adenocarcinomas to characterize the biology, prognosis and potential therapeutic response of predicted SC/NE‐like tumors. Assessing SCGScore in a prospective cohort of 17,967 RP and 6,697 biopsy treatment‐naïve primary tumors from the Decipher Genomic Resource Information Database registry, approximately 1% of the patients were found to have a SC/NE‐like transcriptional profile, whereas 0.5 and 3% of GG1 and GG5 patients respectively showed to be SC/NE‐like. More than 80% of these patients are genomically high‐risk based on Decipher score. Interrogating in vitro drug sensitivity analyses, SC/NE‐like prostatic tumors showed higher response to PARP and HDAC inhibitors. What's new? While genomic/transcriptomic data analysis has revolutionized cancer biology, this analysis is frequently only available late in the cancer history, often after years of therapy. Here the authors built a single sample genomic classifier to predict primary prostate cancer tumors with early small cell neuroendocrine differentiation. They show in three independent cohorts that small cell neuroendocrine tumors of the prostate are similar to small cell tumors of the lung and predict the specific prostate tumors to be responsive to inhibitors of poly ADP ribose polymerase and histone deacetylases, underscoring the use of these drugs in this subtype of prostate cancer.