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Importance  Small cell carcinoma/neuroendocrine prostate cancer (NePC) is a lethal, poorly understood prostate cancer (PCa) subtype. Controversy exists about the origin of NePC in this setting.    Objective  To molecularly profile archived biopsy specimens from a case of early-onset PCa that rapidly progressed to NePC to identify drivers of the aggressive course and mechanisms of NePC origin and progression.    Design, setting, and participants  A 47-year-old patient presented with metastatic prostatic adenocarcinoma (Gleason score 9). After a 6-month response to androgen deprivation therapy, the patient developed jaundice and liver biopsy revealed exclusively NePC. Targeted next generation sequencing (NGS) from formalin-fixed paraffin-embedded (FFPE)-isolated DNA was performed from the diagnostic prostate biopsy and the liver biopsy at progression.    Intervention  Androgen deprivation therapy for adenocarcinoma followed by multiagent chemotherapy for NePC.    Main outcomes and measures  Identification of the mutational landscape in primary adenocarcinoma and NePC liver metastasis. Whether the NePC arose independently or was derived from the primary adenocarcinoma was considered based on mutational profiles.    Results  A deleterious somatic  SMAD4  L535fs variant was present in both prostate and liver specimens; however, a  TP53  R282W mutation was exclusively enriched in the liver specimen. Copy number analysis identified concordant, low-level alterations in both specimens, with focal  MYCL  amplification and homozygous  PTEN ,  RB1 , and  MAP2K4  losses identified exclusively in the NePC specimen. Integration with published genomic profiles identified  MYCL  as a recurrently amplified in NePC.    Conclusions and relevance  NGS of routine biopsy samples from an exceptional non-responder identified  SMAD4  as a driver of the aggressive course and supports derivation of NePC from primary adenocarcinoma (transdifferentiation).    Electronic supplementary material  The online version of this article (doi:10.1186/s13045-015-0204-7) contains supplementary material, which is available to authorized users.

journal of hematology and oncology

Comprehensive serial molecular profiling of an “N of 1” exceptional non-responder with metastatic prostate cancer progressing to small cell carcinoma on treatment