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Case Reports
. 2015 Oct 6:8:109.
doi: 10.1186/s13045-015-0204-7.

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

Kunal C Kadakia  1 , Scott A Tomlins  2 , Saagar K Sanghvi  3 , Andi K Cani  4 , Kei Omata  5 , Daniel H Hovelson  6 , Chia-Jen Liu  7 , Kathleen A Cooney  8
Affiliations
Case Reports

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

Kunal C Kadakia et al. J Hematol Oncol. .

Abstract

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).

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Figures

Fig. 1
Fig. 1
Histology of diagnostic (Dx) prostate biopsy (PR-259) with Gleason score 4 + 5 = 9 adenocarcinoma and subsequent post-treatment (Tx) liver biopsy (PR-258) containing small cell/neuroendocrine prostate carcinoma (NePC). Hematoxylin and eosin-stained diagnostic biopsy cores (top and middle panels) and liver biopsy (bottom panel) are shown. Original magnification 10× (insets indicated by green boxes 40×)
Fig. 2
Fig. 2
MRI Liver at the time of clinical progression. Axial T2-weighted MRI shows interval development of innumerable solid lesions in the liver, replacing a majority of the parenchyma in both hepatic lobes with development of a pseudocirrhotic appearance of the liver with a nodular surface contour
Fig. 3
Fig. 3
Next generation sequencing (NGS) genomic profiles support transdifferentiaton from prostatic adenocarcinoma (PR-259) to small cell/neuroendocrine prostate carcinoma (NePC, PR-258). Copy number plots and prioritized somatic mutations are shown. Points represent the log2 copy number ratio for all targeted genes (shown in genome order). Clonal gains and losses are shown in red and blue, respectively. Prioritized high-level copy number alterations (CNAs) alterations and somatic mutations (with variant allele frequency [%] and coverage depth [x]) are indicated. Clonal prioritized SMAD4 mutation and SCC enriched TP53 mutation and MYCL, PTEN, RB1, and MAP2K4 copy number alterations are indicated
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