- Case report
- Open Access
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. Sanghvi3,
- Andi K. Cani4,
- Kei Omata4,
- Daniel H. Hovelson4,
- Chia-Jen Liu4 and
- Kathleen A. Cooney1Email author
© Kadakia et al. 2015
Received: 22 July 2015
Accepted: 28 September 2015
Published: 6 October 2015
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.
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.
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.
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).
Precision oncology heralds an era in which tumors are biopsied and profiled in the metastatic setting with the goal of identifying therapeutic targets. Although next generation sequencing (NGS) of “N of 1” cases have identified mechanisms of exceptional response to investigational therapies [1–4], such approaches have largely not been applied to exceptional non-responders. Likewise, NGS profiling of pre-/post-treatment samples in cases with marked histologic progression, which enables assessment of progression mechanisms, is challenging due to difficulties in obtaining and assessing routine diagnostic biopsy samples. Here, we describe NGS assessment of routine clinical samples from a patient diagnosed with metastatic PCa at a young age who rapidly progressed and died from disease approximately 1 year from diagnosis. Importantly, while his primary tumor exclusively contained conventional prostatic adenocarcinoma, a post-treatment liver metastasis biopsy exclusively contained prostatic small cell carcinoma/NePC. Hence, this case provided a unique opportunity to assess the utility of NGS-based profiling of serial routine biopsy specimens from an “exceptional non-responder” who showed rapid histologic progression during treatment.
The patient signed a consent form to participate in an IRB-approved research study to sequence tumor and germline DNA from men presenting with metastatic PCa before age 60 years.
Tumor sequencing and analysis
Sequencing statistics for the diagnostic prostate biopsy sample containing conventional adenocarcinoma (PR-259) and subsequent liver metastasis with small cell/neuroendocrine carcinoma (PR-258)
Mapped reads (n)
On target reads (%)
Total aligned base reads
Total base reads on target
Average base coverage depth
Uniformity of base coverage
Target base coverage at 20×
Target base coverage at 100×
Target bases with no strand bias
Total called variantsa
Variants passing filteringb
Prioritized somatic variantsd
Total reads (n)
Uniquely mapped to genome (%)
Identified gene fusions (n)
High confidence, non-synonymous variants identified in the diagnostic prostate biopsy sample containing conventional adenocarcinoma (Dx [PR-259]) and subsequent liver metastasis with small cell/neuroendocrine carcinoma (NePC [PR-258])
Var. allele frequency (FAO/FDP)
Read depth (FDP)
Var. allele frequency (FAO/FDP)
Read depth (FDP)
We next compared NGS-derived copy number profiles between PR-259 and PR-258 using our well-validated approach [5–7]. Copy number profiling revealed broad one copy loss of 10q (containing PTEN), 18q, and a complex alteration on chromosome 19 in both specimens, whereas the post-treatment liver biopsy (PR-258) exclusively demonstrated focal, high-level MYCL amplification, and focal homozygous PTEN, RB1, and MAP2K4 deletions. Lastly, no gene fusions were identified in either PR-259 or PR-258 from targeted multiplexed PCR-based RNAseq on co-isolated RNA (see Additional file 1). Taken together with the somatic variant analysis, copy number profiling supported the clonal relationship between PR-259 and PR-285, and identified highly enriched, focal, high-level copy number alterations in the post-therapy NePC specimen.
Small cell carcinoma/(NePC) is a rare PCa variant with an aggressive phenotype. Although de novo NePC constitutes <1 % of all PCa, autopsy series of castration-resistant prostate cancer (CRPCa) suggest the presence of NePC in 10–25 % of cases . Despite high initial overall response rates (75–85 %) to platinum combinations, relapse to a chemo-refractory state is nearly universal with a median survival of less than 18 months .
Although initially posited as due to clonal selection of malignant neuroendocrine cells [10, 11], recent genetic evidence supports a model of NePC development due to transformation of prostate adenocarcinoma cells to a neuroendocrine phenotype, termed transdifferentiation (see review ). Consistent with the concept of a common clonal origin, recurrent prostate adenocarcinoma-specific alterations, such as recurrent ETS gene rearrangements, show concordant status in PCa admixed with NePC, and ETS rearrangement frequency is similar in conventional PCa and NePC [13–15]. Additionally, identical mutations in the DNA-binding domains of TP53 have been observed in paired prostate adenocarcinoma and NePC . The molecular mechanism of NePC development via transdifferentiation is also supported by a recent report showing gene amplification of AURKA and MYCN present in 65 % of adenocarcinomas that develop into NePC following ADT whereas only 5 % of unselected adenocarcinomas showing similar amplifications . Lastly, RNAseq profiling in matched NePC and prostate adenocarcinomas showed downregulation of the transcriptional complex REST, which is integral to the repression of neuronal differentiation .
SMAD4 mutation and MYCL1 amplification frequency in prostate cancer NGS and copy number profiling studies available in cBioPortal
Cases with mutation data (n)
Cases with CNA data (n)
Cases with SMAD4 mutations (%)
Cases with MYCL amplifications (%)
Prostate (Broad/Cornell 2013)
1 (1.8 %)
0 (0 %)
Prostate (TCGA 2015)
3 (0.9 %)
0 (0 %)
Prostate (Broad/Cornell 2012)
1 (0.9 %)
0 (0 %)
Prostate (MSKCC 2014)
0 (0 %)
PCa and CRPC
1 (1.6 %)
0 (0 %)
Prostate (MSKCC 2010)
PCa and CRPC
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
Hovelson et al. 2015
PCa and CRPC
1^ (0.8 %)
6 (0.7 %)
1 (0.08 %)
The TP53 p.R282W mutation enrichment and homozygous RB1 loss in the NePC sample herein supports single gene studies and our recent targeted NGS profiling of eight NePC that show frequent inactivation of these genes in NePC [7, 24, 25]. Likewise, in a recent study, we used qRT-PCR and a combination of exome/targeted NGS to profile distinct conventional PCa and NePC components from an FFPE transurethral resection specimen, which demonstrated enrichment of a TP53 p.N151fs mutation exclusively in the NePC component . Although both oncogenic and metastasis suppressive roles for MAP2K4 have been reported in PCa [27–29], its role in NePC has not been described and will require additional investigation.
As described above, recurrent MYCN amplifications have been well-described in NePC . Although a recent report identified recurrent MYCL amplifications in ~25 % of untreated Gleason score 7 PCa (>2 copies in 8–20 % of malignant glands) , clonal, high-level MYCL amplifications have not been observed in 1166 prior SNP-, aCGH-, or NGS-based copy number profiled untreated PCa or CRPC in cBioPortal (Table 3). However, in our previous NGS-based profiling of 116 aggressive PCas, we identified a single NePC (of 8 profiled) that harbored a high-level MCYL amplification (Additional file 2: Figure S1) . Likewise, copy number profiling of mouse NePC resulting from prostate-specific p53 and RB inactivation identified recurrent MYCL gains . MYCL amplifications and gene fusions have also been identified and shown to drive proliferation in small cell lung carcinomas [32–34]. Taken together with our previous NGS profiling study, herein we identify recurrent MYCL1 amplifications in NePC, which will need to be confirmed in additional NePC cohorts.
Alternate mechanisms for the development and maintenance of NE transdifferentiation have been described. The process of “epithelial plasticity” provides evidence for the diverse phenotype of NE-like tumor cells, such as the variable expression of epithelial and NE markers following androgen deprivation [12, 35–37]. This plasticity, which can occur via epithelial-to-mesenchymal transition (EMT) or mesenchymal-to-epithelial transition (MET), is regulated by a complex system of transcriptional networks and signaling pathways. The TMPRSS2-ERG fusion gene and certain microRNAs (i.e., miR-200 family) appear to promote the EMT phenotype leading, in part, to the castrate-resistant state [38, 39].
Importantly, neuroendocrine cancers involving other organ sites appear to have distinct molecular aberrations and highlight the need for individualized therapies . For example, telomerase reverse transcriptase (TERT) promoter mutations are observed in many human epithelial cancers as well as the vast majority of urothelial neuroendocrine carcinomas, however, they are rarely found in NE-prostate or -lung cancers [41, 42]. Given the molecular heterogeneity of neuroendocrine carcinomas, targeted approaches guided by appropriate biomarker identification, rather than or in addition to cytotoxic therapies, are paramount to improve outcomes .
A variety of novel therapeutics targeting receptor tyrosine kinases, mammalian target of rapamycin (mTOR), angiogenesis, cell cycle, epigenetics, and immunotherapy have been tested, largely in small cell lung cancer, with limited success [44, 45]. Specific to the mutational landscape of NEPC, a number of targeted therapies have been investigated in in vitro and in murine models with varied success (see review ). Targeting tumor suppressor loss (TP53, RB1, and PTEN) is particularly relevant to NEPC given the high frequency of these alterations. For example, SAR405838, a novel small molecule inhibitor of the oncoprotein murine double minute 2 (MDM2)-TP53 protein-protein interaction, showed significant activity in wild-type TP53 murine models, including LNCaP prostate cancer lines . Multiple small molecules that can activate TP53 are in early phase clinical trials, however, none at this time are recruiting patients with NEPC [46,48]. A phase II study of MLN8237, a small molecule inhibitor of Aurora Kinase A, is currently the only molecularly targeted trial enrolling men with CRPC with neuroendocrine features (NCT01799278).
A limitation of the current report is that it is based on NGS from one patient. Future case studies should consider application of immunohistochemical and morphoproteomic analyses, which might elucidate alternative mechanisms of resistance. The application of these tools has previously revealed means of response and resistance in two cases of refractory Ewing sarcoma that responded to combination therapy with insulin-like growth factor 1 receptor and mTOR inhibition .
“N of 1” cases provide unique hypothesis-generating opportunities with the potential to provide new information about pathogenic mechanisms and/or therapeutic response [2, 4]. We suggest that profiling of “exceptional non-responders” and temporally/histologically distinct tumor components [26, 50], as shown herein, may be as informative as “exceptional responder” studies and can exploit the wealth of archived diagnostic tissue specimens. Such studies may be particularly important for identifying the prognostic and predictive associations of rare alterations, such as SMAD4 mutations in prostate cancer, as well as identifying adaptive alterations associated with treatment resistance/progression such as MCYL amplifications.
Through comprehensive profiling of archived diagnostic and liver biopsy specimens from a single patient with an aggressive clinical course, we identify molecular alterations associated with rapid progression from prostatic adenocarcinoma to NePC, and more broadly identify MYCL as a recurrently amplified gene specifically in NePC.
This work was supported in part by the Evans Foundation/Prostate Cancer Foundation (to S.A.T), the National Institutes of Health (R01 CA183857 to S.A.T) and the Department of Defense (PC120464 to K.A.C.). S.A.T. was supported by University of Michigan Prostate SPORE Career Development Award and the A. Alfred Taubman Medical Research Institute.
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