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. 2019 Nov:121:7-18.
doi: 10.1016/j.ejca.2019.08.011. Epub 2019 Sep 13.

Clinical features of neuroendocrine prostate cancer

Vincenza Conteduca  1 , Clara Oromendia  2 , Kenneth W Eng  3 , Rohan Bareja  3 , Michael Sigouros  4 , Ana Molina  5 , Bishoy M Faltas  5 , Andrea Sboner  3 , Juan Miguel Mosquera  6 , Olivier Elemento  3 , David M Nanus  5 , Scott T Tagawa  5 , Karla V Ballman  2 , Himisha Beltran  7
Affiliations

Clinical features of neuroendocrine prostate cancer

Vincenza Conteduca et al. Eur J Cancer. 2019 Nov.

Abstract

Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. Despite being important to recognise, the clinical features of NEPC are poorly defined and could help guide when to perform a biopsy to look for NEPC histologic transformation.

Methods: We reviewed baseline, treatment and outcome data of 87 patients with metastatic prostate cancer and tumour biopsy confirming NEPC histology. Forty-seven (54.0%) NEPC cases presented de novo, and 40 (46.0%) were therapy-related (t-NEPC). Thirty-six (41.4%) were classified as pure small-cell carcinoma, and 51 (58.6%) demonstrated mixed features with both small-cell carcinoma and adenocarcinoma present. Genomic data were available for 47 patients.

Results: The median age at time of NEPC was 68.1 years, median prostate-specific antigen (PSA) was 1.20 ng/ml (0.14 ng/mL small-cell carcinoma, 1.55 ng/mL mixed carcinoma) and sites of metastases included bone (72.6%), lymph node (47.0%), and viscera (65.5%). Median time from adenocarcinoma to t-NEPC diagnosis was 39.7 months (range, 24.5-93.8) with a median of two lines of prior systemic therapy. Platinum chemotherapy was used to treat 57.5% of patients, with a median progression-free survival of 3.9 months. Small-cell carcinoma was associated with worse overall survival (OS) than mixed histology (8.9 months from NEPC diagnosis versus 26.1 months, P < 0.001). Median OS of de novo NEPC was shorter than that of t-NEPC (16.8 months from prostate cancer diagnosis versus 53.5 months, P = 0.043). An average PSA rise per month of ≤0.7 ng/ml before t-NEPC; elevated lactate dehydrogenase levels, RB1 and TP53 loss and liver metastases were poor prognostic features.

Conclusions: We describe the clinical features of a cohort of patients with NEPC. These characteristics may inform future diagnostic strategies.

Keywords: Aggressive variant; Neuroendocrine prostate cancer; Small-cell carcinoma; Treatment resistance.

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Conflict of interest statement

Conflict of interest statement

V.C. received speaker honoraria or travel support from Astellas, Janssen-Cilag, Ipsen Fund and Sanofi Gemzyme and consulting fee from Bayer. S.T. has served as consultant/advisory board member for Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomeidics, Karyiopharm Therapeutics, Abbvie, Tolmar, QED, Amgen, Sanofi, Pfizer, and has received research funding (Inst) from Lilly, Sanofi, Janssen, Astellas Pharma, Progenics, Millenium, Amgen, Brystol-Myers Squibb, Dendreon, Rexahn Pharamceuticals, Bayer, Genentech, Newlink Genetics,Inovio Pharamceuticals, AstraZaneca, Immunomedics, Novartis, AVEO, Boehringer Ingelheim, Merck, Stem CentRx, Karyopharm Therapeutics, Abbvie, Medivation, Endocyte, Exelixis, Clovis Oncology, and has received speaker honoraria or travel support from Sanofi, Immunomedics, and Amgen. H.B. has served as a consultant/advisory board member for Janssen, Sanofi and Astellas and has received research funding from Janssen Oncology (Inst), AbbVie / Stem-centrx, Eli Lilly (Inst) and Millennium Pharmaceuticals (Inst). No potential conflicts of interest were disclosed by the other authors.

Figures

Fig. 1.
Fig. 1.
Flow chart of evaluable clinical and molecular profiling in patients with NEPC. NEPC, neuroendocrine prostate cancer; ADT, androgen deprivation therapy.
Fig. 2.
Fig. 2.. Overall survival (OS) in a cohort of patients with NEPC.
OS from diagnosis of prostate cancer (PCA) (A) and from diagnosis of NEPC (B). OS in mixed versus small-cell carcinoma from diagnosis of PCA (C) and from diagnosis of NEPC (D). OS in de novo versus therapy-related NEPC from diagnosis of PCA (E) and from diagnosis of NEPC (F). In the X axis of survival curves, different time scales are used for A, C and E compared with B, D and F panels because of significant different time intervals between OS from PCA diagnosis and OS from NEPC diagnosis. NEPC, neuroendocrine prostate cancer.
Fig. 3.
Fig. 3.. Genomic landscape of NEPC and CRPC adenocarcinoma cases detected by whole-exome sequencing.
Genomic aberrations (point mutations and copy number variations) were for selected genes including AR, TP53, RB1, DNA repair pathway (BRCA1, BRCA2, ATM) and PTEN. NEPC, neuroendocrine prostate cancer; CRPC, castration-resistant prostate cancer.
Fig. 4.
Fig. 4.. Exploratory CRPC adenocarcinoma patterns of early transformation into NEPC.
Frequency of liver metastasis (A) and laboratory values (PSA, CGA, NSE) (B) at different time points from diagnosis of prostate cancer (PCA) through the castration-resistant state (CRPC) to the appearance of NEPC. NEPC, neuroendocrine prostate cancer; CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen; CGA, chromogranin A; NSE, neuron-specific enolase.
See this image and copyright information in PMC

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