Molecular Testing Identifies Determinants of Exceptional Response and Guides Precision Therapy in a Patient with Lethal, Treatment-emergent Neuroendocrine Prostate Cancer

Abstract

Nearly all prostate cancers start out as adenocarcinomas driven by the androgen receptor (AR). Neuroendocrine prostate cancer (NEPC) is a rare, AR-independent subtype with a poor prognosis and limited treatment options. Importantly, because of the widespread use of novel AR-targeting agents, the incidence of treatment-emergent (t)-NEPC is increasing in frequency. Molecular features commonly found in prostate adenocarcinomas are now well-recognized, including defects in homologous recombination (HR) genes, like breast cancer type 2 susceptibility protein (BRCA2), leading to increased sensitivity to deoxyribonucleic acid (DNA)damaging agents (e.g., platinum chemotherapy or poly adenosine diphosphate-ribose polymerase (PARP) inhibitors). However, our own prior work demonstrates that HR gene defects are uncommon in t-NEPC. Herein, we describe a patient who originally presented with adenocarcinoma but who subsequently developed t-NEPC. Molecular testing determined that his t-NEPC tumor (but not his original adenocarcinoma) harbored complete copy number loss of BRCA2, as well as copy number loss of another HR gene-ataxia telangiectasia, mutated (ATM). Uncharacteristically for t-NEPC, the patient achieved a complete response to platinum chemotherapy. Based on emerging data for the role of maintenance PARP inhibitor therapy in ovarian cancer patients whose tumors harbor BRCA1/2 defects, we treated him with PARP inhibitor maintenance after chemotherapy. At nine months follow-up, the patient was still in complete remission. This report demonstrates the importance of molecular testing to clarify the biology of exceptional responders and to direct treatment. Our results also suggest that clinical trials of PARP inhibitor maintenance may be warranted in select patients with advanced prostate cancer, including those with t-NEPC, whose tumors harbor HR defects.

Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance

“…Another case of BRCA2-alterered t-SCNC was recently reported by Turina et al (2019). In contrast to our patient, their patient did not have a gBRCA2 mutation but rather somatic complete copy-number loss of BRCA2 found on tumor genomic profiling.…”

Brain metastasis in a patient with BRCA2-mutated treatment-related neuroendocrine prostate carcinoma and long-term response to radiotherapy and Olaparib: A case report and literature review

“…Our search of the PubMed database using the keywords "neuroendocrine prostate cancer," "BRCA2 mutation," and "Case" yielded 13 case reports. [10][11][12][13][14][15][16][17][18][19][20][21][22] Of these, 5 cases from 4 articles involved individuals who had no prior history of cancer and were administered olaparib (Table 1). [12,15,21,22] In terms of age and initial PSA levels, the patient was younger and had a significantly higher PSA value than did the other cases presented in the Table 1.…”

“…[10][11][12][13][14][15][16][17][18][19][20][21][22] Of these, 5 cases from 4 articles involved individuals who had no prior history of cancer and were administered olaparib (Table 1). [12,15,21,22] In terms of age and initial PSA levels, the patient was younger and had a significantly higher PSA value than did the other cases presented in the Table 1. Furthermore, specific mutations such as PTEN, AR amplification, and TMPRSS2-ERG fusion were observed in prostate cancer specimens.…”

Narrative review of challenges in the management of advanced neuroendocrine prostate cancer

“…Regardless of the combination treatments, the median progression free survival was less than 5 months. Exceptional response to platinum or PARP inhibitors has been reported for NEPC cases with BRCA1/2 defects (56)(57)(58). In a small series of de-novo and t-NEPC, although the rate of somatic DNA repair alteration (BRCA1/2, and ATM) was similar between de-novo and t-NEPC (3/47 vs. 4/40), there were more patients with germline DNA repair alterations among denovo NEPC compared to t-NEPC (5/47 vs. 1/40) (11).…”