Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance
- Deep Pandya1,6,
- Myra Shah2,6,
- Fuat Kaplan1,
- Candice Martino1,
- Gillian Levy3,
- Mia Kazanjian4,5,
- Stephen Batter5,
- John Martignetti1 and
- Richard C. Frank1,2
- 1Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, Connecticut 06810, USA;
- 2Department of Medicine, Norwalk Hospital, Nuvance Health, Norwalk, Connecticut 06856, USA;
- 3Department of Pathology, Norwalk Hospital, Nuvance Health, Norwalk, Connecticut 06856, USA;
- 4Department of Radiology, Norwalk Hospital, Nuvance Health, Norwalk, Connecticut 06856, USA;
- 5Department of Urology, Norwalk Hospital, Nuvance Health, Norwalk, Connecticut 06856, USA
- Corresponding author: richard.frank{at}nuvancehealth.org
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↵6 These authors contributed equally to this work.
Abstract
Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as BRCA1/2, are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the BRCA2 gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency.
Footnotes
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[Supplemental material is available for this article.]
- Received August 10, 2020.
- Accepted February 6, 2021.
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