BRCA2 Alterations in Neuroendocrine/Small-Cell Carcinoma Prostate Cancer: A Case Series

Introduction

Neuroendocrine prostate cancer (NEPC) is an aggressive variant characterized by poor prognosis, increased frequency of visceral metastasis, and diminished response to hormone therapy.^1-3 The term NEPC generally encompasses a spectrum of histology and molecular characteristics ranging from pure histologic small-cell carcinoma to mixed tumors with prostate adenocarcinoma and carcinoma with neuroendocrine features.^4-6 Transformation of adenocarcinoma to neuroendocrine or small-cell typically emerges later in the disease course after hormonal treatment as a mechanism of resistance.^7,8 De novo neuroendocrine or small-cell prostate cancer is rare, occurring in < 1%-2% of cases at diagnosis³; however, treatment-emergent neuroendocrine differentiation is present in up to 17%-25% of patients with castration-resistant prostate cancer (CRPC).^9-11 DNA damage repair gene mutations including BRCA2 are common in metastatic prostate cancer, and identifying them is crucial since they predict sensitivity to therapeutics such as poly-(ADP ribose) polymerase (PARP) inhibitors and platinum chemotherapy.^12-16 However, there have been conflicting reports regarding the frequency of BRCA2 mutations in NEPC.^10,17 Here, we report the case of a patient with metastatic prostate cancer initially diagnosed with adenocarcinoma which later transdifferentiated into morphologic small-cell carcinoma. He was found to have biallelic loss of BRCA2 and was successfully treated with platinum/etoposide, followed by maintenance olaparib with prolonged response. We additionally report data from our institution which suggest that BRCA2 alterations and NEPC are not mutually exclusive and may co-occur more frequently than previously recognized.

Case

The patient was diagnosed with localized prostate cancer at age 64 years with a prostate-specific antigen (PSA) of 3.9 ng/mL and biopsy which showed Gleason 4 + 3 = 7 adenocarcinoma. His history is also notable for male breast cancer diagnosed at age 47 years, basal cell carcinoma at age 63 years, and a spinal cord tumor (presumed low-grade astrocytoma). He is of Ashkenazi descent, and family history was notable for a sister with uterine cancer, brother with lung cancer (never smoker), paternal uncle with prostate cancer, paternal uncle with colon cancer, and a paternal cousin with breast cancer. Multiple family members also had basal cell carcinomas. He had germline genetic testing performed using multiple platforms including Color Genomics and the University of Washington BROCA test¹⁸ which did not reveal an explanatory germline mutation.

The patient underwent definitive treatment with brachytherapy at the time of prostate cancer diagnosis. Four years later he was found to have local recurrence and initiated intermittent androgen deprivation therapy. After 2 years, he developed nonmetastatic, castration-resistant disease which was treated initially with ketoconazole and prednisone. He then developed biochemical and local progression and transitioned to enzalutamide. After 26 months on enzalutamide, his PSA rose to 2.17 ng/mL, and imaging revealed seminal vesicle enlargement and nodal metastasis. Given the low PSA, biopsy was performed of the nodal metastasis, and pathology demonstrated morphologic small-cell carcinoma of prostatic origin consistent with transdifferentiation on the basis of morphology and uniformly positive synaptophysin staining and focal positive NK3.1 staining by immunohistochemistry. Next-generation sequencing using UW-OncoPlex¹⁹ was also performed, which showed BRCA2 homozygous copy loss. Subsequent fluorodeoxyglucose positron emission tomography imaging showed liver and lung metastases. He was treated with six cycles of carboplatin and etoposide with complete biochemical and radiographic response. He then initiated olaparib maintenance therapy, which he tolerated well and had ongoing complete response (CR).

Eighteen months after initiation of olaparib, he developed worsening cytopenias. Bone marrow biopsy showed > 20% abnormal myeloid blasts/promyelocytes with fluorescent in situ hybridization positive for translocation 15;17 consistent with secondary acute promyelocytic leukemia (APML). He received induction therapy with all-trans retinoic acid and arsenic and achieved a complete remission. He started consolidation chemotherapy, but arsenic was discontinued during the first cycle because of neuropathy. He then completed three cycles of all-trans retinoic acid/idarubicin and remains in remission from APML 22 months after diagnosis. Olaparib was resumed, and he maintains a CR of his prostate cancer with undetectable PSA and no radiographic evidence of disease 48 months after diagnosis of metastatic small-cell carcinoma of the prostate.

Results

We reviewed institutional data to identify patients with both NEPC (as defined previously^4,20) and pathogenic biallelic BRCA2 alterations. Between February 4, 2014, and February 22, 2021, there were 381 patients with prostate cancer who underwent next-generation sequencing by UW-OncoPlex, a multiplexed mutation assay that assesses mutations in over 350 genes including single-nucleotide variants, small insertions and deletions, gene amplifications, and selected gene fusions. In the UW-OncoPlex sequencing set, there were 354 patients with prostate cancer who also had pathology available for review. All patients had metastatic disease. Overall, 37 of 354 (10%) cases had biallelic BRCA2 alterations and 31 of 354 (9%) cases had neuroendocrine or small-cell histology. There were 8 cases (2.3%) that had concurrent NEPC histology and biallelic BRCA2 alterations of whom 4 patients had morphologic small-cell carcinoma and four patients had NEPC.^4,20 An additional three patients were identified with coexisting NEPC and BRCA2 alterations sequenced through other platforms. In total, we identified 11 patients with concurrent biallelic BRCA2 inactivation and NEPC/SCNC. Of the subset of UW-OncoPlex patients positive for NEPC histology, 8 of 31 (26%) had biallelic BRCA2 alterations, which was significantly higher than the incidence of BRCA2 mutations identified in those without NEPC histology (29 of 323, 9%; P = .003; Table 1). Additional features are described in Table 1.

TABLE 1.

Patient and Disease Characteristics

Discussion

NEPC is an aggressive variant of prostate cancer that most commonly occurs in the setting of castration-resistant disease. As NEPC often shares clinical and molecular features of other small cell-carcinomas,²¹ first-line treatment often involves platinum-based chemotherapy regimens.^22-24 However, even after platinum-based treatment, the prognosis is poor with a median survival of < 12 months.² Additional treatment strategies are needed to improve outcomes, and the recognition that biallelic BRCA inactivation is more common in NEPC than previously recognized may provide avenues to improve outcomes.

PARP inhibitors effectively treat BRCA2-deficient tumors by blocking salvage DNA repair pathways, resulting in synthetic lethality.²⁵ PARP inhibitors now play an important role in the treatment of metastatic CRPC, and both olaparib and rucaparib have been US Food and Drug Administration–approved for use in patients with BRCA1/2 alterations.^13,26,27 Identifying patients with these mutations has become crucial as it may expand effective treatment options.

Somatic mutations in DNA repair pathway genes, including BRCA2, are common, with 13% of patients with mCRPC harboring somatic and/or and germline BRCA2 alterations, and approximately 90% of these demonstrate biallelic inactivation.¹⁵ However, data regarding the frequency of DNA repair pathway gene alterations in NEPC remain conflicting. Aggarwal et al previously reported that the presence of deleterious mutations and/or copy number loss in DNA repair pathway genes (eg, BRCA2) was nearly mutually exclusive in the setting of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC).¹⁰ They conducted a multi-institutional prospective study to characterize the features of t-SCNC and found that only 1 of 12 (8%) of t-SCNC biopsy specimens had evidence of DNA repair inactivation (all types of any DNA repair gene) versus 29 of 73 (40%) of biopsy specimens without t-SCNC, P = .035. However, in a phase II clinical trial of 60 patients with metastatic prostate cancer who met predefined criteria for NEPC, Beltran et al¹⁷ found genomic alterations BRCA2 in 29% of patients, although only four (8%) patients had identifiable biallelic alterations.

We report that in this series, 26% of patients with NEPC had detectable biallelic BRCA2 alterations and that 21% of these occurred in NEPC. This suggests that a higher proportion of patients with NEPC have biallelic BRCA2 alterations than has previously been described and supports sequencing of these patients to detect these alterations. Although we surveyed all patients with prostate cancer whose tumors had been sequenced with the UW-OncoPlex platform, biases regarding which patients underwent sequencing represent significant confounders. We additionally report the case of one of these patients successfully treated with platinum-based chemotherapy followed by maintenance olaparib with an exceptional response and who currently has no evidence of disease 4 years after diagnosis of t-SCNC. His case, to our knowledge, is also the first published case of secondary APML in a patient with prostate cancer treated with olaparib. Remarkably, both t-SCNC and secondary APML remain in CR and complete remission, respectively, the latter consistent with prior reports of excellent outcomes with contemporary treatment of APML.^28-30

Of note, there is a prior case report of an exceptional responder with de novo small-cell cancer of the prostate and BRCA2 loss and treated with Olaparib.³¹ The current report adds a comprehensive institutional sequencing review of the increased frequency of underlying BRCA2 inactivation in NEPC using a single platform to consistently identify BRCA2. In addition, our patient illustrates the potential for an induction/maintenance approach which decreases toxicity to other agents and is the first reported case of secondary APML due to olaparib exposure in a patient with prostate cancer. Both reports emphasize the importance of an interrogation of tissue for BRCA2 in neuroendocrine or small-cell prostate carcinoma where prognosis is poor and treatment options are limited. Additional multi-institutional studies are needed to better understand the prevalence of BRCA2 alterations in neuroendocrine/small-cell carcinoma prostate cancer and to assess the use of induction/maintenance which may prove an effective treatment strategy.

AUTHOR CONTRIBUTIONS

Conception and design: Peter S. Nelson, Bruce Montgomery

Financial support: Peter S. Nelson

Administrative support: Bruce Montgomery

Provision of study materials or patients: Funda Vakar-Lopez, Heather H. Cheng, Peter S. Nelson, Colin C. Pritchard

Collection and assembly of data: Erik Konnick, Funda Vakar-Lopez, Heather H. Cheng, Colin C. Pritchard, Bruce Montgomery

Data analysis and interpretation: Lynn Symonds, Erik Konnick, Heather H. Cheng, Michael T. Schweizer, Peter S. Nelson, Colin C. Pritchard, Bruce Montgomery

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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