Abstract
Background/Aim: This study aimed to investigate the genomic features of small cell neuroendocrine prostate cancer (SCPC) in Japanese patients, assess their relationships with platinum-based chemotherapy efficacy, and evaluate the potential treatment eligibility for therapies using cancer genomic profiling.
Patients and Methods: This retrospective study included 21 patients diagnosed with SCPC between 2018 and 2022. An expert pathologist reviewed the biopsy specimens according to the World Health Organization prostate cancer classification. Biopsy samples from primary or metastatic lesions were analyzed using FoundationOne® CDx to identify genomic mutations, focusing on DNA damage repair (DDR) mutations and other clinically relevant alterations. Platinum-based chemotherapy efficacy was assessed using progression-free survival (PFS) and overall survival (OS) outcomes.
Results: DDR mutations were detected in eight (38.1%) patients, and BRCA mutations were present in three (14.3%) cases. TP53 and RB1 mutations were identified in 15 (71.4%) and 12 (57.1%) cases, respectively. Three (14.8%) patients were identified with microsatellite instability-high or tumor mutational burden-high, making them eligible for immune checkpoint inhibitor treatment. PFS/OS rates suggested that the presence of these mutations did not significantly impact platinum-based chemotherapy efficacy. Six (28.6%) patients were eligible for treatments approved for prostate cancer in Japan as of 2024.
Conclusion: This study is the first to reveal the SCPC genomic landscape in Japanese patients. Although genomic mutations, including DDR mutations, were not predictive of platinum-based chemotherapy efficacy, active genomic testing may improve access to targeted therapies for this challenging malignancy, especially where treatment options are limited.
Introduction
Androgen deprivation therapy (ADT) plays an essential role in the treatment of prostate cancer. However, tumors can develop resistance and progress to castration-resistant prostate cancer (CRPC) (1). In some cases, ADT leads to the emergence of a highly aggressive phenotype known as neuroendocrine prostate cancer (NEPC), referred to as treatment-related NEPC (t-NEPC) (2). Approximately 20% of patients who receive long-term ADT reportedly develop this histological subtype, suggesting that the actual number of affected patients may be higher than previously believed (3). Furthermore, although improved long-term outcomes have been observed, there is growing concern that the t-NEPC incidence may increase with the recent introduction of androgen receptor signaling inhibitors (ARSIs) at various stages of prostate cancer treatment (4). Unlike conventional CRPC, t-NEPC is less responsive to ARSI or docetaxel treatment. Therefore, patients with t-NEPC are typically treated with platinum-based chemotherapy because of the clinical and molecular similarities with small cell lung cancer (5). However, the prognostic factors remain unclear, and the therapeutic efficacy is often suboptimal (6, 7), highlighting the urgent need for new treatment strategies.
Several studies have analyzed the molecular characteristics of NEPC using next-generation sequencing (NGS) (8, 9). With the increasing availability of cancer genomic profiling in routine practice, precision medicine is now possible based on the presence of specific genetic mutations in a patient’s genome. However, information on the prevalence of certain mutations that can be targeted for treatment remains unclear, partly because of the diagnostic challenges associated with NEPC (10). Additionally, while genetic differences have been reported in patients with prostate cancer across racial backgrounds (11, 12), to the best of our knowledge, no large-scale studies have investigated the genomic features of t-NEPC in Japanese patients.
In this study, we performed cancer genomic profiling on biopsy samples from patients with t-NEPC. We aimed to not only investigate the mutation distribution, but also to assess the efficacy of platinum-based chemotherapy and evaluate the treatment completion rate in this patient population. By exploring these factors, we seek to contribute to a better understanding of the t-NEPC molecular landscape and potentially identify novel therapeutic targets that can improve treatment outcomes.
Patients and Methods
This retrospective study evaluated 25 patients diagnosed with small cell type t-NEPC between October 2018 and December 2022 at Kobe University and affiliated hospitals. All included patients were clinically suspected of having NEPC following more than six months of ADT or ARSI treatment. Biopsy samples were collected from either primary or metastatic lesions at sites of disease progression, with the diagnosis of small cell type NEPC confirmed histologically. An expert pathologist (NJ) reviewed the biopsy specimens according to the World Health Organization classification of prostate cancer (13). Cases diagnosed as large cell neuroendocrine carcinoma or mixed NEPC were excluded from the study.
The biopsy samples underwent cancer genomic profiling (NGS) using FoundationOne® (Foundation Medicine, Inc., Cambridge, MA, USA) (14). The pathogenicity of genetic variants was initially assessed using the FoundationOne report, with manual verification performed via public databases, including the Human Genome Mutation Database (HGMD; Qiagen, Hilden, Germany) and ClinVar (National Center for Biotechnology Information, Bethesda, MD, USA).
Patients were classified as having DNA damage repair gene mutations (DDRmut) if they harbored at least one mutation in any of the following genes: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, NBN, PALB2, RAD50, RAD51, and RAD51C.
All statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Statistical significance was defined as p<0.05. Progression-free survival (PFS) and overall survival (OS) were calculated from the initiation of platinum-based chemotherapy and analyzed using the log-rank test.
The study protocol was approved by the Institutional Ethical Committee of Kobe University Hospital (approval number B220013) and written informed consent was obtained from all patients.
Results
Of the 25 patients diagnosed with t-NEPC, four were excluded because of insufficient specimens for NGS. The clinical characteristics of the remaining 21 patients are presented in Table I. Nine patients (42.9%) had previously received ARSI treatment. The median time from ADT initiation to t-NEPC development was 40.5 months. At the time of t-NEPC diagnosis, 20 patients (95.2%) had visceral metastasis at one or more sites, with seven (33.3%) having liver metastasis, nine (42.9%) having lung metastasis, and 12 (57.1%) having bone metastasis. The median prostate-specific antigen (PSA) level at t-NEPC diagnosis was 0.043 ng/ml.
Baseline characteristics of 21 patients with treatment-related neuroendocrine prostate cancer (t-NEPC).
All patients received platinum-based chemotherapy (cisplatin/carboplatin and etoposide) immediately after being diagnosed with t-NEPC.
Figure 1 illustrates the genomic alterations found in the analyzed t-NEPC samples. All alterations were detected by FoundationOne® CDx. An androgen receptor (AR) amplification was identified in one patient (4.8%). Alterations in RB1 and TP53, which are reportedly associated with neuroendocrine transformation in prostate cancer, were detected in 12 (57.1%) and 15 (71.4%) patients, respectively. In total, 19 patients (90.5%) had alterations in either RB1 or TP53. BRCA2 alterations were observed in three patients (14.3%), including two with frameshift mutations and one with a nonsense mutation. In addition, alterations of DDR-related genes, such as ATM, NBN, and RAD51, were found in two (9.5%), three (14.3%), and one (4.8%) patients, respectively. One patient had both NBN and RAD51 mutations, bringing the total number of patients with DDR mutations to eight (38.1%).
Genetic alterations identified in treatment-related neuroendocrine prostate cancer (t-NEPC) patients. A heatmap summarizing the genetic alterations detected across 21 patients with t-NEPC is shown. Each column represents an individual patient and each row corresponds to a gene commonly mutated in prostate cancer. The percentage on the right indicates the proportion of patients harboring alterations in each gene. The color coding in the figure represents different types of genetic alterations. Red indicates amplification, blue represents deletion, purple corresponds to frameshift mutations, orange denotes nonsense mutations, green indicates missense mutations, yellow represents fusion events, gray refers to splice site mutations, and black signifies high status, specifically for microsatellite instability (MSI) and tumor mutational burden (TMB).
Microsatellite instability-high (MSI-H) was detected in two patients (9.5%). The median tumor mutational burden (TMB) was 2.41 mutations per megabase, with two patients (9.5%) exhibiting more than 10 mutations per megabase.
No significant differences in OS or PFS were observed with the presence of DDR, TP53, RB1, PTEN, MYC, or SPOP gene mutations (Figure 2 and Figure 3).
Kaplan–Meier curves for progression-free survival (PFS) in patients with treatment-related neuroendocrine prostate cancer (t-NEPC), comparing those with and without DNA damage repair (DDR) mutations (A), BRCA2 mutations (B), TP53 mutation (C), RB1 mutation (D), and microsatellite instability (MSI) status (E).
Kaplan–Meier curves for overall survival (OS) in patients with treatment-related neuroendocrine prostate cancer (t-NEPC), comparing those with and without DNA damage repair (DDR) mutations (A), BRCA2 mutations (B), TP53 mutation (C), RB1 mutation (D), and microsatellite instability (MSI) status (E).
Mutations and factors that could potentially lead to the use of treatment options currently approved by Japan’s health insurance system as of 2024, such as BRCA1 mutations, BRCA2 mutations, MSI-H, and high TMB, were identified in six patients (28.6%). Including ATM mutations, a total of eight patients (38.1%) could be eligible for FDA-approved treatments. Additionally, three patients (14.3%) without these mutations had PTEN mutations, for which a phase III clinical trial is ongoing.
Discussion
In this study, we revealed the genomic features of small cell type t-NEPC in Japanese patients for the first time. The results showed that the presence of specific gene mutations detected in the present study may not affect the efficacy of platinum-based chemotherapy, the current standard treatment for this disease. Furthermore, by employing a highly validated cancer genomic test, we were able to accurately assess the eligibility rate for currently available treatments that target approved genomic mutations. These data provide valuable insights into potential therapeutic options.
t-NEPC can be classified as small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, or mixed tumors based on cellular morphology (13). In this study, we specifically focused on gene mutations in small cell carcinoma tumors. This subtype more frequently exhibits dedifferentiation and shares a pathological background more closely resembling that of small cell lung cancer. The previous reports on genomic mutations in neuroendocrine carcinoma mostly include mixed types and cohorts with elevated PSA levels (9, 10, 15). The largest report on pure small cell carcinoma, by Conteduca et al. (16), includes 21 cases, which is the same number as in our study. They reported higher frequencies of TP53 (61.5%) and RB1 (84.6%) mutations in small cell types compared with mixed types. In our cohort, the combination of extremely low PSA levels and the high frequency of these mutations suggests that we successfully isolated a group of pure small cell carcinoma cases, which are otherwise difficult to diagnose.
Poly ADP-ribose polymerase (PARP) inhibitors have been approved for treating CRPC cases with homologous recombination gene mutations, such as in the BRCA1 and BRCA2 genes. Active genomic testing aimed at detecting these DDR mutations is becoming more common. However, the BRCA mutation rate in metastatic CRPC is reported to be approximately 8% to 15% (17). In our analysis of small cell type t-NEPC, BRCA mutations were observed in 14.3% of cases, which aligns with existing reports on CRPC. We also investigated DDR mutations, finding a mutation rate of 38.1%, which was comparable to previous reports on Japanese CRPC cases (18). This mutation rate remains consistent, even when analyzing tumors with the unique morphology of small cell type t-NEPC. Overall, this suggests that DDR mutations may be present early in hormone-sensitive prostate cancer (19) and that neuroendocrine transdifferentiation might not substantially increase the frequency of these mutations.
Although DDR mutations have been associated with worse prognosis in CRPC patients, cancers harboring these mutations reportedly have better sensitivity to cisplatin (20). Similarly, in ovarian cancer, where PARP inhibitors are approved, tumors with DDR mutations are known to respond favorably to cisplatin therapy (21). This likely occurs because cancer cells with DDR mutations cannot effectively repair the DNA damage induced by platinum agents, leading to cell death (22). As previously mentioned, NEPC is typically treated according to the small cell lung cancer guidelines. However, the relationship between DDR mutations and platinum-based chemotherapy efficacy in small cell lung cancer remains inconsistent across studies, with no definitive conclusions (23-25). In our cohort, we observed no significant difference in the effectiveness of platinum-based chemotherapy between NEPC cases with or without DDR mutations. Because of the lack of prior studies on this topic, further large-scale research is warranted.
Similarly, TP53 and RB1 mutations have been reported as markers of platinum-based chemotherapy resistance in ovarian cancer (26). However, in our study, the presence or absence of these mutations did not stratify the response to platinum-based chemotherapy. Moreover, no other gene mutations associated with enhanced sensitivity to platinum-based chemotherapy were identified.
Recently, several targeted therapies have been developed for patients with certain genomic mutations. For prostate cancer, PARP inhibitors showed a survival advantage in patients with BRCA and ATM mutations (27). In addition, novel agents targeting NTRK gene fusions (28), RET fusion genes (29), and BRAF V600E mutations (30) have been approved for solid tumors, including prostate cancer. Furthermore, pembrolizumab, an immune checkpoint inhibitor (ICI), can be used to treat solid tumors with MSI-H and TMB-H (31, 32). In this study, we identified three patients (14.3%) with BRCA mutations and patients eligible for ICI treatment. When ATM mutations were included, a total of eight patients (38.1%) could potentially receive targeted therapies. Furthermore, we identified PTEN mutations in three patients (14.3%). Clinical trials are currently underway to investigate whether capivasertib can be used to treat prostate cancer with this mutation (NCT05348577) (33).
Our study suggests that cancer genomic profiling in routine practice can improve access to targeted therapies for NEPC, a disease with limited treatment options. Unfortunately, in our cohort, only one patient with these genomic mutations received a PARP inhibitor because of the timing of drug approval and the patient’s overall condition, making it difficult to assess the treatment’s efficacy.
To date, no studies have evaluated NEPC from a treatment accessibility perspective with genomic testing. However, a report on CRPC found a treatment accessibility rate of 31% (34), which is comparable to the current accessibility of genome-based therapies for prostate cancer as of 2024. No previous studies have been conducted on the MSI prevalence in NEPC, although MSI has been reported in approximately 3% of CRPC cases (35). Our study is the first to report the prevalence of MSI in NEPC.
Although ICIs have generally shown limited efficacy in prostate cancer (36), there have been reports of successfully treating NEPC cases with MSI-H using these inhibitors (6, 37, 38). Similarly, PARP inhibitors showed a favorable efficacy in NEPC in the previous case series (39), though the therapeutic significance remains unclear.
Study limitations. First, the small sample size and retrospective nature of the study may result in confounding by other clinical factors when evaluating the association between genomic mutations and platinum-based chemotherapy. Second, we used FoundationOne® CDx for genetic analysis. While this is a well-validated method, we analyzed a limited number of genes and could not distinguish between germline and somatic mutations. Additionally, mutations in intronic regions were not detected.
Conclusion
We presented the results of a genomic analysis of small cell prostate cancer using FoundationOne® CDx. The identified genomic mutations, including DDR mutations, did not predict the efficacy of platinum-based chemotherapy. However, 28.6% of patients were eligible for regimens that have been approved for treating prostate cancer as of 2024 in Japan. Because of the limited treatment options for t-NEPC, active genomic testing could potentially enhance patient access to targeted therapies.
Acknowledgements
The Authors thank J. Iacona, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
Footnotes
Authors’ Contributions
J.H.: data curation; formal analysis; investigation; methodology; writing – original draft; writing – review and editing. T.H.: investigation; methodology; writing – review and editing. N.J.: data curation; formal analysis; investigation; methodology; writing – review and editing. H.U.: data curation; writing – review and editing. Y.O.: writing – review and editing. Y.B.: writing – review and editing. K.S.: conceptualization; writing – review and editing. T.T.: conceptualization; writing – review and editing. J.T.: writing – review and editing. K.C.: writing – review and editing. H.M.: supervision.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-profit sectors.
- Received January 27, 2025.
- Revision received February 16, 2025.
- Accepted February 17, 2025.
- Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
