Prostate adenocarcinoma to neuroendocrine tumor: A therapy-driven response?

Abstract

e17024 Background: Androgen deprivation therapy (ADT) remains a cornerstone of treatment for prostate cancer. Some androgen-dependent prostate cancers evolve into androgen-independent forms. Prostate adenocarcinomas, which are androgen receptor (AR)-positive, may transition to AR-negative neuroendocrine prostate cancer (NEPC). There has been a rise in the incidence of NEPC, with a noted increase in neuroendocrine and AR-negative features in recent prostate cancer biopsies, particularly following the introduction of AR signaling inhibitors such as enzalutamide and abiraterone acetate. We investigate whether the introduction of modern AR therapies correlates with an increased transformation rate of prostate adenocarcinomas to NEPC. Methods: We searched years available on the SEER database before the use of enzalutamide and abiraterone acetate, and those after. These time periods were 1992-2010, and 2011-2021, respectively. We call these the Pre-Drug and Post-Drug time periods. To compare transformation rates of prostate adenocarcinoma to neuroendocrine tumors, we divide patients into three groups. The first received a diagnosis of adenocarcinoma and experienced transformation within the Pre-Drug period (Group A). The second group was diagnosed with adenocarcinoma in the Pre-Drug time period and transformed in the Post-Drug period (Group B). The last group experienced diagnosis and transformation exclusively in the Post-Drug period (Group C). These groups are meant to serve as a proxy for drug exposure: Group A had no modern ADT exposure before transformation, Group B received their original adenocarcinoma diagnosis in the era of modern ADT, and Group C represents an intermediate level between Groups A and B. Transformation rates were calculated by number of transformations / total adenocarcinomas in the respective time period. Confidence intervals were calculated using the Poisson Distribution with Exact Method. Rates were compared for statistical significance using the log based (Wald) method. (Software - OpenAI o1, accessed 1/31/25 was used for calculation given raw data and results were confirmed with medcalc.org statistic calculators) Results: 420,586 patients were diagnosed with prostate adenocarcinoma in the Pre-Drug period, compared to 247,490 in the Post-Drug Period. 15, 38, and 63 patients transformed from the adenocarcinoma phenotype to a neuroendocrine tumor in Groups A, B, and C, respectively. Transformation rates per 100,000 were 3.57 (95% CI 2.00-6.09), 9.04 ( 95% CI 6.43-12.11), and 25.46 (95% CI 20.11-31.24) for Groups A, B, and C, respectively. Group B/A Risk Ratio 2.53, (95% CI: 1.39-4.40, p ~ 0.002), and Group C/A Risk Ratio = 7.14 (95% CI: 4.07-12.53, p < 0.0001). Conclusions: The stepwise increase in transformation rates for Groups A, B, and C suggests an association between the rate of transformation of prostate adenocarcinoma into neuroendocrine tumors and the use of modern ADT.