IMPORTANCE Luminal and basal subtypes of primary prostate cancer have been shown to be molecularly distinct and clinically important in predicting response to therapy. These subtypes have not been described in metastatic prostate cancer. OBJECTIVES To identify clinical and molecular correlates of luminal and basal subtypes in metastatic castration-resistant prostate cancer (mCRPC) and investigate differences in survival, particularly after treatment with androgen-signaling inhibitors (ASIs). DESIGN, SETTING, AND PARTICIPANTS In this cohort study, a retrospective analysis was conducted of 4 cohorts with mCRPC (N = 634) across multiple academic centers. Treatment was at the physicians' discretion. Details of the study cohorts have been published elsewhere between 2016 and 2019. Data were analyzed from March 2018 to February 2021. MAIN OUTCOMES AND MEASURES The primary clinical end point was overall survival from the date of tissue biopsy/molecular profiling. Luminal and basal subtypes were also stratified by postbiopsy ASI treatment. The primary molecular analyses included associations with small cell/neuroendocrine prostate cancer (SCNC), molecular pathways, and DNA alterations. RESULTS In the 634 patients, 288 (45%) had tumors classified as luminal, and 346 (55%) had tumors classified as basal. However, 53 of 59 (90%) SCNC tumors were basal (P < .001). Similar to primary prostate cancer, luminal tumors exhibited overexpression of AR pathway genes. In basal tumors, a significantly higher rate of RB1 loss (23% basal vs 4% luminal; P < .001), FOXA1 alterations (36% basal vs 27% luminal; P = .03) and MYC alterations (73% basal vs 56% luminal; P < .001) were identified. Patients with basal tumors had worse overall survival compared with those with luminal tumors only in patients treated with an ASI postbiopsy (East Coast Dream Team: hazard ratio [HR], 0.39; 95% CI, 0.20-0.74; P = .004; West Coast Dream Team: HR, 0.57; 95% CI, 0.33-0.97; P = .04). Among patients with luminal tumors, those treated with an ASI had significantly better survival (HR, 0.27; 95% CI, 0.14-0.53; P < .001), whereas patients with basal tumors did not (HR, 0.62; 95% CI, 0.36-1.04, P = .07). The interaction term between subtype and ASI treatment was statistically significant (HR, 0.42; 95% CI, 0.20-0.89; P = .02). CONCLUSIONS AND RELEVANCE These findings represent the largest integrated clinical, transcriptomic, and genomic analysis of mCRPC samples to date, and suggest that mCRPC can be classified as luminal and basal tumors. Analogous to primary prostate cancer, these data suggest that the benefit of ASI treatment is more pronounced in luminal tumors and support the use of ASIs in this population. In the basal tumors, a chemotherapeutic approach could be considered in some patients given the similarity to SCNC and the diminished benefit of ASI therapy. Further validation in prospective clinical trials is warranted.

中文翻译：

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与转移性前列腺癌的腔和基底亚型相关的预后。

重要性 原发性前列腺癌的管腔和基底亚型已被证明在分子上是不同的，并且在预测对治疗的反应方面具有临床重要性。这些亚型尚未在转移性前列腺癌中描述。目的 确定转移性去势抵抗性前列腺癌 (mCRPC) 中管腔和基底亚型的临床和分子相关性，并研究生存率差异，特别是在使用雄激素信号传导抑制剂 (ASI) 治疗后。设计、设置和参与者 在这项队列研究中，对跨多个学术中心的 4 个 mCRPC 队列（N = 634）进行了回顾性分析。治疗由医生自行决定。研究队列的详细信息已在 2016 年至 2019 年期间在其他地方发表。数据分析时间为 2018 年 3 月至 2021 年 2 月。主要结果和措施 主要临床终点是从组织活检/分子谱分析之日起的总生存期。管腔和基底亚型也通过活检后 ASI 治疗进行分层。主要分子分析包括与小细胞/神经内分泌前列腺癌 (SCNC)、分子通路和 DNA 改变的关联。结果 在 634 名患者中，288 名（45%）的肿瘤被归类为管腔，346 名（55%）的肿瘤被归类为基底。然而，59 例（90%）SCNC 肿瘤中有 53 例为基底（P < .001）。与原发性前列腺癌相似，腔内肿瘤表现出 AR 通路基因的过表达。在基底肿瘤中，RB1 丢失率显着更高（基底 23% vs 腔 4%；P < .001）、FOXA1 改变（基底 36% vs 腔 27%；P = .03）和 MYC 改变（基底 73% vs 56% 管腔；P < . 001) 被识别。与仅接受 ASI 活检后治疗的患者相比，基底肿瘤患者的总生存期更差（东海岸梦之队：风险比 [HR]，0.39；95% CI，0.20-0.74；P = .004；West海岸梦之队：HR，0.57；95% CI，0.33-0.97；P = .04）。在腔内肿瘤患者中，接受 ASI 治疗的患者生存率显着提高（HR，0.27；95% CI，0.14-0.53；P < .001），而基底肿瘤患者则没有（HR，0.62；95% CI， 0.36-1.04，P = .07）。亚型和 ASI 治疗之间的相互作用项具有统计学意义（HR，0.42；95% CI，0.20-0.89；P = .02）。结论和相关性 这些发现代表了迄今为止最大的 mCRPC 样本综合临床、转录组和基因组分析，并提示 mCRPC 可分为管腔和基底肿瘤。与原发性前列腺癌类似，这些数据表明 ASI 治疗的益处在管腔肿瘤中更为明显，并支持在该人群中使用 ASI。在基底肿瘤中，考虑到与 SCNC 的相似性和 ASI 治疗的益处减少，一些患者可以考虑化疗方法。有必要在前瞻性临床试验中进一步验证。