Department of Radiation Oncology, University of Michigan, Ann Arbor
GenomeDx Biosciences Inc, Vancouver, British Columbia, Canada
JAMA Oncol. 2017 Dec 1;3(12):1663-1672. doi: 10.1001/jamaoncol.2017.0751.
There is a clear need for a molecular subtyping approach in prostate cancer to identify clinically distinct subgroups that benefit from specific therapies.
To identify prostate cancer subtypes based on luminal and basal lineage and to determine associations with clinical outcomes and response to treatment.
DESIGN, SETTING, AND PARTICIPANTS: The PAM50 classifier was used to subtype 1567 retrospectively collected (median follow-up, 10 years) and 2215 prospectively collected prostate cancer samples into luminal- and basal-like subtypes.
Metastasis, biochemical recurrence, overall survival, prostate cancer–specific survival, associations with biological pathways, and clinicopathologic variables were the main outcomes.
Among the 3782 samples, the PAM50 classifier consistently segregated prostate cancer into 3 subtypes in both the retrospective and prospective cohorts: luminal A (retrospective, 538 [34.3%]; prospective, 737 [33.3%]), luminal B (retrospective, 447 [28.5%]; prospective, 723 [32.6%]), and basal (retrospective, 582 [37.1%]; prospective, 755 [34.1%]). Known luminal lineage markers, such as NKX3.1 and KRT18, were enriched in luminal-like cancers, and the basal lineage CD49f signature was enriched in basal-like cancers, demonstrating the connection between these subtypes and established prostate cancer biology. In the retrospective cohort, luminal B prostate cancers exhibited the poorest clinical prognoses on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors (10-year biochemical recurrence-free survival [bRFS], 29%; distant metastasis-free survival [DMFS], 53%; prostate cancer-specific survival [PCSS], 78%; overall survival [OS], 69%), followed by basal prostate cancers (10-year bRFS, 39%; DMFS, 73%; PCSS, 86%; OS, 80%) and luminal A prostate cancers (10-year bRFS, 41%; DMFS, 73%; PCSS, 89%; OS, 82%). Although both luminal-like subtypes were associated with increased androgen receptor expression and signaling, only luminal B prostate cancers were significantly associated with postoperative response to androgen deprivation therapy (ADT) in a subset analysis in our retrospective cohorts (n = 315) matching patients based on clinicopathologic variables (luminal B 10-year metastasis: treated, 33% vs untreated, 55%; nonluminal B 10-year metastasis: treated, 37% vs untreated, 21%; P = .006 for interaction).
Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.
在前列腺癌中，需要有一种分子亚型方法来识别从特定治疗中获益的临床特征明显不同的亚群。
根据腔细胞和基底谱系识别前列腺癌亚型，并确定与临床结果和治疗反应的关联。
设计、设置和参与者：使用 PAM50 分类器将 1567 例回顾性收集（中位随访时间 10 年）和 2215 例前瞻性收集的前列腺癌样本分为腔细胞和基底样亚型。
转移、生化复发、总生存、前列腺癌特异性生存、与生物学途径的关联以及临床病理变量是主要结局。
在 3782 个样本中，PAM50 分类器在回顾性和前瞻性队列中一致地将前列腺癌分为 3 种亚型：腔细胞 A（回顾性队列，538[34.3%]；前瞻性队列，737[33.3%]）、腔细胞 B（回顾性队列，447[28.5%]；前瞻性队列，723[32.6%]）和基底（回顾性队列，582[37.1%]；前瞻性队列，755[34.1%]）。已知的腔细胞谱系标记物，如 NKX3.1 和 KRT18，在腔细胞样癌中富集，而基底谱系 CD49f 特征在基底样癌中富集，表明这些亚型与已确立的前列腺癌生物学之间存在联系。在回顾性队列中，腔细胞 B 前列腺癌在考虑标准临床病理预后因素的单变量和多变量分析中表现出最差的临床预后（10 年生化无复发生存率[bRFS]，29%；远处无转移生存率[DMFS]，53%；前列腺癌特异性生存率[PCSS]，78%；总生存率[OS]，69%），其次是基底前列腺癌（10 年 bRFS，39%；DMFS，73%；PCSS，86%；OS，80%）和腔细胞 A 前列腺癌（10 年 bRFS，41%；DMFS，73%；PCSS，89%；OS，82%）。尽管两种腔细胞样亚型均与雄激素受体表达和信号增加相关，但只有腔细胞 B 前列腺癌在我们的回顾性队列（n=315）中基于临床病理变量的亚组分析中与术后对雄激素剥夺治疗（ADT）的反应显著相关（腔细胞 B 10 年转移：治疗，33%vs 未治疗，55%；非腔细胞 B 10 年转移：治疗，37%vs 未治疗，21%；P=0.006 用于交互作用）。
腔细胞和基底样前列腺癌表现出不同的临床行为，且腔细胞 B 肿瘤的患者对术后 ADT 的反应优于非腔细胞 B 肿瘤的患者。这些发现为前列腺癌生物学提供了新的见解，为通过预测哪些男性可能从手术后 ADT 中获益来为前列腺癌提供个性化 ADT 治疗提供了一种潜在的临床工具。
