Beltran Himisha, Antonarakis Emmanuel S, Morris Michael J, Attard Gerhardt
From Weill Cornell Medicine, New York, NY, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, New York, NY; The Institute of Cancer Research, London, United Kingdom, The Royal Marsden Hospital, London, United Kingdom.
Am Soc Clin Oncol Educ Book. 2016;35:131-41. doi: 10.1200/EDBK_159248.
Recent clinical and preclinical studies focused on understanding the molecular landscape of castration-resistant prostate cancer (CRPC) have provided insights into mechanisms of treatment resistance, disease heterogeneity, and potential therapeutic targets. This work has served as a framework for several ongoing clinical studies focused on bringing novel observations into the clinic in the form of tissue, liquid, and imaging biomarkers. Resistance in CRPC typically is driven through reactivation of androgen receptor (AR) signaling, which can occur through AR-activating point mutations, amplification, splice variants (such as AR-V7), or other bypass mechanisms. Detection of AR aberrations in the circulation negatively impacts response to subsequent AR-directed therapies such as abiraterone and enzalutamide. Other potentially clinically relevant alterations in CRPC include defects in DNA damage repair (at either the somatic or germline level) in up to 20% of patients (with implications for PARP1 inhibitor therapy), PI3K/PTEN/Akt pathway activation, WNT signaling pathway alterations, cell cycle gene alterations, and less common but potentially targetable alterations involving RAF and FGFR2. Imaging biomarkers that include those focused on incorporating overexpressed androgen-regulated genes/proteins, such as prostate-specific membrane antigen (PSMA) and dihydrotestosterone (DHT) in combination with CT, can noninvasively identify patterns of AR-driven distribution of CRPC tumor cells, monitor early metastatic lesions, and potentially capture heterogeneity of response to AR-directed therapies and other therapeutics. This article focuses on the current state of clinical biomarker development and future directions for how they might be implemented into the clinic in the near term to improve risk stratification and treatment selection for patients.
近期专注于了解去势抵抗性前列腺癌（CRPC）分子格局的临床和临床前研究，为治疗抵抗机制、疾病异质性及潜在治疗靶点提供了见解。这项工作为多项正在进行的临床研究奠定了框架，这些研究旨在将组织、液体和影像生物标志物形式的新观察结果引入临床。CRPC中的抵抗通常由雄激素受体（AR）信号通路的重新激活驱动，这可通过AR激活点突变、扩增、剪接变体（如AR-V7）或其他旁路机制发生。循环中AR畸变的检测对后续AR靶向治疗（如阿比特龙和恩杂鲁胺）的反应有负面影响。CRPC中其他潜在的临床相关改变包括高达20%的患者存在DNA损伤修复缺陷（体细胞或种系水平，对PARP1抑制剂治疗有影响）、PI3K/PTEN/Akt信号通路激活、WNT信号通路改变、细胞周期基因改变，以及涉及RAF和FGFR2的较罕见但可能可靶向的改变。影像生物标志物，包括那些专注于纳入过表达的雄激素调节基因/蛋白（如前列腺特异性膜抗原（PSMA）和二氢睾酮（DHT））并结合CT的标志物，可无创识别CRPC肿瘤细胞AR驱动的分布模式、监测早期转移灶，并可能捕捉对AR靶向治疗和其他治疗反应的异质性。本文重点介绍临床生物标志物开发的现状以及近期如何将其应用于临床以改善患者风险分层和治疗选择的未来方向。
