El-Deiry Wafik S, Taylor Barry, Neal Joel W
From the Fox Chase Cancer Center, Philadelphia, PA; Memorial Sloan Kettering Cancer Center, New York, NY; Stanford University, Palo Alto, CA.
Am Soc Clin Oncol Educ Book. 2017;37:e8-e15. doi: 10.1200/EDBK_175524.
The clinical and molecular heterogeneity of various cancer types is well documented. In the era of precision oncology whereby molecular profiling of tumors is incorporated into clinical care, both intra- and intertumoral molecular and genetic heterogeneity have been described. Together, they impact patient treatment and outcomes. Host genetics and the tumor microenvironment impact on tumor evolution and heterogeneity through variations in immune cell infiltration, stromal variations, and selection pressures from hypoxia or nutrient stress, among others. Tumor progression and exposure to therapeutic agents lead to further molecular evolution and heterogeneity that is clinically relevant. Moreover, tumors that evolve after diagnosis and as a function of therapy generally become more aggressive and refractory to available therapeutics, including targeted agents and immunotherapy. The evolving clinical and molecular heterogeneity of patient tumors can be explored with various clinical and research-based specimens and testing such as pre- and post-treatment biopsies; serial liquid biopsies; single cell analysis; PDX and organoid models; anatomic, functional, and molecular imaging; and rapid postmortem studies. Other factors that influence tumor heterogeneity include immune checkpoints, cancer stem cells, therapy-acquired resistance mechanisms that may occur through secondary mutations, and adaptive responses. Modern technologic advances for tumor characterization provide opportunities to understand tumor evolution and its impact on clinical outcomes to improve therapeutic regimens. Characterization of novel targets and development of effective therapeutics are needed to target heterogeneity and the evolution of resistance mechanisms.
各种癌症类型的临床和分子异质性已有充分记录。在精准肿瘤学时代，肿瘤的分子特征已被纳入临床治疗，肿瘤内和肿瘤间的分子及基因异质性均已得到描述。它们共同影响患者的治疗和预后。宿主遗传学和肿瘤微环境通过免疫细胞浸润的变化、基质变化以及缺氧或营养应激等选择压力影响肿瘤的进化和异质性。肿瘤进展和接触治疗药物会导致进一步的分子进化和具有临床相关性的异质性。此外，诊断后以及作为治疗作用而演变的肿瘤通常会变得更具侵袭性，并且对包括靶向药物和免疫疗法在内的现有治疗方法产生耐药性。患者肿瘤不断演变的临床和分子异质性可以通过各种临床和基于研究的标本及检测方法进行探索，例如治疗前和治疗后的活检；系列液体活检；单细胞分析；PDX和类器官模型；解剖、功能和分子成像；以及快速尸检研究。影响肿瘤异质性的其他因素包括免疫检查点、癌症干细胞、可能通过二次突变产生的治疗获得性耐药机制以及适应性反应。用于肿瘤特征描述的现代技术进步为理解肿瘤进化及其对临床结果的影响提供了机会，以改善治疗方案。需要对新靶点进行特征描述并开发有效的治疗方法，以针对异质性和耐药机制的演变。
