Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade

• Published in: The oncologist (Dayton, Ohio) Ohio), 2016-10, Vol.21 (10), p.1200-1211
• Main Authors: Lee, Valerie, Murphy, Adrian, Le, Dung T., Diaz, Luis A.
• Format: Article
• Language: English
• Subjects: Colonic neoplasms; Colorectal neoplasms; DNA Mismatch Repair; Gastrointestinal Cancer; Hereditary nonpolyposis; Humans; Immunotherapy; Microsatellite Instability; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - immunology; Programmed Cell Death 1 Receptor - antagonists & inhibitors
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2016-0046

More than 1.6 million new cases of cancer will be diagnosed in the U.S. in 2016, resulting in more than 500,000 deaths. Although chemotherapy has been the mainstay of treatment in advanced cancers, immunotherapy development, particularly with PD‐1 inhibitors, has changed the face of treatment for a number of tumor types. One example is the subset of tumors characterized by mismatch repair deficiency and microsatellite instability that are highly sensitive to PD‐1 blockade. Hereditary forms of cancer have been noted for more than a century, but the molecular changes underlying mismatch repair‐deficient tumors and subsequent microsatellite unstable tumors was not known until the early 1990s. In this review article, we discuss the history and pathophysiology of mismatch repair, the process of testing for mismatch repair deficiency and microsatellite instability, and the role of immunotherapy in this subset of cancers. Implications for Practice: Mismatch repair deficiency has contributed to our understanding of carcinogenesis for the past 2 decades and now identifies a subgroup of traditionally chemotherapy‐insensitive solid tumors as sensitive to PD‐1 blockade. This article seeks to educate oncologists regarding the nature of mismatch repair deficiency, its impact in multiple tumor types, and its implications for predicting the responsiveness of solid tumors to immune checkpoint blockade. 摘要 2016年美国共确诊160万余例新发肿瘤, 这些肿瘤造成50万余例死亡。尽管化疗已成为晚期癌症治疗的支柱, 但免疫治疗特别是PD‐1抑制剂的发展, 已改变了多个瘤种治疗的面貌。其中一个范例是, 以错配修复缺陷和微卫星不稳定性为特点的肿瘤亚型对PD‐1阻滞高度敏感。肿瘤的遗传类型在一个多世纪前已为人所知, 但错配修复缺陷性肿瘤及随后的微卫星不稳定性肿瘤之下隐含的分子学改变直到1990年代早期才被人熟知。本篇综述讨论了错配修复的历史和病理生理学、错配修复缺陷检查的流程及免疫治疗在该亚型肿瘤中的作用。The Oncologist 2016; 21: 1200–1211 对临床实践的提示:在过去20年间, 错配修复缺陷加深了我们对致癌机制的理解, 并鉴定出了一类对传统化疗不敏感但对PD‐1阻滞高度敏感的实体瘤亚型。本文旨在帮助肿瘤科医生学习有关错配修复缺陷的性质、其对众多类型肿瘤的影响, 及其在预测实体瘤对免疫检查点阻滞治疗反应上的临床意义。 In this review article, the history and pathophysiology of mismatch repair, the process of testing for mismatch repair deficiency and microsatellite instability, and the role of immunotherapy in a number of tumor types, including those that are highly sensitive to PD‐1 blockade, are discussed.