DNA的错配修复(MMR)主要负责纠正复制后的错误以及维持基因组的稳定，有时候MMR的异常会引发一系列癌变表型，近日来自约翰霍普金斯基墨尔癌症中心（Johns Hopkins Kimmel Cancer Center ）的研究人员发现，MMR基因的突变或可帮助准确预测病人对化疗药物—PD-1抑制剂的反应。

　　研究者Luis Diaz Jr博士指出，本文研究或为我们提供了一种线索来揭示了化疗如何在癌症中发挥作用，并且可以帮助我们根据癌症的遗传特性来指导化疗的进行。相关研究以“PD-1 Blockade in Tumors with Mismatch-Repair Deficiency”为标题刊登于国际杂志New England Journal of Medicine上。

　　研究者在很少一部分癌症中会发现DNA错配修复基因的缺失，而这种针对免疫反应的生物标志物或可应用于包含DNA修复基因错误的肿瘤中去，利用这种预测性的生物标志物就可以帮助研究人员直接将化疗药物应用于能够产生反应的病人机体中，来避免患者昂贵的治疗及治疗时间的增加。

　　PD-1是典型地抑制细胞毒性免疫反应的调节通路的一部分，很多蛋白都会在肿瘤细胞中被上调，而且携带抗体的该通路如果被阻断就会使得一系列癌症发生明显的临床反应。揭示PD-1抑制剂的作用效果，研究小组就会进行II期临床试验来评估PD-1抑制剂pembrolizumab对41名恶性转移性癌症患者的临床作用效果。在一组MMR缺失的恶性结直肠癌患者中，有60%的患者都会药物疗法产生了反应，而且至少有30%的肿瘤都发生了明显地收缩；然而在25名MMR未发生缺失的患者机体中，所有患者均对pembrolizumab疗法没有任何反应。

　　最后研究者表示，我们非常欣喜的就是看到了，相比DNA错配修复未发生错误的患者而言，DNA错配修复基因发生错误的病人对化疗药物产生了明显的反应，这就为后期开发新型疗法来抑制癌症的进展，以及改善化疗药物的功效提供了新的研究线索和思路。

　　doi:10.1056/NEJMoa1500596

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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

　　Dung T. Le, M.D., Jennifer N. Uram, Ph.D., Hao Wang, Ph.D., Bjarne R. Bartlett, B.S., Holly Kemberling, R.N., Aleksandra D. Eyring, M.Pharm., Andrew D. Skora, Ph.D., Brandon S. Luber, Sc.M., Nilofer S. Azad, M.D., Dan Laheru, M.D., Barbara Biedrzycki, Ph.D., C.N.R.P., Ross C. Donehower, M.D., Atif Zaheer, M.D., George A. Fisher, M.D., Ph.D., Todd S. Crocenzi, M.D., James J. Lee, M.D., Ph.D., Steven M. Duffy, M.D., Richard M. Goldberg, M.D., Albert de la Chapelle, M.D., Ph.D., Minori Koshiji, M.D., Ph.D., Feriyl Bhaijee, M.D., Thomas Huebner, M.D., Ralph H. Hruban, M.D., Laura D. Wood, M.D., Ph.D., Nathan Cuka, M.D., Drew M. Pardoll, M.D., Ph.D., Nickolas Papadopoulos, Ph.D., Kenneth W. Kinzler, Ph.D., Shibin Zhou, M.D., Ph.D., Toby C. Cornish, M.D., Ph.D., Janis M. Taube, M.D., Robert A. Anders, M.D., Ph.D., James R. Eshleman, M.D., Ph.D., Bert Vogelstein, M.D., and Luis A. Diaz, Jr., M.D.

　　BACKGROUND Somatic mutations have the potential toencode“non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. Full Text of Background... METHODS We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41patientswith progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. Full Text of Methods... RESULTS The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair–deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair–proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair–deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair–proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair–deficient noncolorectal cancer had responses similar to those of patients with mismatch repair–deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair–deficient tumors, as compared with 73 in mismatch repair–proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). Full Text of Results... CONCLUSIONS This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.) Full Text of Discussion...