Research progress of predictive markers related to immune checkpoint inhibitor therapy for colorectal cancer
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摘要: 以免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)为代表的免疫疗法开辟了肿瘤治疗的新纪元。目前ICIs已经广泛应用于晚期转移性结直肠癌患者的治疗。预测性标志物是精确筛选可从ICIs治疗中受益的患者群体的重要工具。本文回顾并总结了目前ICIs治疗结直肠癌重要的预测性标志物及其研究现状,包括错配修复缺陷及微卫星不稳定性、肿瘤突变负荷、DNA聚合酶ε/DNA聚合酶δ1以及PD-L1表达等。通过了解这些标志物对于结直肠癌ICIs治疗的响应及患者预后的预测价值,有助于指导临床医生筛选潜在获益人群,提高治疗效率,实现精准化治疗。Abstract: The use of immune checkpoint inhibitors (ICIs) for immunotherapy has launched a new era of tumor treatment. At present, ICIs are widely used in the treatment of patients with advanced metastatic colorectal cancer. Predictive markers are important tools for accurately screening patients that can benefit from ICIs. This paper reviews and summarizes the uses of predictive markers in the treatment of colorectal cancer with ICIs. For example, the paper includes discussions of markers for mismatch repair defects and microsatellite instability, tumor mutation burden, DNA polymerase ε/DNA polymerase δ1, and PD-L1 expression. Understanding the predictive value of these markers for treatment response and patient prognosis will help doctors to screen potential beneficiaries, improve treatment efficiency and provide more accurate treatment.
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表 1 结直肠癌ICIs治疗相关预测性标志物
标志物名称 概述 dMMR/MSI-H 结直肠癌ICIs治疗的主要预测性分子标志物 TMB 具有较高的应用价值,需要确定合理的截断值来定义不同肿瘤突变负荷的患者 PD-L1表达 受限于PD-L1的检测,需要更多的研究确定检测结直肠癌PD-L1表达的统一标准 DNA聚合酶ε或聚合酶δ1突变 仍需更多试验证据支持POLE / POLD1突变作为结直肠癌ICIs治疗的分子标志物 免疫细胞相关标志物 包括免疫评分、中性粒细胞-淋巴细胞比率等,仍需进一步的临床实验探索其应用价值 -
[1] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. doi: 10.3322/caac.21660 [2] Weng J, Li S, Zhu Z, et al. Exploring immunotherapy in colorectal cancer[J]. J Hematol Oncol, 2022, 15(1):95. doi: 10.1186/s13045-022-01294-4 [3] Zhao W, Jin L, Chen P, et al. Colorectal cancer immunotherapy-recent progress and future directions[J]. Cancer Lett, 2022, 545:215816. doi: 10.1016/j.canlet.2022.215816 [4] Casak SJ, Marcus L, Fashoyin-Aje L, et al. FDA approval summary: pembrolizumab for the first-line treatment of patients with MSI-H/dMMR advanced unresectable or metastatic colorectal carcinoma[J]. Clin Cancer Res, 2021, 27(17):4680-4684. doi: 10.1158/1078-0432.CCR-21-0557 [5] Marcus L, Lemery SJ, Keegan P, et al. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors[J]. Clin Cancer Res, 2019, 25(13):3753-3758. doi: 10.1158/1078-0432.CCR-18-4070 [6] Huyghe N, Benidovskaya E, Stevens P, et al. Biomarkers of response and resistance to immunotherapy in microsatellite stable colorectal cancer: toward a new personalized medicine[J]. Cancers (Basel), 2022, 14(9):2241. doi: 10.3390/cancers14092241 [7] Yamamoto H, Imai K. Microsatellite instability: an update[J]. Arch Toxicol, 2015, 89(6):899-921. doi: 10.1007/s00204-015-1474-0 [8] Koopman M, Kortman GA, Mekenkamp L, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer[J]. Br J Cancer, 2009, 100(2):266-273. doi: 10.1038/sj.bjc.6604867 [9] Maby P, Tougeron D, Hamieh M, et al. Correlation between density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy[J]. Cancer Res, 2015, 75(17):3446-3455. doi: 10.1158/0008-5472.CAN-14-3051 [10] Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints[J]. Cancer Discov, 2015, 5(1):43-51. doi: 10.1158/2159-8290.CD-14-0863 [11] Richman S. Deficient mismatch repair: read all about it (Review)[J]. Int J Oncol, 2015, 47(4):1189-1202. doi: 10.3892/ijo.2015.3119 [12] Le DT, Uram JN, Wang H, et al. PD-1 Blockade in tumors with mismatch-repair deficiency[J]. N Engl J Med, 2015, 372(26):2509-2520. doi: 10.1056/NEJMoa1500596 [13] Du F, Liu Y. Predictive molecular markers for the treatment with immune checkpoint inhibitors in colorectal cancer[J]. J Clin Lab Anal, 2022, 36(1):e24141. [14] Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer[J]. N Engl J Med, 2022, 386(25):2363-2376. doi: 10.1056/NEJMoa2201445 [15] No authors listed. Mutation burden predicts anti-PD-1 response[J]. Cancer Discov, 2018, 8(3):258. [16] McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade[J]. Science, 2016, 351(6280):1463-1469. doi: 10.1126/science.aaf1490 [17] Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma[J]. N Engl J Med, 2014, 371(23):2189-2199. doi: 10.1056/NEJMoa1406498 [18] Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types[J]. Nat Genet, 2019, 51(2):202-206. doi: 10.1038/s41588-018-0312-8 [19] Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study[J]. Lancet Oncol, 2020, 21 (10):1353-1365. [20] Friedman CF, Hainsworth JD, Kurzrock R, et al. Atezolizumab treatment of tumors with high tumor mutational burden from mypathway, a multicenter, open-label, phase IIa multiple basket study[J]. Cancer Discov, 2022, 12(3):654-669. doi: 10.1158/2159-8290.CD-21-0450 [21] Schrock AB, Ouyang C, Sandhu J, et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer[J]. Ann Oncol, 2019, 30(7):1096-1103. doi: 10.1093/annonc/mdz134 [22] Fukuoka S, Hara H, Takahashi N, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603)[J]. J Clin Oncol, 2020, 38(18):2053-2061. doi: 10.1200/JCO.19.03296 [23] Chen EX, Jonker DJ, Loree JM, et al. Effect of combined immune checkpoint inhibition vs best supportive care alone in patients with advanced colorectal cancer: the canadian cancer trials group CO. 26 study[J]. JAMA Oncol, 2020, 6(6):831-838. doi: 10.1001/jamaoncol.2020.0910 [24] Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy[J]. Cancer Discov, 2018, 8(9):1069-1086. doi: 10.1158/2159-8290.CD-18-0367 [25] Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer[J]. N Engl J Med, 2012, 366(26):2443-2454. doi: 10.1056/NEJMoa1200690 [26] Garon EB, Hellmann MD, Rizvi NA, et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phaseⅠ KEYNOTE-001 study[J]. J Clin Oncol, 2019, 37 (28):2518-2527. [27] Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial[J]. Lancet, 2019, 393 (10183):1819-1830. [28] Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer[J]. N Engl J Med, 2016, 375(19):1823-1833. doi: 10.1056/NEJMoa1606774 [29] Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study[J]. Lancet Oncol, 2017, 18 (9):182-1191. [30] Wang X, Teng F, Kong L, et al. PD-L1 expression in human cancers and its association with clinical outcomes[J]. Onco Targets Ther, 2016, 9:5023-5039. doi: 10.2147/OTT.S105862 [31] Briggs S, Tomlinson I. Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers[J]. J Pathol, 2013, 230(2):148-153. doi: 10.1002/path.4185 [32] Domingo E, Freeman-Mills L, Rayner E, et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study[J]. Lancet Gastroenterol Hepatol, 2016, 1 (3):207-216. [33] Wang F, Zhao Q, Wang YN, et al. Evaluation of POLE and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types[J]. JAMA Oncol, 2019, 5(10):1504-1506. doi: 10.1001/jamaoncol.2019.2963 [34] Gong J, Wang C, Lee PP, et al. Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring a pole mutation[J]. J Natl Compr Canc Netw, 2017, 15(2):142-147. doi: 10.6004/jnccn.2017.0016 [35] Rozek LS, Schmit SL, Greenson JK, et al. Tumor-infiltrating lymphocytes, Crohn's-like lymphoid reaction, and survival from colorectal cancer[J]. J Natl Cancer Inst, 2016, 108(8):djw027. [36] Loupakis F, Depetris I, Biason P, et al. Prediction of benefit from checkpoint inhibitors in mismatch repair deficient metastatic colorectal cancer: role of tumor infiltrating lymphocytes[J]. Oncologist, 2020, 25(6):481-487. doi: 10.1634/theoncologist.2019-0611 [37] Galon J, Angell HK, Bedognetti D, et al. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures[J]. Immunity, 2013, 39(1):11-26. doi: 10.1016/j.immuni.2013.07.008 [38] Mlecnik B, Bindea G, Angell HK, et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability[J]. Immunity, 2016, 44(3):698-711. doi: 10.1016/j.immuni.2016.02.025 [39] Yomoda T, Sudo T, Kawahara A, et al. The Immunoscore is a superior prognostic tool in stages Ⅱ and III colorectal cancer and is significantly correlated with programmed death-ligand 1 (PD-L1) expression on tumor-infiltrating mononuclear cells[J]. Ann Surg Oncol, 2019, 26 (2):415-424. [40] Moschetta M, Uccello M, Kasenda B, et al. Dynamics of neutrophils-to-lymphocyte ratio predict outcomes of PD-1/PD-L1 blockade[J]. Biomed Res Int, 2017, 2017:1506824. [41] Chen S, Li R, Zhang Z, et al. Prognostic value of baseline and change in neutrophil-to-lymphocyte ratio for survival in advanced non-small cell lung cancer patients with poor performance status receiving PD-1 inhibitors[J]. Transl Lung Cancer Res, 2021, 10(3):1397-1407. [42] Diem S, Schmid S, Krapf M, et al. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab[J]. Lung Cancer, 2017, 111:176-181. doi: 10.1016/j.lungcan.2017.07.024 [43] Ueda T, Chikuie N, Takumida M, et al. Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with clinical outcome in recurrent or metastatic head and neck cancer patients treated with nivolumab[J]. Acta Otolaryngol, 2020, 140(2):181-187. doi: 10.1080/00016489.2019.1699250 [44] Fan X, Wang D, Zhang W, et al. Inflammatory markers predict survival in patients with advanced gastric and colorectal cancers receiving anti-PD-1 therapy[J]. Front Cell Dev Biol, 2021, 9:638312. doi: 10.3389/fcell.2021.638312 [45] 杨长江,赵龙,林易霖,等.结直肠癌免疫检查点抑制剂联合治疗策略的研究进展[J].中华普通外科杂志,2022,37(7):554-557. -

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