Center for Personalized Cancer Therapy, Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, CA.
Caris Life Sciences, Inc, Phoenix, AZ.
Int J Cancer. 2020 Jun 1;146(11):3087-3097. doi: 10.1002/ijc.32661. Epub 2019 Oct 1.
Chemotherapy and checkpoint inhibitor immunotherapies are increasingly used in combinations. We determined associations between the presence of anti-PD-1/PD-L1 therapeutic biomarkers and protein markers of potential chemotherapy response. Data were extracted from a clinical-grade testing database (Caris Life Sciences; February 2015 through November 2017): immunotherapy response markers (microsatellite instability-high [MSI-H], tumor mutational burden-high [TMB-H], and PD-L1 protein expression) and protein chemotherapy response markers (excision repair complementation group 1 [ERCC1], topoisomerase 1 [TOPO1], topoisomerase 2 [TOP2A], thymidylate synthase [TS], tubulin beta 3 [TUBB3], ribonucleotide reductase regulatory subunit M1 [RRM1] and O-6-methyl guanine DNA methyltransferase [MGMT]). Relationships were determined by the Mantel-Haenszel chi-squared test or Fischer's exact tests. Overall, 28,034 patients representing a total of 40 tumor types were assessed. MSI-H was found in 3.3% of patients (73% were also TMB-H), TMB-H, 8.4% (28.3% were also MSI-H) and PD-L1 expression in 11.0% of patients (5.1% were also MSI-H; 16.4% were also TMB-H). Based on concurrent biomarker expression, combinations of immunotherapy with platinum (ERCC1 negativity) or with doxorubicin, epirubicin or etoposide (TOP2A positivity) have a higher probability of response, whereas combinations with irinotecan or topotecan (TOPO1 positivity), with gemcitabine (RRM1 negativity), and fluorouracil, pemetrexed or capecitabine (TS negativity) may be of less benefit. The potential for immunotherapy and taxane (TUBB3 negativity) combinations is present for MSI-H but not TMB-H or PD-L1-expressing tumors; for temozolomide and dacarbazine (MGMT negative), PD-L1 is frequently coexpressed, but MSI-H and TMB-H are not associated. Protein markers of potential chemotherapy response along with next-generation sequencing for immunotherapy response markers can help support rational combinations as part of an individualized, precision oncology approach.
化疗和检查点抑制剂免疫疗法越来越多地联合使用。我们确定了抗 PD-1/PD-L1 治疗性生物标志物与潜在化疗反应的蛋白标志物之间的关联。数据来自临床级测试数据库（Caris Life Sciences；2015 年 2 月至 2017 年 11 月）：免疫治疗反应标志物（微卫星不稳定性高 [MSI-H]、肿瘤突变负担高 [TMB-H] 和 PD-L1 蛋白表达）和蛋白化疗反应标志物（核苷酸切除修复互补群 1 [ERCC1]、拓扑异构酶 1 [TOPO1]、拓扑异构酶 2 [TOP2A]、胸苷酸合成酶 [TS]、微管β 3 [TUBB3]、核苷酸还原酶调节亚基 M1 [RRM1] 和 O-6- 甲基鸟嘌呤 DNA 甲基转移酶 [MGMT]）。通过 Mantel-Haenszel χ2 检验或 Fisher 精确检验确定关系。总体而言，评估了代表 40 种肿瘤类型的 28034 名患者。MSI-H 患者占 3.3%（73% 也为 TMB-H），TMB-H 患者占 8.4%（28.3% 也为 MSI-H），PD-L1 表达患者占 11.0%（5.1% 也为 MSI-H；16.4% 也为 TMB-H）。根据同时存在的生物标志物表达，免疫疗法联合铂类（ERCC1 阴性）或多柔比星、表柔比星或依托泊苷（TOP2A 阳性）具有更高的反应概率，而与伊立替康或拓扑替康（TOPO1 阳性）、吉西他滨（RRM1 阴性）、氟尿嘧啶、培美曲塞或卡培他滨（TS 阴性）联合应用可能益处较小。MSI-H 肿瘤存在免疫治疗和紫杉烷（TUBB3 阴性）联合治疗的潜力，但 TMB-H 或 PD-L1 表达肿瘤则不存在；替莫唑胺和达卡巴嗪（MGMT 阴性）经常共同表达 PD-L1，但 MSI-H 和 TMB-H 则没有关联。潜在化疗反应的蛋白标志物以及用于免疫治疗反应标志物的下一代测序可以帮助支持合理的组合，作为个体化、精准肿瘤学方法的一部分。
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