Increased blood-based intratumor heterogeneity (bITH) is associated with unfavorable outcomes of immune checkpoint inhibitors plus chemotherapy in non-small cell lung cancer.
Increased blood-based intratumor heterogeneity (bITH) is associated with unfavorable outcomes of immune checkpoint inhibitors plus chemotherapy in non-small cell lung cancer.
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血液肿瘤内异质性 (bITH) 增加与免疫检查点抑制剂联合化疗治疗非小细胞肺癌的不良结果相关
DOI：
10.1186/s12916-022-02444-8
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发表时间：
2022-07-29
期刊：
影响因子：
9.3
通讯作者：
Su, Chunxia
中科院分区：
文献类型：
--
作者：
Zhou, Juan;Bao, Minwei;Gao, Guanghui;Cai, Yiran;Wu, Lihong;Lei, Lei;Zhao, Jing;Ji, Xianxiu;Huang, Ying;Su, Chunxia
关键词：
免疫检查点抑制剂（ICI）联合化疗已成为驱动基因阴性的晚期非小细胞肺癌（NSCLC）患者的标准一线治疗。然而，缺乏基于ICIs的联合治疗的疗效生物标志物。我们的目的是确定与基线时ICI加化疗结局和外周血动态变化相关的潜在因素。我们收集了51例基线和/或两个治疗周期的ICI加化疗后EGFR/ALK/ROS 1无改变的晚期NSCLC患者的血浆样本。使用520个基因组，基于体细胞突变的等位基因频率计算基于血液的肿瘤内异质性（bITH）评分。bITH升高定义为bITH评分较基线增加≥ 10%，治疗后进行第二次确证性测量。基线时，转移器官数量和肺免疫预后指数（LIPI）与ICI加化疗的无进展生存期（PFS）较短显著相关，而bITH和其他常见分子生物标志物（包括ctDNA水平、血液肿瘤突变负荷（bTMB）和PD-L1表达）对PFS无影响。基线LRP 1B突变与ICIs+化疗的有利结局显著相关。有37例患者在基线和两个周期治疗后有配对样本，中位间隔时间为53天。有趣的是，与bepaly在线网投稳定或下降的患者相比，bepaly在线网投上升的患者具有显著更短的PFS（HR，4.92; 95%CI，1.72-14.07; P = 0.001）和更低的持久临床获益率（0 vs 41.38%，P = 0.036）。病例研究表明，bITH有望预测疾病进展。本研究首次报告了bITH增加与晚期NSCLC患者中ICI加化疗的不良结局相关。在线版本包含补充材料，可通过10.1186/s12916-022-02444-8获得。
The combination of immune checkpoint inhibitors (ICIs) and chemotherapy has been the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with driver-gene negative. However, efficacy biomarkers for ICIs-based combination therapy are lacking. We aimed to identify potential factors associated with outcomes of ICIs plus chemotherapy at baseline and dynamic changes in peripheral blood. We collected plasma samples of 51 advanced NSCLC patients without EGFR/ALK/ROS1 alteration at baseline and/or after two treatment cycles of ICIs plus chemotherapy. A blood-based intratumor heterogeneity (bITH) score was calculated based on the allele frequencies of somatic mutations using a 520-gene panel. bITH-up was defined as a ≥ 10% increase in bITH score from baseline, with a second confirmatory measurement after treatment. At baseline, the number of metastatic organs and lung immune prognostic index (LIPI) were significantly associated with shorter progression-free survival (PFS) of ICIs plus chemotherapy, while bITH and other common molecular biomarkers, including ctDNA level, blood-based tumor mutational burden (bTMB), and PD-L1 expression, had no effect on PFS. LRP1B mutation at baseline was significantly associated with favorable outcomes to ICIs plus chemotherapy. There were 37 patients who had paired samples at baseline and after two cycles of treatment, with the median interval of 53 days. Intriguingly, patients with bITH-up had significant shorter PFS (HR, 4.92; 95% CI, 1.72–14.07; P = 0.001) and a lower durable clinical benefit rate (0 vs 41.38%, P = 0.036) than those with bITH-stable or down. Case studies indicated that bITH was promising to predict disease progression. The present study is the first to report that increased bITH is associated with unfavorable outcomes of ICIs plus chemotherapy in advanced NSCLC patients. The online version contains supplementary material available at 10.1186/s12916-022-02444-8.
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影响因子：
10.1
作者：
Johnson DB;Frampton GM;Rioth MJ;Yusko E;Xu Y;Guo X;Ennis RC;Fabrizio D;Chalmers ZR;Greenbowe J;Ali SM;Balasubramanian S;Sun JX;He Y;Frederick DT;Puzanov I;Balko JM;Cates JM;Ross JS;Sanders C;Robins H;Shyr Y;Miller VA;Stephens PJ;Sullivan RJ;Sosman JA;Lovly CM
通讯作者：
Lovly CM
DOI：
10.1038/s41577-019-0218-4
发表时间：
2020-01
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Kalbasi A;Ribas A
通讯作者：
Ribas A
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
50.5
作者：
Cabel, L.;Riva, F.;Bidard, F. -C.
通讯作者：
Bidard, F. -C.
影响因子：
45.3
作者：
Gadgeel, Shirish;Rodriguez-Abreu, Delvys;Garassino, Marina C.
通讯作者：
Garassino, Marina C.