肿瘤内血液异质性（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局相关。

Increased blood-based intratumor heterogeneity (bITH) is associated with unfavorable outcomes of immune checkpoint inhibitors plus chemotherapy in non-small cell lung cancer.

机构信息

Department of Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200043, China.

Burning Rock Biotech, Guangzhou, China.

出版信息

BMC Med. 2022 Jul 29;20(1):256. doi: 10.1186/s12916-022-02444-8.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

The present study is the first to report that increased bITH is associated with unfavorable outcomes of ICIs plus chemotherapy in advanced NSCLC patients.

背景

免疫检查点抑制剂（ICIs）联合化疗已成为驱动基因阴性晚期非小细胞肺癌（NSCLC）患者的标准一线治疗方法。然而，ICI 联合治疗的疗效生物标志物仍然缺乏。我们旨在确定基线和外周血动态变化时与 ICI 联合化疗相关的潜在因素。

方法

我们收集了 51 例无 EGFR/ALK/ROS1 改变的晚期 NSCLC 患者的基线和/或 ICI 联合化疗两个治疗周期后的血浆样本。使用 520 个基因panel 基于体细胞突变的等位基因频率计算基于血液的肿瘤异质性（bITH）评分。bITH-up 定义为基线时 bITH 评分增加≥10%，并在治疗后进行第二次确认测量。

结果

基线时，转移器官的数量和肺部免疫预后指数（LIPI）与 ICI 联合化疗的无进展生存期（PFS）显著相关，而 bITH 和其他常见的分子生物标志物，包括 ctDNA 水平、基于血液的肿瘤突变负担（bTMB）和 PD-L1 表达，对 PFS 没有影响。基线时 LRP1B 突变与 ICI 联合化疗的良好结果显著相关。有 37 例患者在基线和治疗两个周期后有配对样本，中位间隔为 53 天。有趣的是，bITH-up 患者的 PFS 明显更短（HR，4.92；95%CI，1.72-14.07；P=0.001），持久临床获益率（0 与 41.38%，P=0.036）也更低。病例研究表明，bITH 有希望预测疾病进展。