PO.PR01.04 · 预防研究
早期BMI升高作为晚期NSCLC中免疫检查点抑制剂±化疗疗效的预测性生物标志物：整合临床、基因组和循环蛋白质组数据
Early BMI increase as a predictive biomarker for immune checkpoint inhibitor ±chemotherapy efficacyin advanced NSCLC: Integrating clinical, genomic, and circulating proteomic data
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摘要 Abstract
中文摘要
背景：基线体重指数（BMI）已成为晚期NSCLC中免疫检查点抑制剂（ICI）的一个预后因素。然而，随着化疗-免疫联合治疗成为标准治疗，早期BMI变化是否能预测疗效以及是否因治疗方案而异仍不明确。识别早期预测性变化可为及时干预以改善治疗疗效提供依据。
方法：这项回顾性研究纳入了接受ICI±化疗治疗的晚期NSCLC患者。收集了基线和纵向BMI。基线协变量包括年龄、性别、组织学、吸烟状态、ECOG PS、TMB、PD-L1 TPS和治疗线数。多变量logistic和Cox模型评估了第3、6和9周的早期BMI变化与客观缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）之间的关系，校正基线BMI和协变量。时间依赖性分析验证了时序关联。为理解与基线BMI（≥25对<25 kg/m²）相关的分子特征，我们在141名患者中评估了循环蛋白（Olink，2700种蛋白），在728名患者中评估了基因组改变（OncoPanel），校正年龄、性别和吸烟。
结果：在1,110名患者中（303名化疗-免疫联合治疗，797名ICI单药治疗），早期BMI升高在两种方案中均独立预测更好的结局，其中在化疗-免疫联合治疗中效应更强。在化疗-免疫联合治疗中，第3周BMI升高1%预测更高的ORR（OR 1.48，95% CI 1.15-2.03）、PFS（HR 0.78，95% CI 0.71-0.86）和OS（HR 0.77，95% CI 0.69-0.86）。预测价值随时间（第3、6、9周）下降，尤其是在化疗-免疫联合治疗中。有吸烟史、TMB较低、接受化疗-免疫联合治疗的年长患者更可能在3周内出现体重下降。在基因组方面，KRAS、KMT2A、RASA1、FANCA、CTNNB1和ATM突变在较高BMI患者中富集，而EGFR、PMS1、FH、TP53和BAP1突变在较低BMI患者中更常见。循环蛋白（较高BMI中的SSC4D、LEP、CDHR2；较低BMI中的FSHB、GHRL）显示出性别特异性模式和代谢调节作用。
结论：早期BMI升高预测晚期NSCLC中更好的ICI结局，体重监测为优化疗效提供了机会。与基线BMI相关的基因组和蛋白质组特征提供了互补的见解：循环蛋白建立了慢性代谢选择性环境，而肿瘤突变则代表了进化结局。
查看英文原文 English abstract
Background: Baseline body mass index (BMI) has emerged as a prognostic factor for immune checkpoint inhibitor (ICI) in advanced NSCLC. However, with chemo-immunotherapy becoming standard of care, whether early BMI changes predict efficacy and differ by treatment regimen remains unclear. Identifying early predictive changes could inform timely interventions to improve treatment efficacy.
Methods: This retrospective study included patients with advanced NSCLC treated with ICI +/- chemotherapy. Baseline and longitudinal BMI were collected. Baseline covariates included age, sex, histology, smoking status, ECOG PS, TMB, PD-L1 TPS, and therapy line. Multivariable logistic and Cox models assessed early BMI changes at 3, 6, and 9 weeks and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), adjusting for baseline BMI and covariates. Time-dependent analyses verified temporal associations. To understand molecular profiles associated with baseline BMI (≥25 vs. <25 kg/m²), we assessed circulating proteins (Olink, 2700 proteins) in 141 patients and genomic alterations (OncoPanel) in 728 patients, adjusting for age, sex, and smoking.
Results: Among 1,110 patients (303 chemo-immunotherapy, 797 ICI monotherapy), early BMI increase independently predicted improved outcomes in both regimens, with stronger effects in chemo-immunotherapy. In chemo-immunotherapy, 1% BMI increase at 3 weeks predicted higher ORR (OR 1.48, 95% CI 1.15-2.03), PFS (HR 0.78, 95% CI 0.71-0.86), and OS (HR 0.77, 95% CI 0.69-0.86). Predictive value decreased over time (3, 6, 9 weeks), particularly in chemo-immunotherapy. Older patients with smoking history, lower TMB receiving chemo-immunotherapy were more likely to lose weight within 3 weeks. Genomically, KRAS, KMT2A, RASA1, FANCA, CTNNB1, and ATM mutations were enriched in higher BMI patients, while EGFR, PMS1, FH, TP53, and BAP1 mutations were more common in lower BMI patients. Circulating proteins (SSC4D, LEP, CDHR2 in higher BMI; FSHB, GHRL in lower BMI) showed sex-specific patterns and metabolic regulatory roles.
Conclusions: Early BMI increase predicts improved ICI outcomes in advanced NSCLC, with weight monitoring offering opportunities to optimize efficacy. Baseline BMI-associated genomic and proteomic profiles provide complementary insights: circulating proteins establish chronic metabolic selective environments, while tumor mutations represent evolutionary outcomes.
利益披露 Disclosure
X. Wang, None..
F. Pecci, None..
V. Santo, None..
E. Gariazzo, None..
E. Garbo, None..
A. Federico, None..
J. Alessi, None..
Y. Li, None.