Development of a Classifier for Metabolic Subtypes of Nasopharyngeal Carcinoma to Guide Personalized Immunotherapy Strategies: Biomarker Analysis of the Phase III CONTINUUM and DIPPER Trials.

We aim to identify biomarkers predictive of immunotherapy benefits, using data from the phase III CONTINUUM (ClinicalTrials.gov identifier: NCT03700476) and DIPPER (ClinicalTrials.gov identifier: NCT03427827) randomized clinical trials.

我们旨在使用来自第三阶段CONTINUUM（ClinicalTrials.gov注册号：NCT03700476）和DIPPER（ClinicalTrials.gov注册号：NCT03427827）随机临床试验的数据，识别预测免疫治疗益处的生物标志物。

patients_and_methods

Tumor samples from 407 patients in the CONTINUUM (discovery cohort) and DIPPER (validation cohort) trials were subjected to RNA sequencing.

在CONTINUUM（发现队列）和DIPPER（验证队列）试验中，407名患者的肿瘤样本接受了RNA测序。

In the discovery cohort, metabolic gene-based consensus clustering was performed to determine subtypes.

在发现队列中，进行了基于代谢基因的共识聚类以确定亚型。

A machine learning-based classifier was subsequently developed in the discovery cohort and then applied to the validation cohort to assign metabolic subtypes.

随后在发现队列中开发了一种基于机器学习的分类器，然后将其应用于验证队列以分配代谢亚型。

Gene set enrichment analyses were used to characterize the biological features of each metabolic subtype.

使用基因集富集分析来表征每种代谢亚型的生物学特征。

The clinical end point was event-free survival (EFS).

临床终点是无事件生存（EFS）。

Results

In the discovery cohort, three metabolic subtypes were identified with distinct tumor-intrinsic and immune features as well as differential EFS benefits from adding anti-PD-1 to chemoradiotherapy (CRT).

在发现队列中，通过添加抗PD-1到放化疗（CRT）的不同无事件生存（EFS）获益，识别出三种具有不同肿瘤固有和免疫特征的代谢亚型。

Specifically, the MS1 subtype exhibited a significant improvement in 3-year EFS in the anti-PD-1 plus CRT arm compared with the CRT-alone arm (3-year EFS, 90.2% v 69.6%; hazard ratio, 0.27 [95% CI, 0.11 to 0.67]), whereas MS2 (3-year EFS, 94.1% v 93.8%) and MS3 subtypes (3-year EFS, 75.0% v 75.0%) derived no significant survival benefit.

具体来说，MS1亚型在抗PD-1联合放化疗组与单纯放化疗组相比，3年无事件生存率显著提高（3年无事件生存率，90.2%对比69.6%；风险比，0.27 [95%置信区间，0.11至0.67]），而MS2（3年无事件生存率，94.1%对比93.8%）和MS3亚型（3年无事件生存率，75.0%对比75.0%）没有显著的生存获益。

The subtype features were preserved in the validation cohort, with consistent prognostic and predictive value.

这些亚型特征在验证队列中得以保持，具有持续的预后和预测价值。

A pooled analysis of both cohorts demonstrated the significant interaction between metabolic subtypes and the treatment effect (Pinteraction = 0.0074).

对两个队列的汇总分析显示，代谢亚型与治疗效果之间存在显著的相互作用（Pinteraction = 0.0074）。

Conclusions

In this biomarker study, we defined metabolic subtypes of NPC that predicted the EFS benefit from immunotherapy.

在这项生物标志物研究中，我们定义了鼻咽癌的代谢亚型，这些亚型预测了从免疫治疗中获得的无进展生存（EFS）益处。

This novel molecular classification provides a promising predictive biomarker for personalized treatment decision for patients with locoregionally advanced NPC.

这种新型分子分类为具有局部区域晚期鼻咽癌（NPC）的患者提供了个性治疗决策的有希望的预测生物标志物。