共识分子亚型（CMS）的预后影响及其对转移性结直肠癌贝伐珠单抗获益的预测作用：AGITG MAX 临床试验的分子分析。

The prognostic impact of consensus molecular subtypes (CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: molecular analysis of the AGITG MAX clinical trial.

机构信息

Olivia Newton-John Cancer Research Institute, Heidelberg; Department of Medicine, University of Melbourne, Melbourne, Australia.

Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.

出版信息

Ann Oncol. 2018 Nov 1;29(11):2240-2246. doi: 10.1093/annonc/mdy410.

DOI:10.1093/annonc/mdy410

PMID:30247524

Abstract

BACKGROUND

The consensus molecular subtypes (CMS) is a transcriptome-based classification of colorectal cancer (CRC) initially described in early-stage cohorts, but the associations of CMS with treatment outcomes in the metastatic setting are yet to be established. This study aimed to evaluate the prognostic impact of CMS classification and its predictive effects for bevacizumab benefit in metastatic CRC by correlative analysis of the AGITG MAX trial.

PATIENTS AND METHODS

The MAX trial previously reported improved progression-free survival (PFS) for the addition of bevacizumab (B) to chemotherapy [capecitabine (C)±mitomycin (M)]. Archival primary tumours from 237 patients (50% of trial population) underwent gene expression profiling and classification into CMS groups. CMS groups were correlated to PFS and overall survival (OS). The interaction of CMS with treatment was assessed by proportional hazards model.

RESULTS

The distribution of CMS in MAX were CMS1 18%, CMS2 47%, CMS3 12%, CMS4 23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 was the predominant subtype in left-sided. CMS was prognostic of OS (P = 0.008), with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an independent prognostic factor in a multivariate analysis. There was a significant interaction between CMS and treatment (P-interaction = 0.03), for PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS1, 2, 3 and 4: 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25), respectively.

CONCLUSIONS

This exploratory study found that CMS stratified OS outcomes in metastatic CRC regardless of first-line treatment, with prognostic effects of CMS groups distinct from those previously reported in early-stage cohorts. In CMS associations with treatment, CMS2 and possibly CMS3 tumours may preferentially benefit from the addition of bevacizumab to first-line capecitabine-based chemotherapy, compared with other CMS groups. Validation of these findings in additional cohorts is warranted.

CLINICAL TRIAL NUMBER

This is a molecular sub-study of MAX clinical trial (NCT00294359).

摘要

背景

共识分子亚型（CMS）是一种基于转录组的结直肠癌（CRC）分类方法，最初在早期队列中描述，但 CMS 与转移性环境中的治疗结果的关联尚未建立。本研究旨在通过 AGITG MAX 试验的相关性分析，评估 CMS 分类的预后影响及其对转移性 CRC 贝伐单抗获益的预测作用。

患者和方法

MAX 试验先前报道，贝伐单抗（B）联合化疗[卡培他滨（C）±丝裂霉素（M）]可改善无进展生存期（PFS）。对 237 例患者（试验人群的 50%）的存档原发肿瘤进行基因表达谱分析，并分为 CMS 组。将 CMS 组与 PFS 和总生存期（OS）相关联。通过比例风险模型评估 CMS 与治疗的相互作用。

结果

MAX 中的 CMS 分布为 CMS1 18%、CMS2 47%、CMS3 12%、CMS4 23%。CMS1 是右侧原发性肿瘤的主要亚型，而 CMS2 是左侧的主要亚型。CMS 与 OS 相关（P=0.008），CMS2 与最佳结果相关，CMS1 与最差结果相关。CMS 在多变量分析中仍然是一个独立的预后因素。CMS 与治疗之间存在显著的相互作用（P 交互=0.03），对于 PFS，CMS1、2、3 和 4 中 CB+CBM 与 C 臂的危险比（95%CI）分别为 0.83（0.43-1.62）、0.50（0.33-0.76）、0.31（0.13-0.75）和 1.24（0.68-2.25）。