具有微卫星不稳定性/DNA错配修复缺陷的遗传性和散发性转移性结直肠癌的临床和分子特征

Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency.

作者信息

Cohen R, Buhard O, Cervera P, Hain E, Dumont S, Bardier A, Bachet J-B, Gornet J-M, Lopez-Trabada D, Dumont S, Kaci R, Bertheau P, Renaud F, Bibeau F, Parc Y, Vernerey D, Duval A, Svrcek M, André Thierry

机构信息

Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France; INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisee par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France; Sorbonne Universités, UPMC Univ Paris 06, France.

INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisee par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France.

出版信息

Eur J Cancer. 2017 Nov;86:266-274. doi: 10.1016/j.ejca.2017.09.022. Epub 2017 Oct 19.

DOI:10.1016/j.ejca.2017.09.022

PMID:29055842

Abstract

BACKGROUND

Patients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs.

PATIENTS AND METHODS

MSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2 loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation.

RESULTS

Among 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (37%) had sporadic tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR, BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were associated with more frequent liver involvement, metastatic resection and better disease-free survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar between the two groups (4.2 and 4.2 months; P = 0.44).

CONCLUSIONS

LS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs in these two populations.

摘要

背景

接受化疗的微卫星高度不稳定（MSI）和/或错配修复缺陷（dMMR）的转移性结直肠癌（mCRC）患者预后较差。我们旨在评估区分散发性与林奇综合征（LS）样mCRC的相关性。

患者与方法

在六家法国医院对MSI/dMMR mCRC患者进行回顾性鉴定。对肿瘤样本进行MSI、dMMR、RAS/RAF突变和MLH1甲基化检测。散发性病例在分子水平上定义为那些表现出MLH1/PMS2表达缺失、BRAFV600E和/或MLH1高甲基化且无MMR种系突变的病例。

结果

在129例MSI/dMMR mCRC患者中，81例（63%）为LS样，48例（37%）为散发性肿瘤；与对MMR、BRAF和MLH1甲基化状态进行系统评估相比，使用基于当地病历（年龄、阿姆斯特丹II标准、当地检测时的BRAF和MMR状态）的算法会使22%的MLH1/PMS2阴性mCRC被错误分类。单因素分析中，与更好总生存相关的参数为年龄（P < 0.0001）、转移灶切除（P = 0.001）和LS样mCRC（P = 0.01），而非BRAFV600E。多因素分析中，年龄（风险比（HR）= 3.19，P = 0.01）和转移灶切除（HR = 4.2，P = 0.001）与总生存相关，但与LS无关。LS样患者肝转移、转移灶切除更常见，转移灶切除后无病生存更好（HR = 0.28，P = 0.01）。两组一线化疗的中位无进展生存期相似（4.2和4.2个月；P = 0.44）。