Department of Gastroenterology and GI oncology, Sorbonne Paris Cité, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France.
Department of Health Science Research, Mayo Clinic, Rochester.
Ann Oncol. 2019 Sep 1;30(9):1466-1471. doi: 10.1093/annonc/mdz208.
BACKGROUND: Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates the association. PATIENTS AND METHODS: Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence. RESULTS: Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69-0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58-1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73-2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67-4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence. CONCLUSIONS: In stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAFV600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients. TRIAL IDENTIFICATION NUMBERS: NCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.
背景：已报道微卫星不稳定/缺陷错配修复（MSI/dMMR）转移性结直肠癌预后不良。MSI/dMMR 与 BRAFV600E 频繁共现使相关性变得复杂。
患者和方法：对来自七个辅助研究的 2630 例接受过 III 期结肠癌（CC）切除术且有疾病复发和 MMR 及 BRAFV600E 状态数据的患者进行分析。主要终点为复发后的生存（SAR）。使用 Cox 比例风险模型对与 SAR 相关的标志物进行分析，模型调整了年龄、性别、体能状态、T 分期、N 分期、原发肿瘤位置、分级、KRAS 状态和复发时间等因素。
结果：在 2630 例癌症复发患者中（1491 例男性[56.7%]，平均年龄为 58.5[19-85]岁），多变量分析显示，MSI/dMMR 肿瘤患者的 SAR 显著长于微卫星稳定/高效错配修复（MSS/pMMR）肿瘤患者（调整后的危险比[aHR]，0.82；95%置信区间[CI]，0.69-0.98；P=0.029）。当仅分析接受标准奥沙利铂辅助化疗方案治疗的患者时，发现了同样的 SAR 趋势（aHR，0.76；95% CI，0.58-1.00；P=0.048）。在分析 MSI/dMMR 与 MSS/pMMR 肿瘤亚组时，观察到了同样的 SAR 趋势，这些亚组缺乏 BRAFV600E（aHR，0.84；P=0.10）或存在 BRAFV600E（aHR，0.88；P=0.43），但未达到统计学意义。此外，BRAFV600E 阳性肿瘤的 SAR 显著短于 BRAFV600E 阴性肿瘤（aHR，2.06；95% CI，1.73-2.46；P<0.0001），即使在 MSI/dMMR 肿瘤亚组中也是如此（aHR，2.65；95% CI，1.67-4.21；P<0.0001）。其他与 SAR 较短相关的因素包括：年龄较大、男性、T4/N2、近端原发肿瘤位置、低分化腺癌和早期复发。
结论：在接受辅助化疗后复发且在免疫治疗时代之前的 III 期 CC 患者中，与 MSS/pMMR 相比，MSI/dMMR 表型与 SAR 更好相关。BRAFV600E 突变是 MSI/dMMR 和 MSS/pMMR 患者的不良预后因素。
临床试验注册号：NCT00079274、NCT00265811、NCT00004931、NCT00004931、NCT00026273、NCT00096278、NCT00112918。
J Natl Cancer Inst. 2016-12-31
Appl Biochem Biotechnol. 2025-5-10
DNA Repair (Amst). 2025-5
Ecancermedicalscience. 2024-12-4
J Gastrointest Oncol. 2025-2-28
J Gastrointest Oncol. 2024-12-31
Cancer Res Commun. 2024-10-1
Cancer Treat Rev. 2019-2-26
Zotero 插件