Division of Surgical Oncology, Department of Surgery, UPMC Cancer Pavilion, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Surgery, University of Illinois at Chicago College of Medicine, Chicago, IL, USA.
Ann Surg Oncol. 2023 Jul;30(7):4459-4470. doi: 10.1245/s10434-023-13463-x. Epub 2023 Apr 21.
Colorectal cancer leads to peritoneal metastases (CRPM) in 10% of cases. Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) improves survival. Primary tumor location and abnormalities in RAS, BRAF, and mismatch repair/microsatellite stability (MMR/MSI) may affect post-CRS-HIPEC survival, but studies have not been consistent. We estimated the effects of primary tumor site and genomic alterations on post-CRS-HIPEC survival.
This retrospective cohort study included CRS-HIPEC cases for CRPM at a high-volume center from 2001 to 2020. Next-generation sequencing and microsatellite testing defined the RAS, BRAF, and MMR/MSI genotypes. Adjusted effects of tumor sidedness and genomics on survival were evaluated using a multivariable Cox proportional hazards model. We analyzed these variables' effects on progression-free survival and the effects of immune checkpoint-inhibitors.
A total of 250 patients underwent CRS-HIPEC with testing for RAS, BRAF, and MMR/MSI; 50.8% of patients were RAS-mutated, 12.4% were BRAF-mutated, and 6.8% were deficient-MMR/MSI-high (dMMR/MSI-H). Genomic alterations predominated in right-sided cancers. After adjustment for comorbidities and oncological and perioperative variables, rectal origin [hazard ratio (HR) 1.9, p = 0.01], RAS mutation (HR 1.6, p = 0.01), and BRAF mutation (HR 1.7, p = 0.05) were associated with worse survival. RAS mutation was also associated with shorter progression-free survival (HR 1.6, p = 0.01 at 6 months post-operatively), and dMMR/MSI-H status was associated with superior survival (HR 0.3, p = 0.01 at 2 years). dMMR/MSI-H patients receiving immune checkpoint-inhibitors trended toward superior survival.
Rectal origin, RAS mutations, and BRAF mutations are each associated with poorer survival after CRS-HIPEC for CRPM. Patients with CRPM and dMMR/MSI-H status have superior survival. Further research should evaluate benefits of immune checkpoint-inhibitors in this subgroup.
结直肠癌在 10%的病例中导致腹膜转移（CRPM）。细胞减灭术联合腹腔内热灌注化疗（CRS-HIPEC）可提高生存率。原发肿瘤的位置和 RAS、BRAF 以及错配修复/微卫星不稳定性（MMR/MSI）的异常可能会影响 CRS-HIPEC 后的生存，但研究结果并不一致。我们评估了原发肿瘤部位和基因组改变对 CRS-HIPEC 后生存的影响。
本回顾性队列研究纳入了 2001 年至 2020 年在一家高容量中心接受 CRS-HIPEC 治疗 CRPM 的病例。下一代测序和微卫星检测确定了 RAS、BRAF 和 MMR/MSI 的基因型。使用多变量 Cox 比例风险模型评估肿瘤侧别和基因组对生存的调整影响。我们分析了这些变量对无进展生存期的影响以及免疫检查点抑制剂的影响。
共有 250 例患者接受了 CRS-HIPEC 治疗，并进行了 RAS、BRAF 和 MMR/MSI 检测；50.8%的患者存在 RAS 突变，12.4%的患者存在 BRAF 突变，6.8%的患者存在错配修复/微卫星不稳定性高（dMMR/MSI-H）。基因组改变主要发生在右侧肿瘤。在调整了合并症以及肿瘤学和围手术期变量后，直肠起源（风险比 [HR] 1.9，p=0.01）、RAS 突变（HR 1.6，p=0.01）和 BRAF 突变（HR 1.7，p=0.05）与较差的生存率相关。RAS 突变还与较短的无进展生存期相关（术后 6 个月时 HR 为 1.6，p=0.01），dMMR/MSI-H 状态与较好的生存率相关（HR 为 0.3，p=0.01，2 年时）。接受免疫检查点抑制剂治疗的 dMMR/MSI-H 患者的生存情况有改善趋势。
直肠起源、RAS 突变和 BRAF 突变均与 CRS-HIPEC 治疗 CRPM 后的生存率较差相关。CRPM 患者存在 dMMR/MSI-H 状态具有较好的生存率。进一步的研究应评估免疫检查点抑制剂在这一分组中的获益。
