微卫星状态和 RAS/RAF 基因突变状态作为细胞减灭术和腹腔热灌注化疗（HIPEC）治疗结直肠腹膜转移的预后因素。
Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).
机构信息
Unit of Surgical Oncology of the Esophagus and Digestive Tract, Surgical Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
Peritoneal Surface Malignancy Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
出版信息
Ann Surg Oncol. 2022 Jun;29(6):3405-3417. doi: 10.1245/s10434-021-11045-3. Epub 2021 Nov 16.
BACKGROUND
Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS.
METHODS
Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS).
RESULTS
The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4-51.2 months], and the median DFS was 13.6 months (95% CI, 12.3-14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4-24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS.
CONCLUSION
For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.
背景
细胞减灭术（CRS）联合腹腔热灌注化疗（HIPEC）可显著延长结直肠（CRC）腹膜转移（PM）患者的生存时间。本研究旨在分析 KRAS/RAF 基因突变和微卫星（MS）状态对接受 CRS 治疗的患者的预后作用。
方法
数据来自意大利外科肿瘤学会协作组的 13 家腹膜转移治疗专长的意大利中心。临床和病理变量以及 KRAS/NRAS/BRAF 突变和 MS 状态与总生存（OS）和无病生存（DFS）相关。
结果
本研究共纳入 437 例接受 CRS-HIPEC 治疗的患者。中位 OS 为 42.3 个月（95%CI，33.4-51.2 个月），中位 DFS 为 13.6 个月（95%CI，12.3-14.9 个月）。局部（腹膜）DFS 为 20.5 个月（95%CI，16.4-24.6 个月）。除了已知的临床因素外，KRAS 突变（p=0.005）、BRAF 突变（p=0.01）和 MS 状态（p=0.04）与生存相关。KRAS 和 BRAF 突变患者的生存时间短于野生型（WT）患者（5 年 OS 分别为 29.4%和 26.8%和 51.5%）。微卫星不稳定（MSI）患者的生存时间长于微卫星稳定（MSS）患者（5 年 OS 分别为 58.3%和 36.7%）。MSI/WT 患者的预后最佳。MSS/WT 和 MSI/突变患者的生存情况相似，而 MSS/突变患者的预后最差（5 年 OS 分别为 70.6%、48.1%和 23.4%；p=0.0001）。多变量分析显示，OS 与腹膜癌指数[风险比（HR），每点增加 1.05]、细胞减灭术（CC）评分（HR，2.8）、N 状态（HR，1.6）、印戒细胞（HR，2.4）、MSI/WT（HR，0.5）和 MSS/WT-MSI/突变（HR，0.4）有关。DFS 也得到了类似的结果。
结论
对于有条件接受 CRS 的 CRC-PM 患者，临床和病理标准需要与分子特征（KRAS/BRAF 突变）相结合。微卫星状态应被强烈考虑，因为 MSI 比 MSS 更具生存优势，即使对突变患者也是如此。
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