Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Ann Surg Oncol. 2022 Nov;29(12):7579-7588. doi: 10.1245/s10434-022-12085-z. Epub 2022 Jul 27.
Despite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy.
Patients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis.
Of 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval [CI] 48-65%) and 51% (95% CI 41-60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43-58%) and 45% (95% CI 36-54%), respectively. More ER was observed with tumors harboring altered KRAS (38% [95% CI 25-50%] vs. 63% [95% CI 53-71%], p-adj = 0.003) and RAS/RAF (36% [95% CI 25-48%] vs. 66% [95% CI 56-74%], p-adj < 0.001) than wild-type. Co-altered RAS/RAF-TP53 was associated with worse AR (26% [95% CI 14-40%] vs. 48% [95% CI 39-57%], p-unadj < 0.001), ER (30% [95% CI 17-45%] vs. 62% [95% CI 53-70%], p-unadj < 0.001), and LR rate (40% [95% CI 24-57%] vs. 70% [95% CI 60-77%], p-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-TP53 was associated with increased risk for AR (HR = 2.14, 95% CI 1.38-3.31, p-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06-3.02, p-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78-4.44, p-unadj < 0.001).
Altered KRAS, RAS/RAF, and RAS/RAF-TP53 associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-TP53 was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy.
尽管进行了治愈性肝切除术，但大多数结直肠癌肝转移（CRLM）患者在 2 年内仍会局部复发。肝复发的基因组预测因子了解甚少。本研究旨在确定接受辅助肝动脉输注（HAI）和/或全身（SYS）化疗的接受根治性肝切除术的 CRLM 患者中与复发相关的基因组特征。
对 2000 年 1 月至 2017 年 10 月期间接受根治性肝切除术和辅助 HAI+SYS 或 SYS 治疗并具有下一代测序数据的患者进行了编目。使用 Kaplan-Meier 分析检查基因和信号级别的改变与任何（AR）、肝（LR）和肝外（ER）复发的时间之间的关联。
在 172 例接受 HAI+SYS 的患者中，有 100 例患者复发，其中 69 例为 LR，83 例为 ER。5 年和 10 年 LR 无复发生存率分别为 57%（95%置信区间 [CI] 48-65%）和 51%（95% CI 41-60%）。5 年和 10 年 ER 无复发生存率分别为 51%（95% CI 43-58%）和 45%（95% CI 36-54%）。与野生型相比，肿瘤中存在改变的 KRAS（38%[95%CI 25-50%]比 63%[95%CI 53-71%]，p 调整 < 0.003）和 RAS/RAF（36%[95%CI 25-48%]比 66%[95%CI 56-74%]，p 调整 < 0.001）观察到更多的 ER。共同改变的 RAS/RAF-TP53 与 AR（26%[95%CI 14-40%]比 48%[95%CI 39-57%]，p 未调整 < 0.001）、ER（30%[95%CI 17-45%]比 62%[95%CI 53-70%]，p 未调整 < 0.001）和 LR 率（40%[95%CI 24-57%]比 70%[95%CI 60-77%]，p 未调整 = 0.002）的风险增加相关。在多变量分析中，控制临床风险评分、消融、边缘状态和原发性 T 期后，共同改变的 RAS/RAF-TP53 与 AR（HR = 2.14，95%CI 1.38-3.31，p 未调整 < 0.001）、LR（HR = 1.79，95%CI 1.06-3.02，p 未调整 = 0.029）和 ER（HR = 2.81，95%CI 1.78-4.44，p 未调整 < 0.001）的风险增加相关。
改变的 KRAS、RAS/RAF 和 RAS/RAF-TP53 与接受辅助 HAI+SYS 的接受根治性肝切除术的 CRLM 患者的早期局部和远处复发相关。共同改变的 RAS/RAF-TP53 是 LR 的一个新预测因子，值得研究基因组协同作用是否与这种复发表型相关。需要针对高风险肿瘤生物学的系统治疗来减少肝切除术后的远处复发。
