Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
Immuno-oncology Service, Human Oncology and Pathogenesis Program, Memorial, Sloan Kettering Cancer Center New York, NY.
Ann Surg. 2022 Feb 1;275(2):371-381. doi: 10.1097/SLA.0000000000005315.
To determine whether genomic risk groups identified by somatic mutation testing of colorectal liver metastasis (CRLM) can be used for "molecularly-guided" selection for adjuvant systemic chemotherapy and hepatic artery infusion of FUDR (SYS+HAI-FUDR).
Several genomic biomarkers have been associated with clinical phenotype and survival for patients with resectable CRLM. It is unknown whether prognostication afforded by genomic stratification translates into enhanced patient selection for adjuvant hepatic artery infusion therapy.
Consecutive patients with resected CRLM and available mutational characterization via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets were reviewed from a prospective institutional database. Patients were stratified into three genomic risk groups based on previously defined alterations in SMAD4, EGFR and the RAS/RAF pathway. The association between SYS+HAI-FUDR and overall survival, relative to adjuvant chemotherapy alone (SYS), was evaluated in each genomic risk group by Cox proportional hazard regression and propensity score matched analyses.
A total of 334 patients (SYS+HAI-FUDR 204; SYS 130) were identified; the rates of RAS/RAF alterations and SMAD4 inactivation were 47.4% and 11.7%, respectively. After a median follow-up of 58 months, adjuvant SYS+HAI-FUDR was independently associated with a reduced risk of death (HR 0.50, 95%CI 0.26-0.98, P = 0.045) in the low-risk genomic group, but not in the moderate-risk (HR 1.07, 95%CI 0.5-2.07, P = 0.749) or high-risk (HR 1.62, 95%CI 0.29-9.12, P = 0.537) cohorts. Following propensity score matching, adjuvant SYS+HAI-FUDR remained associated with significant improvements in long-term survival selectively in the low-risk genomic cohort (5-year actuarial survival: 89% vs. 68%, P = 0.019).
Genomic alterations in RAS/RAF, SMAD4, and EGFR may be useful to guide treatment selection in resectable CRLM patients and warrant external validation and integration in future clinical trial design.
确定结直肠癌肝转移（CRLM）的体细胞突变检测确定的基因组风险组是否可用于“分子指导”选择辅助全身化疗和氟尿嘧啶肝动脉输注（SYS+HAI-FUDR）。
已有几种基因组生物标志物与可切除 CRLM 患者的临床表型和生存相关。尚不清楚基因组分层提供的预后是否会转化为增强对辅助肝动脉输注治疗的患者选择。
从前瞻性机构数据库中回顾性分析了接受切除术治疗的 CRLM 且有可用突变特征的连续患者，这些特征通过 Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets 进行检测。根据先前在 SMAD4、EGFR 和 RAS/RAF 通路中定义的改变，患者被分为三个基因组风险组。通过 Cox 比例风险回归和倾向评分匹配分析，在每个基因组风险组中评估 SYS+HAI-FUDR 与单独辅助化疗（SYS）相比对总生存率的相关性。
共确定了 334 例患者（SYS+HAI-FUDR 204 例；SYS 130 例）；RAS/RAF 改变和 SMAD4 失活的发生率分别为 47.4%和 11.7%。中位随访 58 个月后，低风险基因组组中辅助 SYS+HAI-FUDR 与死亡风险降低独立相关（HR 0.50，95%CI 0.26-0.98，P = 0.045），但在中危风险（HR 1.07，95%CI 0.5-2.07，P = 0.749）或高危风险（HR 1.62，95%CI 0.29-9.12，P = 0.537）组中则不然。在进行倾向评分匹配后，辅助 SYS+HAI-FUDR 仍然与低风险基因组组中长期生存的显著改善相关（5 年实际生存率：89% vs. 68%，P = 0.019）。
RAS/RAF、SMAD4 和 EGFR 的基因组改变可能有助于指导可切除 CRLM 患者的治疗选择，需要在未来的临床试验设计中进行外部验证和整合。
