未经批准:抗血管生成药物(AAD)通过抑制血管生成引发的氧气和营养素消耗将葡萄糖依赖性代谢转变为脂质依赖性代谢。阻断脂肪酸氧化可增强AAD介导的结直肠癌(CRC)抗肿瘤作用。因此,我们假设脂质代谢途径中的遗传变异可以预测临床结果[总体反应率(ORR),接受贝伐单抗一线治疗的转移性CRC(mCRC)患者的总生存期(OS)和无进展生存期(PFS)].
未经证实:来自FIRE-3患者血液样本的基因组DNA(全球,随机化,开放标签,第三阶段试验,在2007-6-23和2012-9-19之间,发现队列:FOLFIRI/贝伐单抗组,n=107;对照组:FOLFIRI/西妥昔单抗组,n=129)和MAVERICC(全球,随机化,开放标签,第二阶段研究,在2011-8和2015-7之间,在美国,加拿大,爱沙尼亚,爱尔兰,瑞士,挪威,葡萄牙。验证队列:FOLFIRI/贝伐单抗组,n=163)试验,使用OncoArray-500K珠芯片面板进行基因分型。7个参与脂质代谢途径的基因(CD36,FABP4,LPCAT1/2,CPT1A,FASN,ACACA)使用卡普兰-迈耶曲线进行分析,单变量分析的对数秩检验和多变量分析的Cox比例风险回归参数的似然比检验.使用卡方或Fisher精确检验评估ORR和SNP关联。
UNASSIGNED:在发现队列中,在多变量分析(HR=2.87;95CI1.4-5.9;p=0.00675)中,与G/G携带者(n=62)相比,FASNrs4485435任何C等位基因(n=21)患者的PFS显著缩短(中位PFS:8.69vs13.48个月).这些数据在多变量分析的验证队列中得到证实(HR=2.07,95CI:1.15-3.74;p=0.02),但在FIRE-3的西妥昔单抗队列中未观察到关联.在FIRE-3中贝伐单抗与西妥昔单抗臂的比较中,显示了与FASNrs4485435(p=0.017)对PFS的显着相互作用。
未经评估:我们的研究首次证明,根据我们的知识,FASN多态性可以预测mCRC患者贝伐单抗治疗的结局.这些发现支持脂质代谢途径在对抗VEGF治疗的抗性中的可能作用。
UNASSIGNED:这项工作得到了国家癌症研究所的支持[P30CA014089toH.-J.L.],GloriaBorgesWunderGlo基金会,Dhont家庭基金会,维多利亚和菲利普·威尔逊研究基金,圣佩德罗半岛癌症协会,明谢研究基金,埃迪·马霍尼纪念研究基金,上海帆船项目(22YF1407000),国家创新人才博士后计划(BX20220084),中国博士后科学基金(2022M710768),国家自然科学基金(82202892).
UNASSIGNED: Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches glucose-dependent to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer (CRC). Therefore, we hypothesised that genetic variants in the lipid metabolism pathway may predict clinical outcomes [overall response rate (ORR), overall survival (OS) and progression-free survival (PFS)] in metastatic CRC (mCRC) patients receiving bevacizumab-based first-line treatment.
UNASSIGNED: Genomic DNA from blood samples of patients enrolled in FIRE-3 (a global, randomised, open-label, phase 3 trial, between 2007-6-23 and 2012-9-19, discovery cohort: FOLFIRI/bevacizumab arm, n = 107; control cohort: FOLFIRI/cetuximab arm, n = 129) and MAVERICC (a global, randomised, open-label, phase II study, between 2011-8 and 2015-7, in United States, Canada, Estonia, Ireland, Switzerland, Norway, and Portugal. Validation cohort: FOLFIRI/bevacizumab arm, n = 163) trials, was genotyped using the OncoArray-500 K beadchip panel. The impact on OS and PFS of 17 selected SNPs in 7 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1/2, CPT1A, FASN, ACACA) was analysed using Kaplan-Meier curves, the log-rank test for univariate analyses and likelihood ratio tests of Cox proportional hazards regression parameters for multivariable analyses. ORR and SNP associations were evaluated using Chi-square or Fisher\'s exact tests.
UNASSIGNED: In the discovery cohort, patients with FASN rs4485435 any C allele (n = 21) showed significantly shorter PFS (median PFS: 8.69 vs 13.48 months) compared to carriers of G/G (n = 62) in multivariable (HR = 2.87; 95%CI 1.4-5.9; p = 0.00675) analysis. These data were confirmed in the validation cohort in multivariable analysis (HR = 2.07, 95%CI: 1.15-3.74; p = 0.02), but no association was observed in the cetuximab cohort of FIRE-3. In the comparison of bevacizumab vs cetuximab arm in FIRE-3, a significant interaction was shown with FASN rs4485435 (p = 0.017) on PFS.
UNASSIGNED: Our study demonstrates for the first time, to our knowledge, that FASN polymorphisms may predict outcome of bevacizumab-based treatment in patients with mCRC. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF treatment.
UNASSIGNED: This work was supported by the National Cancer Institute [P30CA 014089 to H.-J.L.], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, Ming Hsieh Research Fund, Eddie Mahoney Memorial Research Fund, Shanghai Sailing Program (22YF1407000), China National Postdoctoral Program for Innovative Talents (BX20220084), China Postdoctoral Science Foundation (2022M710768), National Natural Science Foundation of China (82202892).