Key result
Patients with metastatic colorectal cancer carrying the FASN rs4485435 any C allele had significantly shorter progression-free survival when receiving bevacizumab-based chemotherapy compared to G/G carriers (HR 2.87).
Why the study?
Do genetic variants in the lipid metabolism pathway predict clinical outcomes in mCRC patients receiving bevacizumab-based first-line treatment?
Cohort (n=399)
Open-label
Yes
Do genetic variants in the lipid metabolism pathway predict clinical outcomes in mCRC patients receiving bevacizumab-based first-line treatment?
Hazard Ratio: 2.87 (95% CI 1.4–5.9)
Absolute Event Rate: 8.69% vs 13.48%
p-value: p=0.00675
Genetic polymorphisms in the lipid metabolism pathway may predict progression-free survival in patients with metastatic colorectal cancer receiving bevacizumab-based chemotherapy, suggesting a role in resistance to anti-VEGF treatment.
FASN genotyping should not yet guide bevacizumab decisions in mCRC; leaves open predictive utility of lipid pathway variants for prospective validation.
Background: 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. Methods: 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. Findings: 0.017) on PFS Interpretation: 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. Funding: 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).
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Wang et al. (2023) conducted a cohort in Metastatic colorectal cancer (n=399). FASN rs4485435 any C allele vs. FASN rs4485435 G/G genotype was evaluated on Progression-free survival (HR 2.87, 95% CI 1.4-5.9, p=0.00675). Patients with metastatic colorectal cancer carrying the FASN rs4485435 any C allele had significantly shorter progression-free survival when receiving bevacizumab-based chemotherapy compared to G/G carriers (HR 2.87).
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