Impact of Genetic Variants Involved in the Lipid Metabolism Pathway on Progression Free Survival in Patients Receiving Bevacizumab-based Chemotherapy in Metastatic Colorectal Cancer: a Retrospective Analysis of FIRE-3 and MAVERICC Trials

Overview

Journal EClinicalMedicine

Specialty General Medicine

Date 2023 Feb 23

PMID 36816347

Authors

Jingyuan Wang

Joshua Millstein

Yan Yang

Sebastian Stintzing

Hiroyuki Arai

Francesca Battaglin

Natsuko Kawanishi

Shivani Soni

Wu Zhang

Christoph Mancao

Chiara Cremolini

Tianshu Liu

Volker Heinemann

Alfredo Falcone

Lin Shen

Heinz-Josef Lenz

Affiliations

Soon will be listed here.

Abstract

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: In the discovery cohort, patients with 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; 0.00675) analysis. These data were confirmed in the validation cohort in multivariable analysis (HR = 2.07, 95%CI: 1.15-3.74; 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 rs4485435 ( 0.017) on PFS

Interpretation: Our study demonstrates for the first time, to our knowledge, that 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).

References

Stintzing S, Modest D, Rossius L, Lerch M, Fischer von Weikersthal L, Decker T . FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016; 17(10):1426-1434. DOI: 10.1016/S1470-2045(16)30269-8. View

Shukla S, Babcock Z, Pizzi L, Brunetti L . Impact of body mass index on survival and serious adverse events in advanced non-small cell lung cancer treated with bevacizumab: a meta-analysis of randomized clinical trials. Curr Med Res Opin. 2021; 37(5):811-817. DOI: 10.1080/03007995.2021.1900091. View

Asaoka Y, Ijichi H, Koike K . PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015; 373(20):1979. DOI: 10.1056/NEJMc1510353. View

Incio J, Ligibel J, McManus D, Suboj P, Jung K, Kawaguchi K . Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. Sci Transl Med. 2018; 10(432). PMC: 5936748. DOI: 10.1126/scitranslmed.aag0945. View

Schumacher F, Schmit S, Jiao S, Edlund C, Wang H, Zhang B . Genome-wide association study of colorectal cancer identifies six new susceptibility loci. Nat Commun. 2015; 6:7138. PMC: 4967357. DOI: 10.1038/ncomms8138. View

Wakil S, Abu-Elheiga L . Fatty acid metabolism: target for metabolic syndrome. J Lipid Res. 2008; 50 Suppl:S138-43. PMC: 2674721. DOI: 10.1194/jlr.R800079-JLR200. View

Sounni N, Cimino J, Blacher S, Primac I, Truong A, Mazzucchelli G . Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab. 2014; 20(2):280-94. DOI: 10.1016/j.cmet.2014.05.022. View

Drury J, Rychahou P, He D, Jafari N, Wang C, Lee E . Inhibition of Fatty Acid Synthase Upregulates Expression of CD36 to Sustain Proliferation of Colorectal Cancer Cells. Front Oncol. 2020; 10:1185. PMC: 7411002. DOI: 10.3389/fonc.2020.01185. View

Van Cutsem E, Kohne C, Hitre E, Zaluski J, Chang Chien C, Makhson A . Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360(14):1408-17. DOI: 10.1056/NEJMoa0805019. View

10.

Iwamoto H, Abe M, Yang Y, Cui D, Seki T, Nakamura M . Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance. Cell Metab. 2018; 28(1):104-117.e5. DOI: 10.1016/j.cmet.2018.05.005. View

11.

Falchook G, Infante J, Arkenau H, Patel M, Dean E, Borazanci E . First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors. EClinicalMedicine. 2021; 34:100797. PMC: 8040281. DOI: 10.1016/j.eclinm.2021.100797. View

12.

Mansilla F, da Costa K, Wang S, Kruhoffer M, Lewin T, Orntoft T . Lysophosphatidylcholine acyltransferase 1 (LPCAT1) overexpression in human colorectal cancer. J Mol Med (Berl). 2008; 87(1):85-97. PMC: 2614561. DOI: 10.1007/s00109-008-0409-0. View

13.

Cotte A, Aires V, Fredon M, Limagne E, Derangere V, Thibaudin M . Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance. Nat Commun. 2018; 9(1):322. PMC: 5778070. DOI: 10.1038/s41467-017-02732-5. View

14.

Jiang H, Dai J, Huang X, Chen Y, Qu P, Li J . Genetic variants in de novo lipogenic pathway genes predict the prognosis of surgically-treated hepatocellular carcinoma. Sci Rep. 2015; 5:9536. PMC: 4379911. DOI: 10.1038/srep09536. View

15.

Ye H, Liu Y, Wu K, Luo H, Cui L . AMPK activation overcomes anti-EGFR antibody resistance induced by KRAS mutation in colorectal cancer. Cell Commun Signal. 2020; 18(1):115. PMC: 7376720. DOI: 10.1186/s12964-020-00584-z. View

16.

Li Q, Wang Y, Wu S, Zhou Z, Ding X, Shi R . CircACC1 Regulates Assembly and Activation of AMPK Complex under Metabolic Stress. Cell Metab. 2019; 30(1):157-173.e7. DOI: 10.1016/j.cmet.2019.05.009. View

17.

Parikh A, Lee F, Yau L, Koh H, Knost J, Mitchell E . MAVERICC, a Randomized, Biomarker-stratified, Phase II Study of mFOLFOX6-Bevacizumab versus FOLFIRI-Bevacizumab as First-line Chemotherapy in Metastatic Colorectal Cancer. Clin Cancer Res. 2018; 25(10):2988-2995. PMC: 9022943. DOI: 10.1158/1078-0432.CCR-18-1221. View

18.

Zhang Y, Zhao X, Deng L, Li X, Wang G, Li Y . High expression of FABP4 and FABP6 in patients with colorectal cancer. World J Surg Oncol. 2019; 17(1):171. PMC: 6814121. DOI: 10.1186/s12957-019-1714-5. View

19.

Wang Y, Zeng Z, Lu J, Wang Y, Liu Z, He M . CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. Oncogene. 2018; 37(46):6025-6040. DOI: 10.1038/s41388-018-0384-z. View

20.

Jin X, Zhang K, Guo X, Myers R, Ye Z, Zhang Z . Fatty acid synthesis pathway genetic variants and clinical outcome of non-small cell lung cancer patients after surgery. Asian Pac J Cancer Prev. 2014; 15(17):7097-103. DOI: 10.7314/apjcp.2014.15.17.7097. View