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

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

doi:10.1016/j.eclinm.2023.101827

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

EClinicalMedicine. 2023 Feb 4:57:101827. doi: 10.1016/j.eclinm.2023.101827. eCollection 2023 Mar.

Authors

Jingyuan Wang^{1

2

3

4}, Joshua Millstein⁵, Yan Yang⁵, Sebastian Stintzing⁶, Hiroyuki Arai², Francesca Battaglin², Natsuko Kawanishi², Shivani Soni², Wu Zhang², Christoph Mancao⁷, Chiara Cremolini⁸, Tianshu Liu¹, Volker Heinemann⁹, Alfredo Falcone⁸, Lin Shen³, Heinz-Josef Lenz²

Affiliations

¹ Department of Medical Oncology, Zhongshan Hospital, Fudan University, Xuhui District, Shanghai, 200032, China.
² Division of Medical Oncology, Norris Comprehensive Cancer Centre, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
⁴ Cancer Centre, Zhongshan Hospital Fudan University, Xuhui District, Shanghai, 200032, China.
⁵ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, USA.
⁶ Department of Hematology, Oncology and Cancer Immunology (CCM), Charité- Universitaetsmedizin Berlin, Germany.
⁷ Oncology Biomarker Development, Genentech Inc., Basel, Switzerland.
⁸ Department of Translational Medicine, University of Pisa, Italy.
⁹ Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.

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 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.

Interpretation: 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.

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).

Keywords: 3' UTR, 3′ untranslated regions; ACACA, acetyl-coA carboxylase; ADD, antiangiogenic drug; AIM, ancestry informative markers; Bevacizumab; Biomarker; CEU, Utah residents with Northern and Western European ancestry from the CEPH collection; CORECT, Colorectal Cancer Transdisciplinary; CPT1A, carnitine palmitoyl transferase 1A; CRC, colorectal cancer; Colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; FAO, fatty acids β-oxidation; FASN, fatty acid synthase; LPCAT1, lysolecithin acyltransferase 1; LPCAT2, lysolecithin acyltransferase 2; Lipid metabolism; MAF, minor allele frequency; MUFA, monounsaturated fatty acids; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SNP, single nucleotide polymorphisms; mCRC, metastatic colorectal cancer.

Grants and funding

P30 CA014089/CA/NCI NIH HHS/United States