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.
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
Journal
EClinicalMedicine
ISSN: 2589-5370
Titre abrégé: EClinicalMedicine
Pays: England
ID NLM: 101733727
Informations de publication
Date de publication:
Mar 2023
Mar 2023
Historique:
received:
01
08
2022
revised:
02
01
2023
accepted:
04
01
2023
entrez:
23
2
2023
pubmed:
24
2
2023
medline:
24
2
2023
Statut:
epublish
Résumé
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. 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. In the discovery cohort, patients with Our study demonstrates for the first time, to our knowledge, that 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).
Sections du résumé
Background
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.
Methods
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.
Findings
UNASSIGNED
In the discovery cohort, patients with
Interpretation
UNASSIGNED
Our study demonstrates for the first time, to our knowledge, that
Funding
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).
Identifiants
pubmed: 36816347
doi: 10.1016/j.eclinm.2023.101827
pii: S2589-5370(23)00004-4
pmc: PMC9932345
doi:
Types de publication
Journal Article
Langues
eng
Pagination
101827Informations de copyright
© 2023 The Authors.
Déclaration de conflit d'intérêts
H.-J.L. reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. S.S. reports receiving honoraria for talks and advisory board role: AMGEN, Bayer, BMS, Pierre-Fabre, Merck KGaA; MSD, Leo-Pharma, Lilly, Sanofi, Servier, Roche, Takeda, Taiho. A.F reports receiving honoraria as consultant/advisory board for Amgen, Bayer, Bristol, Daiichi Sankyo, Incyte, Lilly, Merck, MSD, Pierre-Fabre, Roche, Servier. C.M was a full time employee of Roche/Genentech when the MAVERICC data was generated. All remaining authors have declared no conflicts of interest.
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