TY - JOUR
T1 - Autophagy-related polymorphisms predict hypertension in patients with metastatic colorectal cancer treated with FOLFIRI and bevacizumab
T2 - Results from TRIBE and FIRE-3 trials
AU - Berger, Martin D.
AU - Yamauchi, Shinichi
AU - Cao, Shu
AU - Hanna, Diana L.
AU - Sunakawa, Yu
AU - Schirripa, Marta
AU - Matsusaka, Satoshi
AU - Yang, Dongyun
AU - Groshen, Susan
AU - Zhang, Wu
AU - Ning, Yan
AU - Okazaki, Satoshi
AU - Miyamoto, Yuji
AU - Suenaga, Mitsukuni
AU - Lonardi, Sara
AU - Cremolini, Chiara
AU - Falcone, Alfredo
AU - Heinemann, Volker
AU - Loupakis, Fotios
AU - Stintzing, Sebastian
AU - Lenz, Heinz Josef
N1 - attenzione: Schirripa affiliata anche a Univeristy of Southern California - Los Angeles, in quanto progetto condotto tra due enti. Richiesta correzione del documento, rifiutato dall'editore
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Purpose The most frequent bevacizumab-related side-effects are hypertension, proteinuria, bleeding and thromboembolism. To date, there is no biomarker that predicts anti-VEGF–associated toxicity. As autophagy inhibits angiogenesis, we hypothesised that single-nucleotide polymorphisms (SNPs) within autophagy-related genes may predict bevacizumab-mediated toxicity in patients with metastatic colorectal cancer (mCRC). Patients and methods Patients with mCRC treated with first-line FOLFIRI and bevacizumab in two phase III randomised trials, namely the TRIBE trial (n = 219, discovery cohort) and the FIRE-3 trial (n = 234, validation cohort) were included in this study. Patients receiving treatment with FOLFIRI and cetuximab (FIRE-3, n = 204) served as a negative control. 12 SNPs in eight autophagy-related genes (ATG3/5/8/13, beclin 1, FIP200, unc-51-like kinase 1, UVRAG) were analysed by PCR-based direct sequencing. Results The FIP200 rs1129660 variant showed significant associations with hypertension in the TRIBE cohort. Patients harbouring any G allele of the FIP200 rs1129660 SNP showed a significantly lower rate of grade 2–3 hypertension compared with the A/A genotype (3% versus 15%, odds ratio [OR] 0.17; 95% confidence interval [CI], 0.02–0.73; P = 0.009). Similarly, G allele carriers of the FIP200 rs1129660 SNP were less likely to develop grade 2–3 hypertension than patients with an A/A genotype in the FIRE-3 validation cohort (9% versus 20%, OR 0.43; 95% CI, 0.14–1.11; P = 0.077), whereas this association could not be observed in the control cohort (12% versus 9%, OR 1.40; 95% CI, 0.45–4.04; P = 0.60). Conclusion This is the first report demonstrating that polymorphisms in the autophagy-related FIP200 gene may predict hypertension in patients with mCRC treated with FOLFIRI and bevacizumab.
AB - Purpose The most frequent bevacizumab-related side-effects are hypertension, proteinuria, bleeding and thromboembolism. To date, there is no biomarker that predicts anti-VEGF–associated toxicity. As autophagy inhibits angiogenesis, we hypothesised that single-nucleotide polymorphisms (SNPs) within autophagy-related genes may predict bevacizumab-mediated toxicity in patients with metastatic colorectal cancer (mCRC). Patients and methods Patients with mCRC treated with first-line FOLFIRI and bevacizumab in two phase III randomised trials, namely the TRIBE trial (n = 219, discovery cohort) and the FIRE-3 trial (n = 234, validation cohort) were included in this study. Patients receiving treatment with FOLFIRI and cetuximab (FIRE-3, n = 204) served as a negative control. 12 SNPs in eight autophagy-related genes (ATG3/5/8/13, beclin 1, FIP200, unc-51-like kinase 1, UVRAG) were analysed by PCR-based direct sequencing. Results The FIP200 rs1129660 variant showed significant associations with hypertension in the TRIBE cohort. Patients harbouring any G allele of the FIP200 rs1129660 SNP showed a significantly lower rate of grade 2–3 hypertension compared with the A/A genotype (3% versus 15%, odds ratio [OR] 0.17; 95% confidence interval [CI], 0.02–0.73; P = 0.009). Similarly, G allele carriers of the FIP200 rs1129660 SNP were less likely to develop grade 2–3 hypertension than patients with an A/A genotype in the FIRE-3 validation cohort (9% versus 20%, OR 0.43; 95% CI, 0.14–1.11; P = 0.077), whereas this association could not be observed in the control cohort (12% versus 9%, OR 1.40; 95% CI, 0.45–4.04; P = 0.60). Conclusion This is the first report demonstrating that polymorphisms in the autophagy-related FIP200 gene may predict hypertension in patients with mCRC treated with FOLFIRI and bevacizumab.
KW - Autophagy
KW - Bevacizumab-associated toxicity
KW - Colorectal cancer
KW - FOLFIRI/bevacizumab
KW - Hypertension
KW - Single-nucleotide polymorphism
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U2 - 10.1016/j.ejca.2017.02.020
DO - 10.1016/j.ejca.2017.02.020
M3 - Article
C2 - 28347919
AN - SCOPUS:85016010845
VL - 77
SP - 13
EP - 20
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
ER -