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Berger, Martin D.; Yamauchi, Shinichi; Cao, Shu; Hanna, Diana L.; Sunakawa, Yu; Schirripa, Marta; Matsusaka, Satoshi; Yang, Dongyun; Groshen, Susan; Zhang, Wu; Ning, Yan; Okazaki, Satoshi; Miyamoto, Yuji; Suenaga, Mitsukuni; Lonardi, Sara; Cremolini, Chiara; Falcone, Alfredo; Heinemann, Volker; Loupakis, Fotios; Stintzing, Sebastian; Lenz, Heinz-Josef (2017): Autophagy-related polymorphisms predict hypertension in patients with metastatic colorectal cancer treated with FOLFIRI and bevacizumab: Results from TRIBE and FIRE-3 trials. In: European Journal of Cancer, Vol. 77: pp. 13-20
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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.