Autophagy-related polymorphisms predict hypertension in patients with metastatic colorectal cancer treated with FOLFIRI and bevacizumab: Results from TRIBE and FIRE-3 trials

Martin D. Berger, Shinichi Yamauchi, Shu Cao, Diana L. Hanna, Yu Sunakawa, Marta Schirripa, Satoshi Matsusaka, Dongyun Yang, Susan Groshen, Wu Zhang, Yan Ning, Satoshi Okazaki, Yuji Miyamoto, Mitsukuni Suenaga, Sara Lonardi, Chiara Cremolini, Alfredo Falcone, Volker Heinemann, Fotios Loupakis, Sebastian StintzingHeinz Josef Lenz

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)13-20
Number of pages8
JournalEuropean Journal of Cancer
Volume77
DOIs
Publication statusPublished - May 1 2017

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Keywords

  • Autophagy
  • Bevacizumab-associated toxicity
  • Colorectal cancer
  • FOLFIRI/bevacizumab
  • Hypertension
  • Single-nucleotide polymorphism

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Berger, M. D., Yamauchi, S., Cao, S., Hanna, D. L., Sunakawa, Y., Schirripa, M., Matsusaka, S., Yang, D., Groshen, S., Zhang, W., Ning, Y., Okazaki, S., Miyamoto, Y., Suenaga, M., Lonardi, S., Cremolini, C., Falcone, A., Heinemann, V., Loupakis, F., ... Lenz, H. J. (2017). Autophagy-related polymorphisms predict hypertension in patients with metastatic colorectal cancer treated with FOLFIRI and bevacizumab: Results from TRIBE and FIRE-3 trials. European Journal of Cancer, 77, 13-20. https://doi.org/10.1016/j.ejca.2017.02.020