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

被引：21

作者：

Berger, Martin D. ^{[1
]}

Yamauchi, Shinichi ^{[1
]}

Cao, Shu ^{[2
]}

Hanna, Diana L. ^{[1
]}

Sunakawa, Yu ^{[1
]}

Schirripa, Marta ^{[1
,5
]}

Matsusaka, Satoshi ^{[1
]}

Yang, Dongyun ^{[2
]}

Groshen, Susan ^{[2
]}

Zhang, Wu ^{[1
]}

Ning, Yan ^{[1
]}

Okazaki, Satoshi ^{[1
]}

Miyamoto, Yuji ^{[1
]}

Suenaga, Mitsukuni ^{[1
]}

Lonardi, Sara ^{[5
]}

Cremolini, Chiara ^{[6
]}

Falcone, Alfredo ^{[6
]}

Heinemann, Volker ^{[3
,4
]}

Loupakis, Fotios ^{[5
]}

Stintzing, Sebastian ^{[3
,4
]}

Lenz, Heinz-Josef ^{[1
,2
]}

机构：

[1] Univ Southern Calif, Div Med Oncol, Norris Comprehens Canc Ctr, Keck Sch Med, 1441 Eastlake Ave, Los Angeles, CA 90033 USA

[2] Univ Southern Calif, Dept Prevent Med, Norris Comprehens Canc Ctr, Keck Sch Med, 1441 Eastlake Ave, Los Angeles, CA 90033 USA

[3] Univ Munich LMU, Dept Med Oncol, Marchioninistr 15, D-81377 Munich, Germany

[4] Univ Munich LMU, Ctr Comprehens Canc, Marchioninistr 15, D-81377 Munich, Germany

[5] IRCCS, Oncol Med 1, Ist Oncol Veneto, Via Gattamelata 64, I-35128 Padua, Italy

[6] Azienda Osped Univ Pisana, Ist Toscano Tumori, UO Oncol Med, Via Roma 67, I-56126 Pisa, Italy

来源：

EUROPEAN JOURNAL OF CANCER | 2017年 / 77卷

基金：

日本学术振兴会;

关键词：

Autophagy; Hypertension; Colorectal cancer; Single-nucleotide polymorphism; Bevacizumab-associated toxicity; FOLFIRI/bevacizumab; PLUS BEVACIZUMAB; INHIBITION; STRESS; PROGRESSION; SENESCENCE; APOPTOSIS;

D O I：

10.1016/j.ejca.2017.02.020

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：13 / 20

页数：8

共 37 条

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