Martin D Berger1, Shinichi Yamauchi1, Shu Cao2, Diana L Hanna1, Yu Sunakawa1, Marta Schirripa3, Satoshi Matsusaka1, Dongyun Yang2, Susan Groshen2, Wu Zhang1, Yan Ning1, Satoshi Okazaki1, Yuji Miyamoto1, Mitsukuni Suenaga1, Sara Lonardi4, Chiara Cremolini5, Alfredo Falcone5, Volker Heinemann6, Fotios Loupakis4, Sebastian Stintzing6, Heinz-Josef Lenz7. 1. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. 2. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. 3. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA; Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Gattamelata 64, 35128 Padova, Italy. 4. Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Gattamelata 64, 35128 Padova, Italy. 5. U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Via Roma 67, 56126 Pisa, Italy. 6. Department of Medical Oncology and Comprehensive Cancer Center, University of Munich (LMU), Marchioninistrasse 15, 81377 Munich, Germany. 7. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA; Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. Electronic address: lenz@med.usc.edu.
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 withFOLFIRI and bevacizumab.
RCT Entities:
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 FIP200rs1129660 variant showed significant associations with hypertension in the TRIBE cohort. Patients harbouring any G allele of the FIP200rs1129660 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 FIP200rs1129660 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.
Authors: Megan Li; Flora Mulkey; Chen Jiang; Bert H O'Neil; Bryan P Schneider; Fei Shen; Paula N Friedman; Yukihide Momozawa; Michiaki Kubo; Donna Niedzwiecki; Howard S Hochster; Heinz-Josef Lenz; James N Atkins; Hope S Rugo; Susan Halabi; William Kevin Kelly; Howard L McLeod; Federico Innocenti; Mark J Ratain; Alan P Venook; Kouros Owzar; Deanna L Kroetz Journal: Clin Cancer Res Date: 2018-06-05 Impact factor: 12.531
Authors: John M Mariadason; Niall C Tebbutt; Fiona Chionh; Val Gebski; Sheren J Al-Obaidi; Jennifer K Mooi; Maressa A Bruhn; Chee K Lee; Anderly C Chüeh; David S Williams; Andrew J Weickhardt; Kate Wilson; Andrew M Scott; John Simes; Jennifer E Hardingham; Timothy J Price Journal: Sci Rep Date: 2022-01-24 Impact factor: 4.379