Genetic susceptibility to severe toxicities and toxic deaths among 1,626 cancer patients trated with bevacizumab: implications for treatment and personalized therapy

• Grant number: 18/04491-2
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): January 01, 2019
• Effective date (End): December 21, 2019
• Field of knowledge: Health Sciences - Pharmacy
• Principal researcher: Patricia Moriel
• Grantee: Júlia Coelho França Quintanilha
• Supervisor abroad: Federico Innocenti
• Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Research place: University of North Carolina at Chapel Hill (UNC), United States
• Associated to the scholarship: 17/02338-0 - MicroRNAs and oxidated molecules as possible biomarkers of cisplatin-induced nephrotoxicity in patients with head and neck cancer, BP.DR

Abstract

Bevacizumab is the most commonly used anti-angiogenesis drug, approved in the USA in combination with chemotherapy for patients with advanced colorectal, lung, renal cell, ovarian, breast, and cervical cancers. The survival advantage conferred by bevacizumab is accompanied by significant toxicity. Some of these adverse reactions can be life threatening. Currently, there are no biomarkers to select patients for whom bevacizumab is safe. We aim to identify genetic variants of bevacizumab-related toxicities and deaths by utilizing clinical and genomic data available from 1,626 patients enrolled in phase III randomized clinical trials. The large sample size and the reproducibility of the associations in independent studies increase the clinical validity of genetic markers, as well as increasing the likelihood that these findings could be incorporated into the label of bevacizumab and other anti-angiogenic drugs. Translation of these findings into clinical practice could result in a simple genetic test to assess a risk score for bevacizumab-related toxicity. Patients with high risk of toxicity could be spared treatment and alternative therapies could then be selected. Our goal will include a federally funded follow-up study to validate the genetic associations of toxicity through functional analysis to elucidate the molecular mechanisms associated with a predisposition to adverse reactions. Our objective is to achieve precision medicine through the intersection of clinical, statistical and functional analysis and provide clinicians the genomic tools for a risk/benefit assessment of cancer patients with metastatic disease who might benefit from treatment with bevacizumab.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

QUINTANILHA, JULIA C. F.; RACIOPPI, ALESSANDRO; WANG, JIN; ETHERIDGE, AMY S.; DENNING, STEFANIE; PENA, CAROL E.; SKOL, ANDREW D.; CRONA, DANIEL J.; LIN, DANYU; INNOCENTI, FEDERICO. IK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitor. PHARMACOGENOMICS JOURNAL, v. 22, n. 1 NOV 2021. Web of Science Citations: 1.

QUINTANILHA, JULIA C. F.; WANG, JIN; SIBLEY, ALEXANDER B.; JIANG, CHEN; ETHERIDGE, AMY S.; SHEN, FEI; JIANG, GUANGLONG; MULKEY, FLORA; PATEL, JAI N.; HERTZ, DANIEL L.; DEES, ELIZABETH CLAIRE; MCLEOD, HOWARD L.; BERTAGNOLLI, MONICA; RUGO, HOPE; KINDLER, HEDY L.; KELLY, WILLIAM KEVIN; RATAIN, MARK J.; KROETZ, DEANNA L.; OWZAR, KOUROS; SCHNEIDER, BRYAN P.; LIN, DANYU; INNOCENTI, FEDERICO. evacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patient. BRITISH JOURNAL OF CANCER, v. 126, n. 2 OCT 2021. Web of Science Citations: 1.

QUINTANILHA, JULIA C. F.; WANG, JIN; SIBLEY, ALEXANDER B.; XU, WEI; ESPIN-GARCIA, OSVALDO; JIANG, CHEN; ETHERIDGE, AMY S.; RATAIN, MARK J.; LENZ, HEINZ-JOSEF; BERTAGNOLLI, MONICA; KINDLER, HEDY L.; DICKLER, MAURA N.; VENOOK, ALAN; LIU, GEOFFREY; OWZAR, KOUROS; LIN, DANYU; INNOCENTI, FEDERICO. Genome-wide association studies of survival in 1520 cancer patients treated with bevacizumab-containing regimens. International Journal of Cancer, v. 150, n. 2 OCT 2021. Web of Science Citations: 0.