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UNC Lineberger’s Federico Innocenti, MD, PhD.

Bevacizumab is a monoclonal antibody that is effective in treating a number of cancers, including colorectal, liver, kidney and ovarian cancer, but the therapy can cause elevated blood pressure, an overabundance of protein in urine and other side effects.

During a plenary session of the 32nd EORTC-NCI-AACR virtual symposium on molecular targets and cancer therapeutics, a multi-institutional team of researchers, including from UNC Lineberger Comprehensive Cancer Center, reported they have identified variations in DNA sequencing that may help predict whether a person may be at risk of bevacizumab-induced hypertension. They also found another genetic predictor for proteinuria, or too much protein in urine, but additional research is needed to confirm their discovery.

Bevacizumab blocks the ability of vascular endothelial growth factor, VEGF, to promote the formation of new blood vessels. Solid tumors, needing a supply of blood to grow, can secrete chemical signals that spur new blood vessels to grow. Inhibiting the development of new blood vessels has proven to be effective in treating some cancers. However, studies have shown that patients treated with bevacizumab can experience side effects.

“These toxicities are common, and have been observed in up to 40% of patients treated with bevacizumab,” said UNC Lineberger’s Federico Innocenti, MD, PhD, associate professor at the UNC Eshelman School of Pharmacy and the study’s first author. “They can cause discomfort and harm to patients, and they can develop quickly and become severe, which requires delaying or discontinuing treatment, which limits efficacy. In some cases, the side effects can be fatal.”

Innocenti and his colleagues conducted genome-wide association studies (GWAS) in 1,041 patients treated with bevacizumab in clinical trials from The Alliance for Clinical Trials in Oncology and who experienced moderate or greater bevacizumab-related hypertension and proteinuria. Their goal for conducting the largest GWAS of bevacizumab-induced toxicity from randomized trials was to identify associations between variations in the DNA sequence of patients called single-nucleotide polymorphisms (SNPs) and toxicity.

They discovered a number of new common variants associated with bevacizumab-induced hypertension and proteinuria. Among them, rs6770663 in KCNAB1 was further validated in another external cohort of 582 cancer patients treated with bevacizumab. This study proposes the rs6770663 variant as a new biomarker to predict the risk of bevacizumab-induced hypertension. This finding can be used to inform decisions when considering treating patients with bevacizumab.

The findings will enable doctors to improve the treatment of their patients and avoid severe adverse side effects. This may include treating patients who have the rs6770663 variant with another drug, if available, using a reduced dose of bevacizumab to see what happens, or using increased monitoring.

“Efforts are now underway to develop a prospective observational study using this discovery,” said Innocenti. “The goal is to give doctors a test they can use to screen patients for these genetic predictors and update their treatment regimens as necessary.”