Up to 40% of patients with cancer who are treated with bevacizumab develop severe hypertension and renal toxicity. But now, a simple genetic test performed before treatment could identify patients at highest risk for this potentially life-threatening complication, investigators said.
A study of genetic variants in more than 1000 patients treated with bevacizumab in clinical trials found that those who developed kidney toxicities were more than twice as likely to have a single-nucleotide polymorphism (SNP) that has been associated with kidney disease than patients who did not develop kidney toxicity.
In addition, one SNP was detected in the germline DNA of patients with hypertension twice as often as in patients who did not develop hypertension. This finding was replicated in data from another clinical trial, reported Federico Innocenti, MD, PhD, from the University of North Carolina at Chapel Hill.
The goal of a genetic test for specific SNPs before initiating treatment with bevacizumab “would be to minimize the risk of toxicity and at the same time maximize the benefit of treatment,” he said.
Genetic testing would allow early identification of patients at risk for hypertension and renal toxicities and might guide interventions such as initiation of antihypertensive therapy before treatment with bevacizumab or increased monitoring for toxicity, Innocenti added.
Innocenti was speaking at a press briefing prior to his presentation of the data in a plenary session during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, held online because of the COVID-19 pandemic.
Meeting co-chair William R. Sellers, MD, from the Broad Institute of the Massachusetts Institute of Technology and Harvard University in Cambridge, Massachussets, who was not involved in the study but attended the briefing, commented that this research illustrates a practical application of genomics to clinical care.
“This study is a good example of how our increasing ability to study the human genome easily and in depth is producing findings that may have an impact, either immediately or fairly soon, on patient health and outcomes,” he said. “Side effects from bevacizumab can be extremely debilitating, so if we can use a simple genetic test to identify which patients will experience toxicities and take appropriate measures to avoid these toxicities, this could help to provide better and more effective treatments for our patients.”
The investigators conducted a genome-wide association study involving more than 1000 patients with advanced breast, prostate, or pancreatic cancer who underwent treatment with bevacizumab in various combinations. The patients were enrolled in one of five studies conducted by the Alliance for Clinical Trials in Oncology.
The researchers characterized hundreds of thousands of genetic variations in the germline of patients and compared the frequency of variations between patients who developed hypertension and/or kidney toxicities with those who did not.
They identified 10 SNPs associated with high blood pressure and 10 associated with kidney toxicity. In a separate group of 582 patients who were enrolled in the ECOG-ACRIN 5103 trial, two SNPs were associated with hypertension.
One of the SNPs, labeled rs6770663 in the gene KCNAB1, was significantly associated with an increased risk for systolic blood pressure of 160 mmHg or higher.
“This finding is important, providing further evidence for the possible use of this variant as an indicator of the risk of toxicity from bevacizumab. It appears twice as often in patients experiencing high blood pressure as in those who do not,” Innocenti said.
KCNAB1 encodes for a protein that regulates the function of potassium channels in blood plasma membranes, he explained.
“Reduced function of this protein increases blood vessel constriction, and we think that patients with rs6770663 have greater narrowing of the blood vessels in response to bevacizumab treatment, resulting in an increased risk of high blood pressure. The biological basis for this finding is quite strong,” he said.
Innocenti also said that “rs6770663 can be regarded as a new, validated biological marker to predict high blood pressure caused by bevacizumab.”
The investigators also identified an SNP, labelled rs339947, that is located in the intergenetic region between DNAH5 and TRIO, the latter of which encodes for a protein that contributes to renal injury that can lead to proteinuria. This finding and its clinical significance has yet to be validated in an independent cohort.
The study was supported by the Alliance for Clinical Trials in Oncology. Innocenti has served as an advisor for Emerald Lake Safety and Symberix and is inventor on a patent on UGT1A1 testing and safety in oncology. Sellers reported no relevant financial relationships.
32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics: Abstract 6, presented October 25, 2020.