Two common genetic variants appear to be linked to toxicity induced by bevacizumab, researchers reported at the 32nd European Organisation for Research and Treatment of Cancer (EORTC)–National Cancer Institute (NCI)–American Association for Cancer Research (AACR) Symposium on Molecular Targets and Cancer, which was held virtually.1 The variants rs6770663 and rs339947 occurred more than twice as often in patients with hypertension and renal toxicity, respectively, according to Federico Innocenti, MD, PhD, Associate Professor at the Eshelman School of Pharmacy at the University of North Carolina, Chapel Hill.
The side effects of bevacizumab, which targets vascular endothelial growth factor (VEGF), are often vascular-related, with hypertension reported in 3% to 43% of clinical trial participants and proteinuria reported in 21% to 41%. The identification of genetic biomarkers of these toxicities could help identify the patients at risk and directing interventions aimed at improving the safety of patients without compromising the efficacy of the treatment, Dr. Innocenti said.
“We believe that rs6770663 can be regarded as a new validated biologic marker to predict high blood pressure caused by bevacizumab,” said Dr. Innocenti. “We think we can now move to clinical application of this genetic variation for predicting risk.”
The rs6770663 variant is found in up to 20% of people of European origin, 30% of those of Asian origin, and 80% of those of African origin, “so these findings may have an impact on a considerable number of patients,” he said.
The variant associated with renal toxicity, rs339947, awaits validation in a large study.
Hundreds of Thousands of Variants Examined
As Dr. Innocenti noted, toxicities associated with bevacizumab can be severe and occasionally life-threatening. Bevacizumab is often given as a part of a multidrug regimen, where the occurrence of adverse events frequently necessitates dose reductions or interruptions. “The efficacy of the whole cocktail can be compromised, …. and there are safety issues,” he said.
Based on their hypothesis that an underlying genetic susceptibility may underlie some of this risk for toxicity, Dr. Innocenti and colleagues analyzed hundreds of thousands of variants in the genes of 1,039 patients with advanced breast, prostate, or pancreatic cancer treated with bevacizumab in four clinical trials from the Alliance for Clinical Trials in Oncology. They found that hypertension of grade ≥ 2 developed in 15% to 51% of patients, and proteinuria of grade ≥ 2 occurred in 6% to 31%.
By comparing the presence of variants in patients who developed toxicities to those who did not, they ultimately identified the variant rs6770663, located on the KCNAB1 gene, as being linked to the occurrence of hypertension, and rs339947, located close to the TRIO gene, as being linked to grade ≥ 2 proteinuria.
“We wanted to get external validation, so we obtained data from a different trial—ECOG-ACRIN E5103—which tested bevacizumab in 582 patients with breast cancer. We saw there, as well, that the genetic variation rs6770663 occurred at a higher frequency in patients with hypertension,” he said. Patients carrying the rs6770663 variant had a 66% increased risk for hypertension (P = .005).
There are biologic rationales for why these particular genetic variants may be implicated in these toxicities, according to Dr. Innocenti. “We postulate that, in patients with the variant allele of rs6770663, lower activation of KCNAB1, impaired activation of the sodium channel, and increased vasoconstriction result in an increased risk of bevacizumab-induced hypertension,” he said. Indeed, he added, in knockout mice that lack KCNAB1, elevated blood pressure and cardiac hypertrophy were observed. In the case of renal toxicity, rs339947 is positioned close to the TRIO gene, which induces activity of a protein known to contribute to renal damage.
Implications for Treatment
Dr. Innocenti said the findings might someday be applied clinically to personalize treatment with bevacizumab. Patients found on genetic profiling to have these variants might receive an alternative (and similarly efficacious) drug, receive a reduced dose of bevacizumab, or be monitored more intensively and treated with an antihypertensive agent at the first signs of an elevation in blood pressure.
“Early identification is a potential double win: it will help doctors identify who is at risk and apply different interventions,” he said.
Dr. Innocenti acknowledged that genetic testing for safety has been overlooked for too long and is not routinely applied to oncology drugs, with a handful of exceptions. “But, at the same time, it’s also physician-dependent,” he pointed out. “There are some oncologists who probably have a better understanding of what genetic risks of safety may mean in this setting, physicians who are more comfortable in using and interpreting the results of this test.”
The investigators are developing a prospective observational study in which patients are screened for the rs6770663 variant, with their treatment regimens modified according to the findings.
DISCLOSURE: Dr. Innocenti has served as a consultant or advisor to Emerald Lake Safety and Symberix and holds cancer treatment–related patents.
1. Innocenti F, Wang J, Sibley A, et al: Bevacizumab-induced hypertension and proteinuria: A genome-wide analysis of more than 1,000 patients. 2020 EORTC-NCI-AACR Symposium. Abstract 6. Presented October 25, 2020.
William R. Sellers, MD, Professor of Medicine at Harvard Medical School and the Dana-Farber Cancer Institute and Co-Chair of the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer, commented: “This study is a good example of how our increasing ability to study the human genome easily and in...