Researchers have found two common genetic variants that may be used to predict whether patients with cancer may have severe adverse events when treated with the anti-VEGF monoclonal antibody bevacizumab. A genome-wide association study—according to researchers, the largest such study in patients being treated with bevacizumab—was presented at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics by Federico Innocenti, MD, PhD, and colleagues (Abstract 6).
Bevacizumab is used to treat a number of different cancers, often in combination with other drugs. The new study is unique because researchers found and analyzed hundreds of thousands of genetic variations in all the genes of more than 1,000 patients with advanced breast, prostate, or pancreatic cancer taking part in five clinical trials.
"Patients treated with bevacizumab can experience an increase in blood pressure and kidney problems caused by proteins leaking into urine. These toxicities are common and have been observed in up to 40% of patients treated with bevacizumab."— Federico Innocenti, MD, PhD
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Dr. Innocenti, Associate Professor at the Eshelman School of Pharmacy of the University of North Carolina, Chapel Hill, said, “VEGF inhibitors like bevacizumab have revolutionized cancer treatment, but because they work by impacting how the body builds and regulates blood vessels, side effects are usually vascular-related. Patients treated with bevacizumab can experience an increase in blood pressure and kidney problems caused by proteins leaking into urine. These toxicities are common and have been observed in up to 40% of patients treated with bevacizumab. They can cause discomfort and harm to patients; they can develop quickly and become severe, even fatal; and they can lead to delaying or discontinuing treatment, which limits their efficacy.”
He contined: “Currently, there is no way of identifying patients who are likely to experience these toxicities. Some of this risk is likely to be due to each individual patient’s genetic make-up, and so we set out to identify new genes and their variants that may improve the prediction and management of bevacizumab-induced adverse side effects.”
Dr. Innocenti described the methods of the study by adding, “We characterized hundreds of thousands of genetic variations in more than 1,000 patients. We were not looking for variations in the tumor DNA, but rather, the heritable DNA of the patients…. A group of these patients experienced the side effects of high blood pressure and kidney toxicity, and so we compared the frequency of DNA variations between these patients and the patients who did not suffer these side effects. In this way we were able to discover a series of variations that increased or reduced the risk of these toxicities.”
Variant Identification
The researchers identified 10 variations (known as single-nucleotide polymorphisms) associated with high blood pressure and 10 with kidney toxicity. They also investigated two variations linked to high blood pressure in a different group of 582 patients. One of these variations—called rs6770663 and located in the KCNAB1 gene—was significantly associated with an increased risk of systolic blood pressure of 160mm Hg or more.
“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,” said Dr. Innocenti. “In addition, KCNAB1 generates instruction for the production of a protein that regulates the function of potassium channels in blood plasma membranes. 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 biologic basis for this finding is quite strong.”
In patients experiencing proteinuria, the most significant variation was rs339947, located between the DNAH5 and TRIO genes. TRIO induces activity of a protein that contributes to damage in the kidney, which can lead to proteinuria. This has not yet been tested in another group of bevacizumab-treated patients and so requires further validation.
Study Implications
The findings may enable doctors to improve the treatment of their patients and avoid severe adverse side effects—for instance, by treating those with the rs6770663 variant with another drug, if available; by giving a reduced dose of bevacizumab; by increased monitoring; or by giving bevacizumab with agents that may control rising blood pressure.
"rs6770663 can be regarded as a new, validated biologic marker to predict high blood pressure caused by bevacizumab. Before treatment with bevacizumab, this variant can be searched for in the DNA of patients with a simple genetic test. If it is found, physicians can decide about various treatment options."— Federico Innocenti, MD, PhD
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“rs6770663 can be regarded as a new, validated biologic marker to predict high blood pressure caused by bevacizumab. Before treatment with bevacizumab, this variant can be searched for in the DNA of patients with a simple genetic test. If it is found, physicians can decide about various treatment options,” said Dr. Innocenti. “Early identification is a potential double win—it will help doctors identify who is at risk and apply different interventions. The rs6770663 variation is found in up to 20% of people of European origin, 30% of Asian origin, and 80% of people of African origin, so these findings can have an impact on a considerable number of people.”
The researchers are continuing to validate rs6770663 and the other variants in different groups of patients, including those of different ethnicities. They are also investigating whether these variants can predict high blood pressure and kidney toxicity for other anticancer drugs.
“Efforts are now underway to set up a prospective observational study that will give doctors and patients a test to screen patients and update their treatment regimens as necessary. Interested clinicians and scientists should contact me,” concluded Dr. Innocenti.
Disclosure: This research was funded with discretionary grants to Dr. Innocenti’s laboratory from the Eshelman School of Pharmacy and the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill. For full disclosures of the study authors, visit cm.eortc.org.
