118PPIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors

Abstract Background Hypertension is one of the major side effect of VEGF-pathway inhibitors. There are no validated biomarkers to predict which cancer patients will develop hypertension. This study aimed to identify genetic predictors of hypertension induced by VEGF-pathway inhibitors. Methods A two-step, discovery-validation approach was used. The discovery set included 140 renal cell carcinoma patients from the TARGET study treated with sorafenib (400 mg twice daily) (PMID 30385613) and genotyped for 1,040 germline variants in 56 genes. The most statistically significant variant from the discovery set (chi-squared test) was tested in a validation set (cause-specific Cox model) consisting of 1,041 cancer patients treated with bevacizumab (10-15 mg/kg every two-three weeks) and genotyped using GWAS microarray platforms. For both studies, grade ≥2 hypertension (CTCAE v. 3.0) was used as the endpoint. Genetic associations were adjusted for age and sex. Results In the discovery set, the most statistically significant variant associated with hypertension in sorafenib-treated patients was rs444904 (G>A, P = 0.006). The A allele of rs444904 (minor allele frequency, MAF 0.14) increased the risk of hypertension. In the validation set, the A allele of rs427554 (G>A, in complete linkage disequilibrium with rs444904) increased the risk of hypertension in bevacizumab-treated patients (P = 0.008, MAF 0.11). rs444904 and rs427554 are intronic variants in PIK3R5. PIK3R5 encodes the regulatory subunit of PI3Kγ, which, when activated by VEGF, leads to nitric oxide (NO) production and vasodilation. These variants have been associated with decreased expression of PIK3R5 in blood (PMID 25954001), consistent with their effect in increasing the risk of hypertension. Conclusions Common genetic variants that could reduce PIK3R5 activity increase the risk of sorafenib- and bevacizumab-induced hypertension. In patients treated with these drugs, reduced activity or expression of PIK3R5 may lead to a reduction in NO production, resulting in vasoconstriction and hypertension. This study, for the first time, provides evidence for new predictive genetic markers of drug-induced hypertension that should be further evaluated for other VEGF-pathway inhibitors. Clinical trial identification TARGET CALGB 80303 NCT00088894 CALGB 40503 NCT00601900 CALGB 40502 NCT00785291 CALGB 90401 NCT00110214. Legal entity responsible for the study Federico Innocenti. Funding Has not received any funding. Dis