Pazopanib Efficacy in Renal Cell Carcinoma: Evidence for Predictive Genetic Markers in Angiogenesis-Related and Exposure-Related Genes

Abstract

Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue.

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…With regard to pazopanib, SNPs in UGT1A1, CYP1A2, and HFE were associated with either bilirubin levels or ALT levels, and SNPs in IL8, HIF1A, NR1I2, and VEGFA were associated with efficacy outcomes on pazopanib. The association of rs1126647 in IL8 with OS was confirmed in two independent data sets including patients treated with either sunitinib or pazopanib [40,42]. Sorafenib toxicity and efficacy were related to genetic polymorphisms in ABCC2, HLA-A, and the only large study (n > 300) available on sorafenib treatment showed rs2071559 in VEGF-R2 was related to efficacy.…”

“…A worse PFS and response rate were observed for AG carriers of rs11549467 in HIF1A compared to wild-type GG. A reduced response rate was also observed for TT carriers of rs3814055 in NR1I2 compared to wild-type CC and for wildtype CC of rs833061 in VEGFA compared to TT genotypes [40].…”

“…In a subsequent study, Xu et al [40] investigated a slightly different set of 27 SNPs in candidate genes (SNPs in IL-8 and HIF1A) to test whether these are related to pazopanib efficacy. In a cohort of 397 RCC patients, a decreased PFS was observed for TT variant carriers of rs1126647 in IL8 compared to wildtype AA.…”

“…Only two pharmacogenetic studies on sorafenib were found in which genetic polymorphisms in ABCC2 and HLA-A were associated with high-grade skin rash and rs2071559 in VEGF-R2 was associated with PFS and OS. For axitinib, no associations were reported [40][41][42][43][44].…”

Molecular Markers of Kidney Cancer Progression, Association with Efficiency of Pazopanib Therapy

“…Xu C.V. has shown the genetic association of HIF-1α with response to pazopanib monotherapy [37]. So, search of molecular markers predicting the effectiveness of targeted therapy is actually for modern oncology.…”