Pharmacogenetic assessment of toxicity in patients treated with taxane-based chemotherapy for solid tumors

Background: Taxanes are active agents widely used to treat many solid tumors. However, the utility of taxane-based therapy could be limited by gastrointestinal toxicities, hematological toxicities, hypersensitivity and cumulative neurotoxicity. Taxanes are metabolized by CYP3A4 and CYP3A5 isoenzymes, and they are a substrate for the ATP binding cassette multidrug-transporters ABCB1. Metabolic pathways of these antitumor agents need a thorough evaluation to understand why some patients experience severe adverse effects. Aim of our study was to evaluate the association between taxane-related toxicities and their metabolism-related genetic polymorphisms in patients affected by solid cancers undergoing taxane-based chemotherapy regimens. Methods: We examined 182 adult patients, ECOG Performance Status ≤ 1, affected by solid tumors who underwent treatment with taxane-based regimens in adjuvant or metastatic setting, planned for at least 3 courses of therapy. Through a peripheral venous blo

Background: Taxanes are active agents widely used to treat many solid tumors. However, the utility of taxane-based therapy could be limited by gastrointestinal toxicities, hematological toxicities, hypersensitivity and cumulative neurotoxicity. Taxanes are metabolized by CYP3A4 and CYP3A5 isoenzymes, and they are a substrate for the ATP binding cassette multidrug-transporters ABCB1. Metabolic pathways of these antitumor agents need a thorough evaluation to understand why some patients experience severe adverse effects. Aim of our study was to evaluate the association between taxane-related toxicities and their metabolism-related genetic polymorphisms in patients affected by solid cancers undergoing taxane-based chemotherapy regimens. Methods: We examined 182 adult patients, ECOG Performance Status ≤ 1, affected by solid tumors who underwent treatment with taxane-based regimens in adjuvant or metastatic setting, planned for at least 3 courses of therapy. Through a peripheral venous blood sampling we genotyped them for selected polymorphisms and ABC-transporters that may influence cellular sensitivity to taxanes: CYP3A4* 1B (A> G), CYP3A5 * 3 (G> A) and ABCB1 (1236 C> T; 3435 C> T). SNPs (Single Nucleotide Polymorphism) were characterized by pyrosequencing. The Sstatistical survey analysis was conducted by MINITAB 16.2.3 software. A value of p<0.05 was considered statistically significant. Results: Toxicities and polymorphisms were evaluated in 182 patients (12 males and 170 females). Median age of patients was 59 (range 30-82). Patients who received taxanes were 95 in adjuvant setting and 87 in the metastatic one. We observed a significant association between normal homozygous genotype for ABCB1 polymorphism (3435 C> T) and lower toxicity during therapy with taxane-based regimens (p= 0.012). An association between mutant homozygous and normal homozygous genotypes with dose limiting toxicities was demonstrated, even though not statistically significant (p= 0.058). A larger cohort of patients must be investigated. The multivariate analysis results were independent from the different taxane-based regimens adopted, age and stage of disease. Conclusions: ABCB1 3435 C>T seems a toxicity predictive biomarker for Taxanes. On the other hand, a larger cohort of patients must be investigated to define the role of CYP3A4, CYP3A5 and ABCB1 (1236 C>T) polymorphisms. In the future, studies with SNP chips and other on the transcriptome, proteome and metabolome level should be performed in order to identify molecular signatures differentiating patients at higher or lower risk of toxicities and relative efficacy of taxanes-based chemotherapy regimens.