Genetic Factors Associated with Platinum Toxicity: A Preliminary Study

Background: Platinum-based doublets are the standard chemotherapy for lung cancer. The identification of markers associated with drug-toxicity may improve the success of the treatment. Single nucleotide polymorphisms (SNPs) mapping into the genes involved in platinum transport or detoxification may explain occurrence of toxicities. In this study, we evaluated the role of 4 SNPs in predicting the onset of adverse events for lung cancer patients receiving cisplatin or carboplatin. Methods: Eighty-two patients affected by non-small-cell and small-cell lung cancer treated with cisplatin- or carboplatin-based chemotherapy (st. II-IV) were enrolled. Before genetic analysis, patients signed a written informed consent. DNA was extracted from peripheral blood samples and genotypes were determined by Real-Time PCR. We selected and analyzed 4 SNPs: ABCC2 -24C>T/rs717620, ABCG2 c.421C>A/rs2231142, ABCB1 c.3435C>T/rs1045642 and GSTP1 c.313A>G/rs1695. Patient characteristics and genotypes were retrospectively correlated with haematological, gastrointestinal, renal and global toxicity as recorded by Common Terminology Criteria for Adverse Event (CTCAE) v4.03. Results: Variant alleles were present in 18.3% of patients for ABCC2 -24C>T, 8.5% for ABCG2 c.421C>A, 53% for ABCB1 c.3435C>T and 34.8% for GSTP1 c.313A>G. Heterozygous “CT” at ABCB1 c.3435 were significantly associated with both global (OR = 0.23; 95% CI 0.07-075; p = 0.02) and haematological (OR = 0.20; 95% CI 0.05-0.69; p = 0.01) toxicity. Similar results were observed by genetic dominant model (CT+TT vs CC) for global (OR = 0.33; 95% CI 0.11-0.96; p = 0.04) and haematological (OR = 0.26; 95% CI 0.09-0.79; p = 0.02) toxicity. No other significant associations were observed. Conclusions: This study reveals that ABCB1 c.3435C> T polymorphism influences platinum toxicity. Variant “T” allele seems to exert a protective effect on the development of toxicities. Further epigenetic regulation studies are needed to validate and shed more light on this association.