ABCB1 c.3435C>T polymorphism is associated with platinum toxicity: a preliminary study

• Published in: Cancer chemotherapy and pharmacology 2019-04, Vol.83 (4), p.803-808
• Main Authors: De Troia, Beatrice, Dalu, Davide, Filipazzi, Virginio, Isabella, Luigi, Tosca, Nicoletta, Ferrario, Sabrina, Gambaro, Anna Rita, Somma, Luisa, Fasola, Cinzia, Cheli, Stefania, Clementi, Emilio, De Francesco, Davide, Falvella, Felicia Stefania, Cattaneo, Maria Teresa
• Format: Article
• Language: English
• Subjects: Alleles; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; ATP Binding Cassette Transporter, Subfamily B - genetics; Cancer; Cancer Research; Carboplatin; Carboplatin - administration & dosage; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Deoxyribonucleic acid; Detoxification; DNA; Female; Gene mapping; Gene polymorphism; Genetic analysis; Genotype; Genotypes; Glutathione transferase; Hematology; Humans; Informed consent; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Mapping; Medicine; Medicine & Public Health; Metastases; Multivariate analysis; Neoplasm Staging; Oncology; Patients; Peripheral blood; Pharmacology/Toxicology; Platinum; Polymorphism; Polymorphism, Single Nucleotide; Short Communication; Single-nucleotide polymorphism; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - pathology; Terminology; Toxicity
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-019-03794-6

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 the occurrence of toxicities. In this study, we evaluated the role of three SNPs in predicting the onset of adverse events for lung cancer patients receiving cisplatin or carboplatin in adjuvant, neo-adjuvant and metastatic settings. Methods Eighty-two patients affected by non-small-cell and small-cell lung cancer treated with cisplatin- or carboplatin-based chemotherapy (stage 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 three SNPs: ABCB1 c.3435C>T/rs1045642, ABCC2 -24C>T/rs717620 and GSTP1 c.313A>G/rs1695. Patient characteristics and genotypes were correlated with hematological, gastrointestinal and renal toxicity as recorded by Common Terminology Criteria for Adverse Event (CTCAE) v4.03. No neurological toxicity was observed in our patients. Results Variant alleles were present in 53% of patients for ABCB1 c.3435C >T, 18.3% for ABCC2 -24C> T, and 34.8% for GSTP1 c.313A>G. Heterozygous CT at ABCB1 c.3435 was associated to a lower risk of hematological toxicity compared to homozygous CC (OR = 0.20; 95% CI 0.05, 0.69; p  = 0.01). Similar results were observed by genetic dominant model (CT + TT vs CC) and hematological toxicity (OR = 0.26; 95% CI 0.09, 0.79; p  = 0.02). No other significant associations were found between toxicity and SNPs. Multivariate analysis confirmed an independent value for the ABCB1 c.3435 C >T polymorphism. Conclusions The present study reveals that ABCB1 c.3435C>T polymorphism influences platinum toxicity. The T allele seems to exert a protective effect on the development of toxicities. Further studies, such as epigenetic regulation ones, are needed to validate and shed more light on this association.