(M0930-04-28) Associations of Polymorphisms of the ABCB1 and ABCC2 Genes with Cisplatin-Induced Nephrotoxicity and Myelosuppression in Patients with Head and Neck Cancer

Purpose: Head and neck squamous cell carcinoma (HNSCC) correspond to a heterogeneous group of neoplasms of the upper aerodigestive tract [1]. Patients are mainly diagnosed in stages III of IV, for which the standard treatment recommendation is concomitant chemoradiotherapy with high doses of cisplatin [2]. Despite its effectiveness, the treatment is also associated with significant adverse drug reactions, with nephrotoxicity and myelosuppression being the two major dose-limiting [3]. Single nucleotide polymorphisms (SNPs) are one of the main genetic factors responsible for the interindividual difference in severity and frequency of cisplatin adverse reactions. So, because ABCB1 and ABCC2 (ATP-binding cassette subfamily B, and C, respectively) account for cisplatin cellular efflux and detoxification [4–6], the present study aimed to evaluate the association of SNPs of these two genes with cisplatin-induced nephrotoxicity and myelosuppression in patients HNSCC.

Methods: This was a prospective, cohort study. Cisplatin-induced adverse reactions was assessed through blood samples collected before and five days (D5) following chemotherapy; variations from baseline biomarkers values were graded for severity in accordance with the Common Toxicity Criteria for Adverse Events (CTCAE) version 4 [7]. Genomic DNA was isolated from peripheral blood cells, and SNPs of ABCB1 gene (rs1045642, rs1128503, rs2032582) and ABCC2 gene (rs717620, rs2273697, and rs3740066) were determined by real-time PCR. To evaluate associations between the SNPs genotypes and the risk of occurrence of renal or hematological adverse reactions, two models were used: ancestral model, for comparing carriers of the ancestral allele with the other subjects; and variant model, for comparing homozygous subjects’ carriers of the variant allele with the other subjects.

Results: 95 participants (n = 95) were included in the study, of which 86 (90.5%) were male patients and 9 (9.5%) were female patients. According to the CTCAE, the majority of participants had less severe grades (prevalence of grade 1) of renal and hematological adverse events during the first chemotherapy cycle. Unlike what was observed with kidney markers, the hematological laboratory markers evaluated were mainly significantly changed after the 20 days of treatment. The genotype data were tested for Hardy-Weinberg equilibrium (HWE), and all polymorphisms considered were found to be in HWE (p >0.05). Regarding associations, ABCB1 rs2032582 ancestral model (CC versus AC + AA) was shown to be a risk factor for hyponatremia (OR = 3.13; 95% CI 1.00 - 9.75; p = 0.02). Hyperuricemia resulted associated with ABCB1 rs1128503 and ABCC2 rs3740066 in opposite consequences: the homozygous subjects’ carriers of the variant allele of rs1128503 appeared to have a higher risk of hyperuricemia (OR = 2.79; 95% CI 1.02 - 7.62; p < 0.05). ABCC2 rs3740066 appeared protective for the development of the same renal adverse reaction (OR = 0.17; 95% CI 0.04 - 0.71; p < 0.05). Regarding the neutropenia adverse reaction, the only association found was with ABCC2 rs717620, which CC genotype seemed to protect from neutropenia (OR = 0.36; 95% CI 0.13 - 0.97; p < 0.05). No significant association was found between the evaluated SNPs and other hematological toxicities.

Conclusion: The study found that the cohort was composed by a majority of male patients at advanced cancer staging. The observed kidney laboratory markers had a significant change after 5 days of treatment, while the hematological laboratory markers evaluated were mainly changed after the 20 days. The study also suggests a possible association between homozygous CC individuals (ABCC2 rs717620 and ABCB1 rs2032582), and homozygous GG individuals (ABCB1 rs1128503) with the presence of adverse reactions.

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Acknowledgements:This research was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) (Finance Code 001) and by the São Paulo Research Foundation (FAPESP), grant number 2019/13250-1. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University of Campinas (protocol code: 69402017.1.0000.5404, August 5, 2017)).