Purpose: To observe association between single nucleotide polymorphism (SNP) in target genes and adverse effects mediated by Cisplatin to identify potential predictive biomarkers of toxicity and the frequency of these SNPs at the Brazilian population.
Methods: This is a prospective, observational study, realized at UNICAMP “Hospital de Clinicas”, a tertiary hospital located in Sao Paulo State, Brazil. Blood samples were collected from patients with head and neck squamous cell carcinoma, treated with radiochemoterapy with high doses of Cisplatin. Samples were collected before and after the first dose of Cisplatin on day 5 (D5) and day 20 (D20) to measure nephro, hepato and hematotoxicities. Gastrotoxicity was evaluated through pharmaceutical anamnesis and all toxicities were classified in grades according to Common Terminology Criteria for Adverse Events (CTCAE v.4). Genotyping were performed through real-time PCR to identify ABCB1 (rs1045642, rs1128503, rs2032582) and CYP2E1 (rs3813687, rs3813865, rs8192772) polymorphisms.
Results: Twenty-four toxicity parameters were analyzed to 46 patients. Five SNPs were statistically related to at least one parameter, as shown (Table 1). The ABCB1 rs1045642 variant genotype was associated to increased creatinine clearance. ABCB1 gene encodes the P-glycoprotein, an efflux bomb, related to Cisplatin resistance that is associated to intracellular concentration so, the increased activity determined by the variant genotype rs1045642 must be related to our findings. rs1128503 was associated to hemoglobin grades of toxicity RR 2.5 (CI 1.20 to 4.51; p 0.0035) and there are few studies about this genotype and Cisplatin pharmacokinetic, but a previous study associated rs1128503 to a higher risk to multiple adverse events of Cisplatin. Similarly, the triallelic SNP rs2032582 was associated to reduced hemoglobin (allele T) and increased albumin levels (allele A) p 0.035 and p 0.0335 respectively. The CYP2E1 genotype rs3813867 was associated to lower levels of Gamma-Glutamyltransferase and there is not agreement about the influence of rs3813867 on toxicity. The genotype rs8192772 was related to toxicity grades of albumin with RR 5.56 (CI 2.25 to 12.37; p 0.0018) and there are no data about toxicity mediated by this genotype, but the adverse effects of Cisplatin treatment are related to damage caused by oxidative stress as well as CYP2E1, that can enhance oxidative stress, especially in mitochondria. So, maybe polymorphisms that enhance the CYP2E1 activity can exacerbate Cisplatin toxicities. RS3813865 genotype was not associated to any parameter with P<0.05 so it is not related in Table 1, but it showed p=0.0790 and p=0.0791 to variations in serum creatinine and creatinine clearance, respectively. The frequency of polymorphisms studied is quite different of the general world population, especially as to ABCB1 gene (Figure 1). Some studies associated ABCB1 polymorphisms to higher risk of head and neck cancer and this should explain our data. There are few studies about frequency of polymorphisms at Brazilian population.
Conclusion: This preliminary data showed associations between ABCB1 and CYP2E1 genes and toxicities mediated by Cisplatin that are indicative of possible predictive biomarkers. Personalized therapy can enhance the quality of treatment and the quality of life of patients. The associations observed are under confirmation for better evaluations, with more patients and additional genes.
Julia Quintanilha– PhD student, State University of Campinas
Marilia Visacri– State University of Campinas
Camila Vaz– State University of Campinas
João Paulo Guarnieri– UNICAMP
Larissa Bastos– State University of Campinas
Nadine Torso– State University of Campinas
Mario Hirata– Universidade de Sao Paulo
Rosario Hirata– Universidade de Sao Paulo
Patricia Moriel– UNICAMP