Assessment of possible associations of genetic polymorphisms with adverse reactions and survival in patients with gynecological tumors treated with paclitaxel and carboplatin

• Grant number: 22/06532-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2023
• End date: November 02, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Patricia Moriel
• Grantee: Nadine de Godoy Torso
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 25/01842-2 - EXPLORING CAUSAL RELATIONS BETWEEN ADVERSE REACTIONS AND PACLITAXEL AND CARBOPLATIN CHEMOTHERAPY IN PATIENTS WITH GYNECOLOGICAL TUMORS IN A BRAZILIAN POPULATION: A MENDELIAN RANDOMIZATION STUDY., BE.EP.DR

Abstract

Gynecological tumors, a group of neoplasms that affect the female reproductive system, are one of the main causes of morbidity and mortality among women worldwide. It includes, among other locations, tumors of the ovary, uterine cervix, and endometrium. In advanced stages of the disease, the recommended treatment is cytoreductive surgery, followed by adjuvant chemotherapy with a platinum derivative and taxane. However, despite good clinical outcome results, the effectiveness of the treatment is limited by several associated adverse effects, especially peripheral neuropathy and hematotoxicity, both of which are dose-limiting. Among recent efforts to reduce the incidence of such reactions is the determination of genetic variants, including single nucleotide polymorphisms (SNPs). However, despite the reasonable number of studies already carried out looking for genetic associations, most of the findings provided inconclusive results or without clinical significance. Therefore, the hypothesis to be investigated is that genetic polymorphisms (selected by systematic literature review) may be associated with inter-individual variability of adverse reactions and effectiveness of the combined paclitaxel-carboplatin treatment. First, a systematic review of the literature will be conducted, with the objective of mapping and summarizing scientific evidence on the main genetic polymorphisms associated with adverse reactions induced by carboplatin/paclitaxel, obtained from the results of in vitro, in vivo or in human beings. humans. After choosing the polymorphisms to be studied, a retrospective cohort study will be carried out, whose participants to be inserted (n = 503) were diagnosed with gynecological cancer and underwent chemotherapy treatment based on paclitaxel (175mg/m²) and carboplatin (AUC 5- 6 using Calvert's formula). Depending on the results found by the literature review, polymorphisms that: a) present a minimum frequency of 10% in populations already characterized will be selected for evaluation in the studied cohort; and b) present promising data (which justifies the possible future translation to the clinical scenario) in 2 or more studies already published. Data related to the clinical history of the patients will be collected. To determine polymorphisms, genomic DNA samples will be isolated from previously collected peripheral blood leukocytes, and the PCR-RT technique will be carried out. The high-resolution melting curve scanning technique (High-Resolution Melting, HRM) will also be performed to identify genes not yet related to paclitaxel/carboplatin, but with possible clinical application. Results are presented as mean ± standard deviation (SD) for continuous variables and as frequencies for categorical variables. The Hardy-Weinberg equilibrium will be evaluated by the chi-square test. The comparison of allelic frequencies will be evaluated by Fisher's exact test and the level of significance adopted in all analyzes will be 5% (p<0.05). (AU)