(T0930-04-28) ABCB1 and HMGB1 Gene Polymorphism and Adverse Reactions to Carboplatin and Paclitaxel Treatment in Patients with Non-small Cell Lung Cancer

Purpose: Smoking is considered the most important modifiable risk factor for the development of lung cancer, being the main cause of morbidity and mortality related to cancer worldwide. The non-small cell lung cancer (NSCLC) could be treated with platinum-derived chemotherapeutics, with carboplatin and paclitaxel (1). However, adverse drug reactions (ADRs) can compromise the effectiveness of treatment. Some genetic polymorphisms may be associated with ADRs, such as polymorphisms in genes related to drug transporters and DNA repair proteins. In this context, High-Mobility Group Box 1 (HMGB1) is a nuclear protein involved in DNA repair and has been associated with drug resistance in several cancers. The ABCB1 gene is involved in drug transport, and polymorphisms in this gene may be related to ADRs and treatment response, compromising the effectiveness of chemotherapy (2). The aim of this study was to investigate whether there is a relationship between polymorphisms in the ABCB1 (rs1128503, rs203282 and rs1045642) and HMGB1 (rs1412125) genes and the presence of ADRs in patients with non-small cell lung cancer treated with carboplatin and paclitaxel.

Methods: This is an observational study that was approved by the Ethics Committee. DNA was isolated from whole blood samples obtained from 113 patients with NSCLC who were receiving carboplatin and paclitaxel. Hematological and biochemical tests were performed before and after 21 days of the first chemotherapy session. Hematological, renal, hepatic, and gastrointestinal ADRs during the first chemotherapy cycle were determined using the Common Terminology Criteria for Adverse Events (CTCAE; v.4) (3). Genomic DNA was extracted and purified from peripheral blood using a Wizard® Genomic DNA Purification Kit (Promega, USA). The ABCB1 and HMGB1 polymorphisms were studied with Taqman® (Applied Biosystems, CA, USA), determined by RT-PCR and haplotypes evaluated by Haploview® software.

Results: A total of 113 patients with NSCLC were included in the study. The majority of the patients had an average age of 63.2 years, were male (53%), caucasian (82.3%), heavy smokers (38.1%), moderate drinkers (34.5%), with a performance status (KPS) of 100% (89.4%), and had the most prevalent histological type of adenocarcinoma (58.4%). After analyzing and classifying ADRs, it was observed that anemia (38.1% grade 1 and 1.8% grade 2) was the most prevalent hematological ADR. Decreased creatinine clearance (23.9%), hypocalcemia (23%), and hyponatremia (21.2%) in grade 1 were the most common renal ADRs. In grade 1, the most frequent hepatic ADRs were hypoalbuminemia (15.4%) and increased alkaline phosphatase (12.4%), which were observed in 59% of the patients. Grade 1 renal ADRs were observed in 74% of the patients, with the most prevalent being reduced creatinine clearance (28%), hyponatremia (24%), and hypocalcemia (18%). Nausea (23.9%), diarrhea (14.2%), and vomiting (11.5%) were gastrointestinal ADRs that occurred in the patients in this study. All frequencies for the different analyzed loci were at Hardy-Weinberg equilibrium. The logistic regression observed that the genotype TT for the HMGB1 rs1412125 gene, when compared to CC+CT, has a higher risk in the development of ADR diarrhea (OR: 8.871; CI: 95% 1.901-41.401; p = 0.0055). Regarding the ABCB1 rs2032582 gene, patients with the T allele have a higher risk of presenting hyponatremia compared to the A and C alleles (OR: 10.579; CI: 95% 1.040-107.626; p = 0.0463). The GGC and AAA haplotypes were the most frequent for the study patients, but there was no association between these haplotypes and ADRs.

Conclusion: Patients in this study show a high prevalence of ADRs. The findings suggest that women have a higher chance of experiencing nausea, and heavy smokers have a higher risk of diarrhea compared to other patients. Patients with the TT genotype for the HMGB1 rs1412125 gene have a higher risk of developing diarrhea, and patients with the presence of the T allele in their genotype have a higher risk of developing hyponatremia.

References: 1.Sateia HF, Choi Y, Stewart RW, Peairs KS. Screening for lung cancer. Semin Oncol. 2017 Feb;44(1):74-82.
2.Peethambaram P, Fridley BL, Vierkant RA, Larson MC, Kalli KR, et. al. Polymorphisms in ABCB1 and ERCC2 associated with ovarian cancer outcome. Int J Mol Epidemiol Genet 2011 Mai; 2(2):185–195.
3. U.S Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). U.S Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Version 4.0, 2010.

Acknowledgements: We thank the State of São Paulo Research Foundation (FAPESP) and the Coordination for the Improvement of Higher Education Personnel (CAPES) for financial support.