CYP3A5 Polymorphism in Circulating Tumor Cells Confers an Increased Disease-Free Survival in DLBCL Patients Treated with R-CHOP

Rafael Cerón Maldonado,1,2 Adolfo Martínez Tovar,2 Christian Omar Ramos Peñafiel,3 Adrián De la Cruz Rosas,2 Anel Irais García Laguna,2 Iveth Mendoza Salas,2 Carlos Martínez Murillo,3 Gilberto Israel Barranco Lampón,3 Efreen Horacio Montaño Figueroa,3 Silvia Jiménez-Morales,4 Irma Olarte Carrillo1,2 1Posgrado en Ciencias Biológicas, Biomedicina, UNAM, CDMX, México; 2Department of Investigation, Hematology Service, Hospital General de México. Dr. Eduardo Liceaga, Mexico City, Mexico; 3Department of Medical Hematology, Hospital General de México. Dr. Eduardo Liceaga, Mexico City, Mexico; 4Laboratorio de Innovación y Medicina de Precisión, Núcleo “A”, Instituto Nacional de Medicina Genómica, Mexico City, MexicoCorrespondence: Irma Olarte Carrillo, Hospital General de México. Dr. Eduardo Liceaga, Dr. Balmis 148, Col. Doctores, Alc. Cuauhtémoc, Mexico City, 06726, Mexico, Tel +525527892000 Ext. 1609, Email [email protected]: Diffuse Large B-Cell Lymphoma (DLBCL) is a heterogeneous aggressive lymphoid neoplasm. Cases of refractoriness and relapse persist in approximately 40% of patients treated with first-line R-CHOP regimen, thus, the identification of factors associated with disease progression have become a necessity. Diverse polymorphisms in genes encoding proteins involved in the metabolism and elimination of chemotherapeutic drugs have been studied as potential causes of treatment failure. In oncology, liquid biopsies have emerged as a non-invasive method for detecting circulating biomarkers, thereby strengthening both diagnosis and prognosis for patients. Therefore, the purpose of this study was to determine polymorphisms in Circulating Tumor Cells (CTCs) to describe the relevance of liquid biopsy in the clinical outcomes of patients with DLBCL.Patients and Methods: We analyzed 102 liquid biopsies of peripheral blood from DLBCL patients, of which CTCs were isolated by density gradient and CD20 immunomagnetic antibodies. Allelic discrimination assays were performed to analyze ABCB1 C3435T, ABCG2 C421A and CYP3A5 A6986G polymorphisms. Overall survival (OS) and disease-free survival (DFS) analysis were performed using Kaplan-Meier curves and risk analysis was performed using Cox regression.Results: We found that GG genotype of CYP3A5 A6986G was associated with a longer DFS (68.6% vs 49%, p=0.019) and lower risk of course with adverse event related to disease (progression, relapse and death) (OR 0.374, CI 0.187– 0.745, p=0.011). No significant associations were found between ABCB1 C3435T and ABCG2 C421A genotype with the clinical outcome.Conclusion: In this study, we demonstrated that in CTCs derived from liquid biopsies, the GG genotype in the CYP3A5 A6986G, which is related to the metabolism and elimination of chemotherapy drugs, impacts in longer DFS. These findings confirm the relevance of circulating biomarkers in non-invasive biological samples for strengthening the prognosis of DLBCL.Keywords: polymorphism, lymphoma, chemoresistance, CTCs, R-CHOP