title: Rituximab response in follicular lymphoma is associated with the rs20575 polymorphism in TRAILR1 extrinsic apoptosis trigger.
abstract: Rituximab in combination with chemotherapy has been proven to increase progression-free and overall survival in follicular lymphoma (FL), but there is considerable interindividual variability in the response. Extrinsic pathway apoptosis triggered by death receptors seems to be involved in the mechanism of action of monoclonal antibodies. This study aimed to assess the association between TRAILR1/TRAIL polymorphisms (rs20575, rs20576, rs2230229, rs12488654) and rituximab response and the relationship with FASL rs763110, previously found to be associated with rituximab response.
  
  
  
  Polymorphisms were determined in a study cohort of 125 FL patients treated with rituximab as first-line treatment and correlated with response, which was scored according to the International Working Group Consensus Revised as complete response, partial response, stable disease, and progressive disease.
  
  
  
  No significant association with response was found for rs20576, rs2230229, and rs12488654 polymorphisms. In contrast, rs20575 GC/GG carriers were more partial/nonresponders (88.2%) than complete responders (72.5%), showing a trend toward statistical significance (P=0.064). In a multivariable setting, we found that female sex [odds ratio=0.355, 95% confidence interval (CI): 0.137-0.922, P=0.033] and the TRAILR1 rs20575 CC genotype (odds ratio=0.162, 95% CI: 0.035-0.757, P=0.021) were independent positive predictive factors of complete clinical response to rituximab, constructing a parsimonious model with good calibration [χ of 5.719 (d.f.=6, P=0.455)] and discrimination (C-statistic=0.739, 95% CI: 0.636-0.842).
  
  
  
  After studying the pharmacogenetic role of TRAILR1/TRAIL polymorphisms in rituximab-treated FL patients, we found that the rs20575 CC genotype is an independent predictive factor of better rituximab response, indicating the possible involvement of death receptors in anti-CD20 mechanisms of action.
authors.affiliation: Departments of aPharmacy bPathology cHematology dCardiology, Statistical Consulting Unit eClinical Analysis, Instituto Murciano de Investigaciones Biomédicas (IMIB), Santa Lucía University Hospital, Cartagena fDepartment of Hematology and Medical Oncology, University Hospital Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB, Murcia, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Gutiérrez-Cívicos
authors.forename: Ana M
authors.initials: AM
authors.lastname: Hurtado
authors.forename: Daniel
authors.initials: D
authors.lastname: Torres-Moreno
authors.forename: José J
authors.initials: JJ
authors.lastname: Sanchez-Blanco
authors.forename: Ignacio
authors.initials: I
authors.lastname: Español
authors.forename: Luciano
authors.initials: L
authors.lastname: Consuegra-Sánchez
authors.forename: Elena
authors.initials: E
authors.lastname: Perez-Ceballos
authors.forename: María D
authors.initials: MD
authors.lastname: Gutiérrez-Meca
authors.forename: Andrés
authors.initials: A
authors.lastname: Jerez
authors.forename: Pablo
authors.initials: P
authors.lastname: Conesa-Zamora
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis; D018572:Disease-Free Survival; D053222:Fas Ligand Protein / Q000235:genetics*; D005260:Female; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D000069283:Rituximab / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D000069283:Rituximab