title: ABCB1 C3435T gene polymorphism as a potential biomarker of clinical outcomes in HER2-positive breast cancer patients.
abstract: HER2-positive breast cancer patients treated with trastuzumab schemes have good initial clinical outcomes. Despite this beneficial effect, many patients experiment resistance to these drugs. Several gene polymorphisms in ABCB1, HER2, and CCND1 have been proposed as potential predictors of clinical outcomes of trastuzumab schemes. The aim of this study was to evaluate the association between 4 gene polymorphisms potentially responsible for bad prognosis (HER2-Ile655Val, CCND1-A870G and ABCB1C1236T, C3435T) and clinical outcomes in HER2-positive BC patients. A retrospective cohorts study was performed. Eighty-four HER2-positive BC patients treated with trastuzumab schemes were included. The four gene polymorphisms were analyzed by PCR Real-Time with Taqman®probes. Genotypes were investigated for their association with tumor response, survival and resistance. Patients with CC genotype of ABCB1-C3435T presented higher risk of resistance to chemotherapy/trastuzumab schemes, compared to those carrying the T-allele (RR: 2.71; CI95%:1.29-5.68; p=0.013888), progression (RR: 1.89; p=0.017964); and exitus (RR: 2.09; p=0.03276). Multivariate logistic regression analysis considering clinical variables and ABCB1-C3435T revealed that the only independent factor associated to resistance to therapy was ABCB1-C3435T gene polymorphism (ORCT/CC: 0.25; p=0.0123; ORTT/CC: 0.09; p=0.0348. The protective effect of ABCB1-C3435T T-allele was confirmed in the multivariate Cox regression analysis for PFS (HRCT/CC: 0.41; p=0.00806; HRTT/CC: 0.22; p=0.01982) and OS (HRCT/CC: 0.49; p=0.0555; HRTT/CC: 0.12; p=0.0398). ABCB1-C1236T, CCND1-A870G and HER2-Ile655Val polymorphisms were not associated to resistance, PFS or OS (p>0.05). The A-allele for CCND1-rs9344 was associated with higher response rates (RR: 3.44; uncorrected p-value: 0.03816) in the bivariate analysis, but no statically association was found after Bonferroni correction (p=0.15264). ABCB1-C3435T, ABCB1-C1236T and HER2-Ile655Val gene polymorphisms were not associated with response. Although this study demonstrates a prognostic value of ABCB1-C3435T gene polymorphism to predict clinical outcomes, further studies with a larger sample will be necessary to validate this result.
authors.affiliation: Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda., Fuerzas Armadas, 2, Spain. Electronic address: adelamadridparedes@gmail.com.
authors.forename: Adela
authors.initials: A
authors.lastname: Madrid-Paredes
authors.affiliation: Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda., Fuerzas Armadas, 2, Spain. Electronic address: marisacgarre@gmail.com.
authors.forename: Marisa
authors.initials: M
authors.lastname: Cañadas-Garre
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, University of Granada, Campus Universitario de Cartuja, s/n, 18071 Granada, Spain. Electronic address: sanchezpster@gmail.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Sánchez-Pozo
authors.affiliation: UGC Anatomía Patológica, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda., Fuerzas Armadas, 2, 18014 Granada, Spain. Electronic address: anichu29@gmail.com.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Segura-Pérez
authors.affiliation: UGC Anatomía Patológica, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda., Fuerzas Armadas, 2, 18014 Granada, Spain. Electronic address: clarae.chamorro.sspa@juntadeandalucia.es.
authors.forename: Clara
authors.initials: C
authors.lastname: Chamorro-Santos
authors.affiliation: UGC Anatomía Patológica, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda., Fuerzas Armadas, 2, 18014 Granada, Spain. Electronic address: mariae.vergara.sspa@juntadeandalucia.es.
authors.forename: Esther
authors.initials: E
authors.lastname: Vergara-Alcaide
authors.affiliation: UGC Oncología Médica, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda., Fuerzas Armadas, 2, 18014 Granada, Spain. Electronic address: luciac.castillo.sspa@juntadeandalucia.es.
authors.forename: Lucía
authors.initials: L
authors.lastname: Castillo-Portellano
authors.affiliation: Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda., Fuerzas Armadas, 2, Spain. Electronic address: mangel.calleja.sspa@juntadeandalucia.es.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Calleja-Hernández
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D012189:Retrospective Studies; D016019:Survival Analysis; D000068878:Trastuzumab / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000074322:Antineoplastic Agents, Immunological; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C513055:ABCB1 protein, human
keywords: ABCB1; Breast cancer; CCND1; HER2; HER2 targeted therapies; Resistance