title: Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer.
abstract: P-glycoprotein, encoded by the MDR-1 gene, confers multi-drug resistance against antineoplastic agents and is important for the transmembrane transition of various other common therapeutic drugs. Recently, a number of polymorphisms in the MDR-1 gene were identified and the T/T genotype at position 3435 in exon 26 was found to correlate with intestinal P-glycoprotein expression and bioavailability of digoxin after oral administration. We analysed the allelic frequencies at the polymorphic site C3435T in a group of patients with locally advanced breast cancer treated by preoperative chemotherapy to evaluate its predictive value. Sixty-eight patients diagnosed between 1998 and 2001 were treated by preoperative chemotherapy with anthracyclines or these agents combined with taxanes. From genomic DNA, a 106 bp fragment of MDR-1 exon 26 was amplified and the C3435T genotype was determined by Pyrosequencing methodology. A potential correlation with therapeutic response was calculated with Fisher's exact test. The overall clinical response rate (cCR and cPR) was 68% but only 7 patients (10.3%) achieved pathological complete response (pCR). Heterozygous C3435T occurred in 57% of the subjects and 22% of the analysed individuals possessed only T alleles. Statistical analysis revealed a significant correlation (p=0.029) between clinical complete response to preoperative chemotherapy and the T/T genotype. MDR-1 polymorphism C3435T in exon 26 may co-determine resistance to chemotherapy and provide useful information to individualize therapy.
authors.affiliation: Department of Obstetrics and Gynecology, University of Ulm Medical School, Ulm, Germany.
authors.forename: Ariane
authors.initials: A
authors.lastname: Kafka
authors.forename: Georg
authors.initials: G
authors.lastname: Sauer
authors.forename: Christoph
authors.initials: C
authors.lastname: Jaeger
authors.forename: Regina
authors.initials: R
authors.lastname: Grundmann
authors.forename: Rolf
authors.initials: R
authors.lastname: Kreienberg
authors.forename: Robert
authors.initials: R
authors.lastname: Zeillinger
authors.forename: Helmut
authors.initials: H
authors.lastname: Deissler
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005091:Exons; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008207:Lymphatic Metastasis; D008593:Menopause; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D004077:Digoxin