title: Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy.
abstract: OBJECTIVE
  Tamoxifen is used in the treatment of breast cancer to prevent recurrences. It is converted to its active metabolite endoxifen by CYP2D6 enzyme. This study was conducted to evaluate the influence of CYP2D6 genetic polymorphisms on the recurrence of breast cancer in patients receiving treatment with tamoxifen as an adjuvant hormonal therapy.
  
  
  METHODS
  Breast cancer patients (n = 141) on adjuvant tamoxifen and not on any concomitant CYP2D6 inhibitors were recruited for the study. Patient characteristics and treatment history were obtained. Five milliliters of venous blood was collected for genotyping CYP2D6 alleles *1, *2, *4, *5 and *10. CYP2D6 activity score was calculated to determine the phenotype based on genotype. The activity scores were compared between patients with recurrence and patients with no recurrence of breast cancer.
  
  
  RESULTS
  Of the 141 patients recruited for the study, genotyping was done for 132 of them. CYP2D6 activity score ≤0.5 is associated with a statistically significant increased risk of recurrence (OR-12.37; 95 % CI-3.23, 47.33; p < 0.001) and shorter recurrence free survival (52.68 ± 10.58 months (mean ± SEM); p < 0.001) as was shown in Kaplan-Meir survival estimates, when compared to activity score ≥1. The hazard ratio for activity score ≤0.5 is 7.29 (p < 0.001) when compared to activity score ≥1. Analysis of known estrogen receptor positive patients also showed statistically significant increased risk of recurrence and shorter recurrence free survival in patients with CYP2D6 activity score ≤0.5. The Cox proportional hazard ratio was found to be 7.15 (p = 0.006) for activity score ≤0.5.
  
  
  CONCLUSIONS
  Reduced CYP2D6 activity is associated with poor treatment outcomes, in terms of increased risk of recurrence and shorter recurrence free survival, in breast cancer patients on adjuvant tamoxifen therapy.
authors.affiliation: ICMR Centre for Advance Research in Pharmacogenomics, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry 605 006, India. damodaran.se@gmail.com
authors.forename: Solai Elango
authors.initials: SE
authors.lastname: Damodaran
authors.forename: Suresh Chandra
authors.initials: SC
authors.lastname: Pradhan
authors.forename: Gurusamy
authors.initials: G
authors.lastname: Umamaheswaran
authors.forename: Dharanipragada
authors.initials: D
authors.lastname: Kadambari
authors.forename: K Sathyanarayana
authors.initials: KS
authors.lastname: Reddy
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Adithan
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000378:metabolism; D018570:Risk Assessment / Q000706:statistics & numerical data; D012307:Risk Factors; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D007527:Isoenzymes; D011960:Receptors, Estrogen; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6