title: Potent CYP2D6 Inhibiting drugs do not increase relapse rate in early breast cancer patients treated with adjuvant tamoxifen.
abstract: Endoxifen, the most active metabolite of the prodrug tamoxifen, is produced by cytochrome P450 CYP2D6. Breast cancer patients treated with tamoxifen who have reduced CYP2D6 activity, related to either genetic variation or drug inhibition, may have inferior outcomes. To assess the effect of concomitant CYP2D6 inhibiting drug use on clinical outcomes of breast cancer patients treated with adjuvant tamoxifen. We conducted a retrospective database analysis. Women with non-metastatic estrogen receptor positive tumors who had completed adjuvant tamoxifen therapy for 2 years, without treatment with adjuvant aromatase inhibitors or early relapse, were included. Patients were classified as users of CYP2D6 inhibitors if they purchased strong CYP2D6 inhibiting drugs for ≥ 4 consecutive months during tamoxifen treatment. Tumors were classified as "high risk" if adjuvant chemotherapy was prescribed. Primary endpoint was disease free (DFS) and secondary endpoint was overall survival (OS). 902 patients treated with tamoxifen (median duration, 4.9 years) were followed for a median period of 5.9 years. Fifty-nine (6.5%) patients were users of CYP2D6 inhibitors (median duration, 23 months). DFS at 3 years (corresponding to 5 years after tamoxifen initiation) did not differ between users and non-users of CYP2D6 inhibiting drugs (92.7 vs. 93.0%, respectively; adjusted P = 0.44). OS at 3 years was lower in the patients using CYP2D6 inhibiting drugs: 89.4 vs. 93.8%, but after adjustment for age and comorbidities this difference was not significant (P = 0.20). Overall recurrence rates did not differ between users and non-users of CYP2D6 inhibiting drugs (11.8 vs. 19.0% respectively, P = 0.23). Concomitant prolonged therapy with strong CYP2D6 inhibiting drugs does not affect adversely DFS and recurrence rates in tamoxifen-treated early breast cancer patients.
authors.affiliation: Department of Specialized Medicine, Maccabi Healthcare Services, Tel Aviv, Israel.
authors.forename: Nava
authors.initials: N
authors.lastname: Siegelmann-Danieli
authors.forename: Daniel
authors.initials: D
authors.lastname: Kurnik
authors.forename: Yossi
authors.initials: Y
authors.lastname: Lomnicky
authors.forename: Janet
authors.initials: J
authors.lastname: Vesterman-Landes
authors.forename: Itzhak
authors.initials: I
authors.lastname: Katzir
authors.forename: Martin
authors.initials: M
authors.lastname: Bialik
authors.forename: Ronen
authors.initials: R
authors.lastname: Loebstein
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D018572:Disease-Free Survival; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen