Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer.
OBJECTIVE
The use of cytochrome P450 2D6-inhibiting drugs (CYP2D6 inhibitors) during tamoxifen treatment leads to a decrease in plasma concentration of endoxifen, the major active tamoxifen metabolite. Concomitant use of CYP2D6 inhibitors, such as selective serotonin reuptake inhibitors, as well as low tamoxifen adherence may negatively impact tamoxifen efficacy in patients with breast cancer. The objectives of this study were to relate concomitant CYP2D6 inhibitor use and tamoxifen adherence to breast cancer event-free time (EFT).


METHODS
Data were from PHARMO and included a community pharmacy dispensing database; PALGA, a nationwide pathology database; and the Dutch Medical Register in the Netherlands. Patients with breast cancer treated with adjuvant tamoxifen between 1994 and 2006 were included. A Cox proportional hazards model with a time-dependent definition for concomitant CYP2D6 inhibitor exposure was used. Adherence calculated over the first year after tamoxifen initiation was related to breast cancer events in the following period.


RESULTS
In total, 1,962 patients with breast cancer using tamoxifen were included, among whom 150 (7.6%) frequently used a CYP2D6 inhibitor during tamoxifen treatment. No association between concomitant CYP2D6 inhibitor use and breast cancer recurrence was observed (adjusted hazard ratio [HR], 0.87; 95% CI, 0.42 to 1.79; P = .69). Poor tamoxifen adherence was associated with lower EFT (adjusted HR, 0.987; 95% CI, 0.975 to 0.999; P = .029).


CONCLUSIONS
This observational study did not show an association between concomitant CYP2D6 inhibitor use and breast cancer recurrence among patients treated with adjuvant tamoxifen despite the strong biologic rationale. This study shows, to the best of our knowledge for the first time, that poor tamoxifen adherence is associated with an increased risk of breast cancer events.
Dezentjé
Vincent O
VO
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands.
van Blijderveen
Nico J C
NJ
Gelderblom
Hans
H
Putter
Hein
H
van Herk-Sukel
Myrthe P P
MP
Casparie
Mariel K
MK
Egberts
Antoine C G
AC
Nortier
Johan W R
JW
Guchelaar
Henk-Jan
HJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009426:Netherlands; D016016:Proportional Hazards Models; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D013629:Tamoxifen / Q000378:metabolism / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D018931:Antineoplastic Agents, Hormonal; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6