CYP2D6 Genotype Predicts Tamoxifen Discontinuation and Prognosis in Patients With Breast Cancer

Abstract

Purpose: To examine the association between CYP2D6 genotype, discontinuation of tamoxifen therapy, and prognosis for breast cancer.

Patients and methods: We conducted a prospective-retrospective study linking data from a clinical breast cancer register, the Swedish Prescribed Drug Register, and self-reported questionnaires. We genotyped CYP2D6 in 1,309 patients with breast cancer who were treated with tamoxifen and were diagnosed from 2005 to 2012; they were categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. We investigated whether metabolizer status was associated with tamoxifen discontinuation and prognosis for breast cancer using Cox regression analysis.

Results: The 6-month discontinuation rates of tamoxifen among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 7.1%, 7.6%, 6.7%, and 18.8%, respectively. A U-shaped association was found between CYP2D6 metabolizer status and breast cancer-specific mortality, with adjusted hazard ratios of 2.59 (95% CI, 1.01 to 6.67) for poor, 1.48 (95% CI, 0.72 to 3.05) for intermediate, 1 (reference) for normal, and 4.52 (95% CI, 1.42 to 14.37) for ultrarapid CYP2D6 metabolizers.

Conclusion: Both poor and ultrarapid CYP2D6 metabolizers of tamoxifen have a worse prognosis for breast cancer compared with normal metabolizers after receiving a standard dose of tamoxifen. This U-shaped association might call for individualized tamoxifen dosage.

FIG 1.

Flowchart of study participants.

FIG 2.

Use of symptom-relieving drugs and tamoxifen discontinuation among patients with breast cancer receiving standard dose of tamoxifen, by CYP2D6 metabolizer status. The use of symptom-relieving drugs was defined as any prescription of corresponding drugs within 90 days of tamoxifen initiation. Women with any prescription of corresponding symptom-relieving drugs 90 days before tamoxifen initiation were excluded from the analyses. No significant difference was found for poor or intermediate metabolizers compared with normal metabolizers for the use of symptom-relieving drugs or tamoxifen discontinuation.

FIG 3.

Treatment discontinuation among patients with breast cancer receiving standard dose of tamoxifen, by CYP2D6 metabolizer status.

FIG A1.

Tamoxifen discontinuation among patients with breast cancer receiving a standard dose of tamoxifen, by use of symptom-relieving drugs. The use of symptom-relieving drugs was defined as any prescription of corresponding drugs within 90 days of tamoxifen initiation. Women with any prescription of corresponding symptom-relieving drugs 90 days before tamoxifen initiation were excluded from the analyses.

FIG A2.

Breast cancer mortality among patients receiving standard dose of tamoxifen designated as those who discontinued tamoxifen therapy versus those who continued tamoxifen therapy (matched). Data from the Swedish Cancer Register, Swedish Prescribed Drug Register, and Swedish Cause of Death Register were linked, and patients were observed until December 2015. The source population is all women diagnosed with stages I to III breast cancer in Sweden from 2005 to 2015. Those who continued therapy were 1:1 matched to those who discontinued therapy on age, calendar year of cancer diagnosis, tumor size, and lymph node involvement. By definition, no death occurred within 180 days after tamoxifen discontinuation.