Adherence to endocrine therapy in early breast cancer in relation to Cytochrome P450 2D6 genotype: a comparison between pharmacy dispensation data and medical records.

PURPOSE: Suboptimal adherence to adjuvant endocrine treatment (AET) is an important clinical concern. A correlation between CYP2D6 activity and tamoxifen discontinuation has been described. The main aim of this study was to investigate the consistency between pharmacy dispensation data and medical records on adherence to AET. METHODS: Adherence was calculated for patients with at least 4.5 years of follow up and was defined as Medical Possession Rate ≥ 80%. Subgroup analyses were performed based on menopausal status, recurrence risk and CYP2D6 activity. RESULTS: In 86% of the 1235 included patients the consistency between the two sources of information was within 80-125%. Poor consistency, < 80%, was most frequent in the premenopausal/ high-risk group and CYP2D6 Poor Metabolizers (PMs). Among 899 patients with at least 4.5 years follow up, 72% were adherent to tamoxifen based on pharmacy dispensation data, compared with 77% as reported by medical records. When including patients who switched to aromatase inhibitors after tamoxifen, adherence increased to 82% and 88%, respectively. Adherence did not differ by menopausal status or risk for recurrence. CYP2D6 PMs had poorer adherence (54%) to tamoxifen compared to patients with the highest CYP2D6 activity (83%). CONCLUSIONS: There was a good consistency between medical records and pharmacy dispensing data on the use of AET. Adherence to AET was adequate, especially when including switch to aromatase inhibitors. Surprisingly, CYP2D6 PMs had low adherence to tamoxifen, despite a likely reduced risk of side effects according to previous data.

Time to Mammographic Density Decrease After Exposure to Tamoxifen.

Mammographic density change has proven to be a reliable proxy for tamoxifen therapy response. The primary aim of this study was to identify time to tamoxifen-induced mammographic density change. We also analyzed side effects and adherence to therapy. In all, 42 women were randomized to 10 or 20 mg of daily oral tamoxifen. Mammograms were taken at baseline, 3, 6, and 9 months. Mammographic density change was measured using the automated STRATUS tool. Adverse events were monitored through a web-based questionnaire based on the FACT-ES tool. Nine out of the 42 (21%) participants discontinued therapy due to adverse events leaving 33 women in the study. A significant decrease in density was seen after 3 months of therapy. Dose did not seem to affect density change, side effects or adherence. Given the size of the study, additional studies are needed to confirm our data.

Impact of systemic adjuvant therapy and CYP2D6 activity on mammographic density in a cohort of tamoxifen-treated breast cancer patients.

PURPOSE: Change in mammographic density has been suggested to be a proxy of tamoxifen response. We investigated the effect of additional adjuvant systemic therapy and CYP2D6 activity on MD change in a cohort of tamoxifen-treated pre- and postmenopausal breast cancer patients. METHODS: Swedish breast cancer patients (n = 699)  operated 2006-2014, genotyped for CYP2D6, having at least three months postoperative tamoxifen treatment, a baseline, and at least one follow-up digital mammogram were included in the study. Other systemic adjuvant treatment included chemotherapy, goserelin, and aromatase inhibitors. Change in MD, dense area, was assessed using the automated STRATUS method. Patients were stratified on baseline characteristics, treatments, and CYP2D6 activity (poor, intermediate, extensive, and ultrarapid). Relative density change was calculated at year 1, 2, and 5 during follow-up in relation to treatments and CYP2D6 activity. RESULTS: Mean relative DA decreased under the follow-up period, with a more pronounced MD reduction in premenopausal patients. No significant effect of chemotherapy, aromatase inhibitors, goserelin, or CYP2D6 activity on DA change was found. DA did not revert to baseline levels after tamoxifen discontinuation. CONCLUSION: Our results indicate that other systemic adjuvant therapy does not further reduce MD in tamoxifen-treated breast cancer patients. We could not confirm the previously suggested association between CYP2D6 activity and MD reduction in a clinical setting with multimodality adjuvant treatment. No rebound effect on MD decline after tamoxifen discontinuation was evident.

Low-Dose Tamoxifen for Mammographic Density Reduction: A Randomized Controlled Trial.

PURPOSE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms. PATIENTS AND METHODS: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis. RESULTS: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group. CONCLUSION: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.

Impairment of endoxifen formation in tamoxifen-treated premenopausal breast cancer patients carrying reduced-function CYP2D6 alleles.

AIMS: Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects. METHODS: In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with on-going postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real-time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography-tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records. RESULTS: In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6-5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced-function alleles, 2 null-alleles, or a null/reduced-function combination. CYP2D6*41 was the most common reduced-function allele (82%) and 17 of 21 CYP2D6*41-carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null-alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels <5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderate-to-severe side effects were reported in a concentration-dependent manner. CONCLUSION: Significantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null-alleles, but also in carriers of 2 reduced-function alleles. This finding may be highly relevant for future, genotype-based dose considerations.

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

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.

CYP2D6 and adjuvant tamoxifen: possible differences of outcome in pre- and post-menopausal patients.

AIM: Previous studies on CYP2D6 activity and the effect of adjuvant tamoxifen in breast cancer are inconsistent. We analyzed the impact of the CYP2D6 polymorphism in pre- and post-menopausal patients that were adherent to tamoxifen treatment for at least a year. MATERIALS & METHODS: A total of 382 breast cancer patients prescribed adjuvant tamoxifen for 5 years constituted the study-base. Clinical information, including compliance and outcome, was retrieved from medical records. Comprehensive CYP2D6 genotyping was performed and translated into predicted metabolic activity. RESULTS & CONCLUSION: In patients adherent to tamoxifen for at least one year (n = 313) there was an association between reduced CYP2D6 activity (≤50% of normal) and recurrence (p = 0.025) and breast cancer-specific mortality (p = 0.034). In a multivariable analysis, CYP2D6 remained an independent predictor of outcome. In a subgroup analysis, the effect of CYP2D6 seemed to derive mainly from premenopausal patients, which represents a new finding that needs validation in a larger study sample. Original submitted 13 November 2012; Revision submitted 1 March 2013.