Endocrine therapy (ET), which consists of tamoxifen or aromatase inhibitors (AIs), is utilized in early BC to significantly reduce the risk of recurrence and to improve overall survival in patients with estrogen receptor–positive (ER+) BC. Moreover, for any treatment to be effective, the patient must adhere to the drug regimen.

Researchers in Sweden conducted a cohort study involving prescription and medical records along with cytochrome 2D6 genotyping. The purpose of this study was threefold: 1) to determine the consistency in data between pharmacy and the medical records on adherence to ET in early BC; 2) to assess the consistency between pharmacy and medical records on the concomitant use of CYP2D6 inhibitors in patients receiving tamoxifen; and 3) to examine a possible association between menopausal status, CYP2D6 activity, estimated risk of recurrence, and adherence to ET.

Using data from the National Quality Registry for Breast Cancer, investigators identified 1,255 patients initiated on tamoxifen who had undergone primary BC surgery between January 2006 and January 2014 who also had DNA CYP2D6 genotype information available. Patients were excluded if they had received an AI or gonadotropin-releasing hormone agonist monotherapy as their first adjuvant ET or if their CYP2D6 genotype was inconclusive. Patients were followed from the date of initiation of tamoxifen therapy (as determined from the medical record) until BC recurrence (local, metastatic, or contralateral), death, or the end of the study. Information was collected retrospectively from the medical record on menopausal status, tumor characteristics, concomitant medications, BC treatment, adherence to ET, adverse events, and follow-up data. Analysis of CYP2D6 genotype was performed using polymerase chain reaction.

A patient’s CYP2D6 phenotype was categorized as poor metabolizers (PMs), normal/immediate metabolizers (NM/IMs), or ultra-metabolizers (UMs) based on recommendations from the Clinical Pharmacogenetics Working Group and the Dutch Pharmacogenetics Working Group. A post hoc analysis incorporated a broader definition of CYP2D6 PM status that included carriers of two reduced-function alleles or the combination of a null-allele and a reduced-function allele since this would also result in a decrease in the formation of tamoxifen’s active metabolite, endoxifen.

Prescription information was obtained from the Swedish Prescribed Drug Register, which maintains statistics on prescribed medications. The drug regimens of patients on tamoxifen were also screened for the concomitant administration of clinically relevant CYP2D6 inhibitors, including fluoxetine, paroxetine, haloperidol, duloxetine, levomepromazine, zuclopenthixol, thioridazine, diphenhydramine, amiodarone, quinidine, terbinafine, cinacalcet, bupropion, and sertraline. Medication possession ratio (MPR), which is the estimate of the proportion of prescribed days’ supply of medication during a specified period, was calculated. Adequate adherence was defined as >80% MPR of the recommended ET for at least 4.5 years. A high rate of recurrence was defined as having positive lymph nodes and/or tumors with high proliferation rate (Ki67 >20/S phase >10%) and/or grade III and/or HER2 amplification and/or having received chemotherapy.

Of the original cohort of 1,255 patients identified, 20 received tamoxifen as second-line therapy and were excluded from the adherence analysis, leaving 1,235 study patients. Of these patients, 40.5% were premenopausal, 57.6% were postmenopausal, and 1.9% were perimenopausal. Almost all (99.4%) patients had ER+ BC. An additional five patients had inconclusive CYP2D6 genotype data and were excluded leaving 1230 patients for CYP2D6 genotyping. Of these 1,230 patients, 7.2% or 90 patients were CYP2D6 PMs.

The investigators found that consistency between information on exposure to tamoxifen therapy in the prescription and medical records was adequate for 84% of patients. Based on these two sources of information, 72% and 77% of patients, respectively, were deemed to be adherent with tamoxifen therapy. Adherence did not differ by menopausal status or risk for recurrence.

Interestingly, CYP2D6 PMs demonstrated poor adherence to ET, with only 54% adherent to tamoxifen and 71% adherent to AI therapy. Adherence was greater in NM/IMs at 73% and 82%, respectively, and in UMs at 83% and 90%, respectively. These findings were surprising since some studies have indicated a reduction in risk of adverse events and discontinuation of tamoxifen in patients with poor CYP2D6 activity compared to those with the highest activity.

Outcome data were limited for the 125 tamoxifen-treated patients who received concomitant CYP2D6 inhibitors as the use of these potentially interacting medications was documented in only 41.6% of medical records. For 58.4% of the population on concomitant tamoxifen and CYP2D6 inhibitors, there was no evidence in the medical record that their oncologic provider was aware of the drug interaction.

The findings of this study pointed to an important role that pharmacist can play in the medication therapy management for patients with early BC as prescribers may often be unaware of the potential for drug-drug interactions with tamoxifen and CYP2D6 inhibitors or of the lack of patient adherence with ET.

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