Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Abstract

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

Therapeutic Drug Monitoring of Endoxifen for Tamoxifen Precision Dosing: Feasible in Patients with Hormone-Sensitive Breast Cancer

“…recurrence rate [17][18][19][20][21][22]. These conflicting results underline the importance of considering other factors that may influence the variability in endoxifen concentration, including concomitant medication, dietary or food supplements, adherence, age, body mass index (BMI), hormonal status, and circadian rhythm [23][24][25][26][27].…”

CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

“…For anticancer drugs, pharmacogenetic testing for CYP450 enzymes is currently limited to CYP2D6 testing for tamoxifen, which needs activation by CYP2D6 [for review, see Mulder et al (2021) ]. A good example of implementation of pharmacogenetic testing in oncology outside the CYP450 field, is DPYD analysis prior to capecitabine treatment, as well as TPMT testing for 6-mercaptopurine for treatment of Acute Lymphatic Leukemia ( Henricks et al, 2018 ; Roden et al, 2019 ).…”

Impact of Neoadjuvant Chemotherapy on Somatic Mutation Status in High-grade Serous Ovarian Carcinoma

“…The Cytochrome P450 Family 2 Subfamily D Member 6 (CYP2D6) gene encodes a member of the cytochrome P450 superfamily. The CYP2D6 enzyme is involved in the metabolism of 20-25% of clinically used drugs and is the main enzyme responsible for the conversion of tamoxifen into endoxifen, its most important metabolite [20]. Genetic variations in the CYP2D6 gene can cause reduced enzyme activity and in uence tamoxifen metabolism.…”

“…Genetic variations in the CYP2D6 gene can cause reduced enzyme activity and in uence tamoxifen metabolism. However, the association between CYP2D6 genotype and clinical outcome in patients with breast cancer treated with tamoxifen is controversial [20]. It is unclear how the mutation in CYP2D6 could impact clinical outcome after NACT in patients with ovarian cancer, as carboplatin is excreted primarily by kidneys and paclitaxel is metabolized mainly by cytochromes P450 2C8 and 3A4 [21].…”