Abstract P1-16-07: Pharmacogenomics-pharmacokinetics study of selective estrogen-receptor modulators with intra-patient dose-escalation for Japanese breast cancer patients

Abstract

Abstract Background The association between CYP2D6 polymorphisms and efficacy of tamoxifen (TAM) is inconclusive, partly due to inaccurate prediction of active metabolite, endoxifen exposure by solely CYP2D6 genotype. Moreover, TAM dose escalation is not effective for poor metabolizers. Since the contribution of CYP2D6 to toremifen (TOR) activation is small, TOR might be a good alternative to TAM for poor metabolizers. Methods Patients who maintained good compliance with TAM or TOR without regular use of strong CYP2D6 inhibitors were enrolled in a screening study. The pharmacokinetics (PK) of TAM or TOR and the pharmacogenomics (PGx) of metabolizing enzymes and transporters were assessed. Associations between TAM and TOR PK and PGx, other CYP inhibitor use, and smoking status were examined by regression analysis. An intra-patient dose escalation study was conducted for patients showing low endoxifen levels during TAM treatment (n = 14). TAM was switched to 40 mg of TOR, and then increased to 120 mg for ≥24 weeks with periodic PK sampling. Total TAM or TOR activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activity. Results CYP2D6 genotype was the major determinant for TAM activity (p < 0.01) for Japanese breast cancer patients. Current smoking status (p = 0.07) and CYP2C19 (p = 0.07), but not CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity sufficiently increased with dose escalation from 40 mg to 120 mg, even among the poor TAM metabolizers, and was maintained for ≥24 weeks. Total Activity of TOR (ng/mL) Screening (n=271)Intra-patient dose escalation (n=14)Dose (mg)4040120120*120/40120*/40120*/120Mean (ng/mL)4168.53218.18758.67268.03.12.60.9Median (ng/mL)3865.43020.38924.67579.72.82.50.8SD1446.21207.01707.11793.21.20.80.2p-value0.04 <0.01<0.010.054*(Sample taken at ≥24 weeks) Conclusion Since the contribution of CYP2D6 to TOR metabolism is relatively small, TOR is a valid alternative to TAM, especially in patients predicted to be poor TAM metabolizers. Further clinical trials are warranted to validate this concept. Citation Format: Ohno S, Ishiguro H, Yamamoto Y, Takao S, Sato N, Fujisawa T, Kadoya T, Kuroi K, Bando H, Teramura Y, Iwata H, Tanaka S, Toi M. Pharmacogenomics-pharmacokinetics study of selective estrogen-receptor modulators with intra-patient dose-escalation for Japanese breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-16-07.