Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N -desmethyltamoxifen (DM-Tam)/ (Z)- endoxifen and CYP2D6 phenotype significantly correlated across ethnicities ( R 2 : 53%, P <10 −77 ). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively ( P <0.001). DM-Tam was influenced by body mass index ( P <0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam /(Z)- endoxifen ( P =0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P =0.013). Low (<14 n M ) compared with high (>35 n M ) endoxifen concentrations were associated with shorter DRFS (univariate P =0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P =0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Black ethnic groups have a higher breast cancer mortality than Whites. American studies have identified variations in tumour biology and unequal health-care access as causative factors. We compared tumour pathology, treatment and outcomes in three ethnic groups in young breast cancer patients treated in the United Kingdom. Women aged ⩽40 years at breast cancer diagnosis were recruited to the POSH national cohort study (MREC: 00/06/69). Personal characteristics, tumour pathology and treatment data were collected at diagnosis. Follow-up data were collected annually. Overall survival (OS) and distant relapse-free survival (DRFS) were assessed using Kaplan–Meier curves, and multivariate analyses were performed using Cox regression. Ethnicity data were available for 2915 patients including 2690 (91.0%) Whites, 118 (4.0%) Blacks and 87 (2.9%) Asians. Median tumour diameter at presentation was greater in Blacks than Whites (26.0 mm vs 22.0 mm, P=0.0103), and multifocal tumours were more frequent in both Blacks (43.4%) and Asians (37.0%) than Whites (28.9%). ER/PR/HER2-negative tumours were significantly more frequent in Blacks (26.1%) than Whites (18.6%, P=0.043). Use of chemotherapy was similarly high in all ethnic groups (89% B vs 88.6% W vs 89.7% A). A 5-year DRFS was significantly lower in Blacks than Asians (62.8% B vs 77.0% A, P=0.0473) or Whites (62.8 B% vs 77.0% W, P=0.0053) and a 5-year OS for Black patients, 71.1% (95% CI: 61.0–79.1%), was significantly lower than that of Whites (82.4%, 95% CI: 80.8–83.9%, W vs B: P=0.0160). In multivariate analysis, Black ethnicity had an effect on DRFS in oestrogen receptor (ER)-positive patients that is independent of body mass index, tumour size, grade or nodal status, HR: 1.60 (95% CI: 1.03–2.47, P=0.035). Despite equal access to health care, young Black women in the United Kingdom have a significantly poorer outcome than White patients. Black ethnicity is an independent risk factor for reduced DRFS particularly in ER-positive patients.