The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor–positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease–free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

Purpose: Tamoxifen has been the mainstay adjuvant hormonal treatment for breast cancer for many years. Conversion of tamoxifen to its active metabolite, endoxifen, is reduced by low activity of the cytochrome P450 enzyme, CYP2D6.We examined the effect of reduced CYP2D6 activity on the response to tamoxifen in patients with familial early-onset breast cancer. Experimental Design: We conducted a case note review and genotyping for the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*41 alleles in 115 patients (47 BRCA1, 68 BRCA2) with familial breast cancer who had been treated with 20-mg tamoxifen following surgery. Results: Eight (7%) individuals had genotypes consistent with poor metabolizer status, and 4 (3.5%) individuals took CYP2D6 inhibitor drugs concomitant with their tamoxifen and were also considered poor metabolizer. Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient group with poor metabolizer CYP2D6 activity. However, a significant effect was confined to patients with BRCA2 mutations with a worse overall survival (median survival, 7 versus 28 years; P = 0.008; adjusted hazard ratio, 9.7). Conclusions: Poor metabolizer status for CYP2D6 predicts worse overall survival in patients with familial breast cancer. Therefore, CYP2D6 inhibitor drugs should not be prescribed concomitantly with tamoxifen. Prospective studies should be undertaken to establish the effect of CYP2D6 status on outcome in familial breast cancer patients treated with tamoxifen.Breast cancer is the most common cancer in females, with more than 1 million women worldwide diagnosed every year (1). In the United States, f170,000 new diagnoses of invasive breast cancer are expected in 2007 (2). Familial susceptibility to breast cancer accounts for f10% to 25% of all breast cancer cases, with the majority of high risk familial breast cancer cases due to mutations in the BRCA1 and BRCA2 genes (3, 4). The lifetime risks for developing breast cancer are 65% to 85% and 45% to 85% for BRCA1 and BRCA2 mutation carriers, respectively (5). In addition, BRCA1 and BRCA2 mutation carriers have increased lifetime risks of ovarian cancer of 37% to 62% and 11% to 23%, respectively (6). Importantly, breast cancer due to BRCA1 and BRCA2 mutations accounts for a disproportionately high number of life-years lost because of the early onset of disease.Currently, the treatment of breast cancer in women with BRCA1 or BRCA2 mutations does not differ from the treatment in women with sporadic breast cancer (7). However, trials of poly(ADP-ribose) polymerase inhibitors and platinum-versus taxane-based chemotherapy are under way in patients with metastatic BRCA1-and BRCA2-related breast cancer, aiming to exploit impaired DNA damage response pathways (8). Often, the presence of a BRCA1 or BRCA2 mutation is unknown at the time of primary treatment and so is unavailable to guide treatment decisions (9). In the majority of studies, ipsilateral and contralateral breast cancer rates of recurrence have been increased in women w...

Purpose: Hypoxia is associated with poor prognosis and is predictive of poor response to cancer treatments, including radiotherapy. Developing noninvasive biomarkers that both detect hypoxia prior to treatment and track change in tumor hypoxia following treatment is required urgently. Experimental Design: We evaluated the ability of oxygenenhanced MRI (OE-MRI) to map and quantify therapyinduced changes in tumor hypoxia by measuring oxygenrefractory signals in perfused tissue (perfused Oxy-R). Clinical first-inhuman study in patients with non-small cell lung cancer (NSCLC) was performed alongside preclinical experiments in two xenograft tumors (Calu6 NSCLC model and U87 glioma model). Results: MRI perfused Oxy-R tumor fraction measurement of hypoxia was validated with ex vivo tissue pathology in both xenograft models. Calu6 and U87 experiments showed that MRI perfused Oxy-R tumor volume was reduced relative to control following single fraction 10-Gy radiation and fractionated chemoradiotherapy (P < 0.001) due to both improved perfusion and reduced oxygen consumption rate. Next, evaluation of 23 patients with NSCLC showed that OE-MRI was clinically feasible and that tumor perfused Oxy-R volume is repeatable [interclass correlation coefficient: 0.961 (95% CI, 0.858-0.990); coefficient of variation: 25.880%]. Group-wise perfused Oxy-R volume was reduced at 14 days following start of radiotherapy (P ¼ 0.015). OE-MRI detected between-subject variation in hypoxia modification in both xenograft and patient tumors. Conclusions: These findings support applying OE-MRI biomarkers to monitor hypoxia modification, to stratify patients in clinical trials of hypoxia-modifying therapies, to identify patients with hypoxic tumors that may fail treatment with immunotherapy, and to guide adaptive radiotherapy by mapping regional hypoxia.

Methods Genotyping of 33 CYP2D6 alleles, using two archival cohorts from tamoxifen-treated women with invasive breast cancer (Dundee, n=391;Manchester, n=227). Estimates for recurrence-free survival (RFS) were calculated based on inferred CYP2D6 phenotypes using Kaplan-Meier andCox proportional hazard models, adjusted for nodal status and tumor size. Conclusions Comprehensive genotyping of CYP2D6 and adherence to tamoxifen therapy may be useful to identify breast cancer patients most likely to benefit from adjuvant tamoxifen. Results3