Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.

Purpose Aromatase inhibitors (AIs) are effective for treatment of hormone receptor–positive breast cancer, but adherence and persistence with therapy are poor. Predictors of treatment discontinuation are not clearly defined. It is unknown whether patients with intolerable toxicity from one AI are able to tolerate another. Patients and Methods Women with early-stage breast cancer initiating AI therapy were enrolled onto a multicenter, prospective, open-label randomized trial of exemestane versus letrozole. Patients completed symptom questionnaires at baseline and serially during therapy. Patients who developed AI-associated intolerable symptoms and discontinued treatment were given the option to switch to the other study AI after a 2- to 8-week washout period. Results Of the 503 enrolled women, 32.4% discontinued initial AI therapy within 2 years because of adverse effects; 24.3% discontinued specifically because of musculoskeletal symptoms. Median time to treatment discontinuation as a result of any symptom was 6.1 months (range, 0.1 to 21.2 months) and was significantly shorter in patients randomly assigned to exemestane (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = .02). Younger age and taxane-based chemotherapy were associated with higher likelihood of treatment discontinuation (HR, 1.4; 95% CI, 1.02 to 1.9; P = .04; and HR, 1.9; 95% CI, 1.00 to 3.6; P = .048, respectively). Of the 83 patients who chose to switch to the second AI, 38.6% continued the alternate AI for a median of 13.7 months. Conclusion Premature discontinuation of initial AI therapy as a result of symptoms is common, although more than one third of patients may be able to tolerate a different AI medication. Additional research is needed to identify predictive tools and interventions for AI-associated treatment-emergent symptoms.

Musculoskeletal side effects were common in AI-treated patients, resulting in therapy discontinuation in more than 10% of patients. There are no identifiable pre-therapy indicators of risk, and the etiology remains elusive.

There is an association of the VEGF-2578A and -1498C alleles with increased breast cancer risk. This association remains significant when adjusted for Gail score-related risk factors.

Propofol can be given safely by appropriately trained nurses under supervision by endoscopists. Technology that allows immediate detection of apnea would likely further improve its safety.

We tested the hypothesis that the stable isotope [13 C]pantoprazole is O-demethylated by cytochrome P450 CYP2C19 and that the 13 CO 2 produced and exhaled in breath as a result can serve as a safe, rapid, and noninvasive phenotyping marker of CYP2C19 activity in vivo. Healthy volunteers who had been genotyped for the CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles were administered a single oral dose of [13 C]pantoprazole sodium-sesquihydrate (100 mg) with 2.1 g of sodium bicarbonate. Exhaled 13 CO 2 and 12 CO 2 were measured by IR spectroscopy before (baseline) and 2.5 to 120 min after dosing. Ratios of 13 CO 2 / 12 CO 2 after [ 13 C]pantoprazole relative to 13 CO 2 / 12 CO 2 at baseline were expressed as change over baseline (DOB). Maximal DOB, DOB 15 to DOB 120 , and area under the DOB versus time curve (AUC 0 -120 and AUC 0 -ϱ ) were significantly different among three genotype groups (CYP2C19*1/ *1, n ϭ 10; CYP2C19*1/*2 or CYP2C19*1/*3, n ϭ 10; and CYP2C19*2/*2, n ϭ 5) with predicted extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) of CYP2C19, respectively (Kruskal-Wallis test, p Ͻ 0.01); linear regression analysis indicated a gene-dose effect relationship (r 2 ranged between 0.236 and 0.522; all p Ͻ 0.05). These breath test indices were significantly lower in PMs than IMs (p Ͻ 0.05) or EMs (p Ͻ 0.01) of CYP2C19. [13 C]Pantoprazole plasma exposure showed significant inverse correlation with breath test indices in the respective subjects (Pearson r ϭ Ϫ0.74; p ϭ 0.038). These feasibility data suggest that the [ 13 C]pantoprazole breath test is a reliable, rapid, and noninvasive probe of CYP2C19 and seems to be a useful tool to optimize drug therapy metabolized by CYP2C19.

Objectives To evaluate the relationships among measures of hot flushes, perceived hot flush interference, sleep disturbance, and measures of quality of life while controlling for potential covariates (patient and treatment variables). Methods Breast cancer survivors (n = 395) due to receive aromatase inhibitor therapy provided demographic information, physiological hot flush data via sternal skin conductance monitoring, hot flush frequency via written diary and electronic event marker, hot flush severity and bother via written diary, and questionnaire data via the Hot Flash Related Daily Interference Scale, Pittsburgh Sleep Quality Index, the EuroQOL, Hospital Anxiety and Depression Scale and the Center for Epidemiologic Studies Depression Scale. Results Confirmatory factor analysis supported a two-factor model for hot flush symptoms (frequency and severity). Although there was strong convergence among self-reported hot flush measures, there was a high degree of unexplained variance associated with physiological measures. This suggests that self-report and physiological measures do not overlap substantially. The structural model showed that greater hot flush frequency and severity were directly related to greater perceived interference with daily life activities. Greater perceived interference, in turn, directly predicted greater sleep disruption, which predicted lower perceived health state and more symptoms of anxiety and depression. Conclusions Findings suggest hot flush interference may be the most appropriate single measure to include in clinical trials of vasomotor symptom therapies. Measuring and ameliorating patients' perceptions of hot flush interference with life activities and subjective sleep quality may be the most direct routes to improving quality of life.

Tamoxifen induces important changes in serum lipid profiles in some women; however, little information is available to predict which women will experience improved lipid profiles during tamoxifen therapy. As part of a multicenter prospective observational trial in 176 breast cancer patients, we tested the hypothesis that tamoxifen-induced lipid changes were associated with genetic variants in candidate target genes (CYP2D6, ESR1, and ESR2). Tamoxifen lowered low-density lipoprotein cholesterol (P<0.0001) by 23.5mg/dl (13.5-33.5mg/dl) and increased triglycerides (P=0.006). In postmenopausal women, the ESR1-XbaI and ESR2-02 genotypes were associated with tamoxifen-induced changes in total cholesterol (P=0.03; GG vs GA/AA) and triglycerides (P=0.01; gene-dose effect), respectively. In premenopausal women, the ESR1-XbaI genotypes were associated with tamoxifen-induced changes in triglycerides (P=0.002; gene-dose effect) and highdensity lipoprotein (P=0.004; gene-dose effect). Our results suggest that estrogen receptor genotyping may be useful in predicting which women would benefit more from tamoxifen.The use of exogenous estrogen to prevent cardiovascular disease in women has been a subject of controversy since data from the Women's Health Initiative trial suggested that postmenopausal women might experience a greater number of cardiovascular events when treated with hormone replacement therapy. 1 There is large interindividual variability in the response to estrogens, and Herrington et al. 2 have suggested that this may be due in part to genetic variants in the estrogen receptors (ERs). As the Women's Health Initiative study made prospective study of the effects of estrogens difficult and as the selective estrogen response modifier tamoxifen acts as an exogenous estrogen on serum lipids, we elected to study the effects of tamoxifen on serum lipids and to test the hypothesis that genetic variants are associated with variability in response. © 2007 American Society for Clinical Pharmacology and TherapeuticsCorrespondence to: DF Hayes, hayesdf@umich.edu. 5 Current address: Division of Hematology/Oncology, Department of Medicine, Ohio State University, Columbus, Ohio, USA. CONFLICT OF INTERESTThe authors declared no conflict of interest. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptTamoxifen is a selective ER modulator widely used in the treatment of ER-or progesterone receptor-positive breast cancer, and it is the only agent approved for the prevention of the disease. [3][4][5][6] As a selective ER modulator, tamoxifen has both estrogenic and anti-estrogenic effects depending on the target tissue. Tamoxifen effects on serum lipid concentration are largely similar to those of estrogen. 7,8 Tamoxifen is documented to cause a reduction in serum total and low-density lipoprotein (LDL), but data on high-density lipoprotein (HDL) and triglycerides have not been consistent. [9][10][11][12][13][14] The effects of tamoxifen vary from patient to patient, and this variabili...