Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer.

PURPOSE: Inter-individual differences in estrogen concentrations during treatment with aromatase inhibitors (AIs) may contribute to therapeutic response and toxicity. The aim of this study was to determine plasma concentrations of estradiol (E2), estrone (E1), and estrone sulfate (E1S) in a large cohort of AI-treated breast cancer patients. METHODS: In a randomized, multicenter trial of postmenopausal women with early-stage breast cancer starting treatment with letrozole (n = 241) or exemestane (n = 228), plasma estrogen concentrations at baseline and after 3 months were quantitated using a sensitive mass spectrometry-based assay. Concentrations and suppression below the lower limit of quantification (LLOQ) were compared between estrogens and between drugs. RESULTS: The ranges of baseline estrogen concentrations were

Association of Variants in Candidate Genes with Lipid Profiles in Women with Early Breast Cancer on Adjuvant Aromatase Inhibitor Therapy.

PURPOSE: Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors. EXPERIMENTAL DESIGN: We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models. RESULTS: A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053). CONCLUSIONS: Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy.

Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover.

Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (-3.2 %) compared to exemestane-treated patients (-1.0 %) (p = 0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane (p = 0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane-treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway.

Substantial effect of efavirenz monotherapy on bilirubin levels in healthy volunteers.

BACKGROUND: Efavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs. OBJECTIVES: To explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers. METHODS: Men and women (aged 18-49 years) with body mass index ≤32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported. RESULTS: Data from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by ~30%, with large intersubject variability) compared with screening values (P < 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r = 0.50; P < 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its effects on hemoglobin. CONCLUSIONS: Efavirenz monotherapy significantly lowers plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, probably through its effects on bilirubin metabolism and transport (uptake and efflux). These findings help explain reversal by efavirenz of hyperbilirubinemia induction observed by some protease inhibitor antiretroviral drugs (eg, atazanavir). Besides its well-documented role on drug interactions, efavirenz may alter the disposition of endogenous compounds relevant in physiologic homeostasis through its interaction with drug metabolizing enzymes and/or drug transporters. ClinicalTrials.gov identifier: NCT00668395.

Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer.

Up to 25 % of patients discontinue adjuvant aromatase inhibitor (AI) therapy due to intolerable symptoms. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity. We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor-positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane versus letrozole. Using multiple genetic models, we evaluated potential associations between discontinuation of AI therapy because of toxicity and 138 variants in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling. To account for multiple comparisons, statistical significance was defined as p < 0.00036. Of the 467 enrolled patients with available germline DNA, 152 (33 %) discontinued AI therapy because of toxicity. Using a recessive statistical model, an intronic variant in ESR1 (rs9322336) was associated with increased risk of musculoskeletal toxicity-related exemestane discontinuation [HR 5.0 (95 % CI 2.1-11.8), p < 0.0002]. An inherited variant potentially affecting estrogen signaling may be associated with exemestane-associated toxicity, which could partially account for intra-patient differences in AI tolerability. Validation of this finding is required.

Predictors of aromatase inhibitor discontinuation as a result of treatment-emergent symptoms in early-stage breast cancer.

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.

Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort.

Women with reduced CYP2D6 activity have low endoxifen concentrations and likely worse long term benefits from tamoxifen. We investigated the association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. We collected hot flash frequency and severity data over 12 months from 297 women initiating tamoxifen. We performed CYP2D6 genotyping using the AmpliChip CYP450 test and correlated inherited genetic polymorphisms in CYP2D6 and tamoxifen-induced hot flashes. Intermediate metabolizers had greater mean hot flash scores after 4 months of tamoxifen therapy (44.3) compared to poor metabolizers (20.6, P = 0.038) or extensive metabolizers (26.9, P = 0.011). At 4 months, we observed a trend toward fewer severe hot flashes in poor metabolizers compared to intermediate plus extensive metabolizers (P = 0.062). CYP2D6 activity may be a modest predictive factor for tamoxifen-induced hot flashes. The presence or absence of hot flashes should not be used to determine tamoxifen's efficacy.

Association of polymorphisms of angiogenesis genes with breast cancer.

BACKGROUND: Few studies have systematically explored a pathway approach: to test the association of multiple polymorphisms from multiple genes important to angiogenesis simultaneously with risk of breast cancer. We report our preliminary data evaluating the association of polymorphisms from seven genes known to influence angiogenesis with the likelihood of having breast cancer. METHODS: We recruited 715 controls and 520 subjects with breast cancer. Subjects provided a blood specimen and completed a questionnaire that included common breast cancer risk factors and breast cancer status. We evaluated candidate polymorphisms in the following genes: Hypoxia Inducible Factor-1 alpha (HIF1alpha), Vascular Endothelial Growth Factor (VEGF), VEGF Receptor 1 (VEGFR-1), VEGFR-2, endothelial Nitric Oxide Synthase (eNOS), Neuropilin-1 (NRP-1) and Neuropilin-2 (NRP-2). Testing for associations between each polymorphism and the presence or absence of breast cancer was performed. RESULTS: VEGF-2578 AA and -1498 CC genotypes were more common in cancer cases than controls (P = 0.06 and P = 0.04, respectively). These two genotypes remained significant predictors of breast cancer status after adjusting for non-genetic risk factors estimated by the Gail model (P = 0.03 and P = 0.03, respectively). When comparing women with invasive versus pre-invasive breast cancer, the eNOS-786 TT and eNOS 894 GG genotypes were associated with a greater likelihood of invasive disease and the eNOS 894 GG genotype was associated with a greater likelihood of having metastatic disease. CONCLUSION: 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.

Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications.

DNA polymorphisms have been identified in the genes encoding a number of the cytochrome P450 (CYP) enzymes, leading to wide interindividual variation in drug clearance. CYP2D6 metabolizes a significant number of clinically used medications, and genetic variants of the CYP2D6 isozyme that result in varying levels of metabolic activity are of clinical importance in some settings. The exact nature of the clinical effect caused by polymorphisms of the gene depends on the drug in question and the specific variant alleles expressed, as individual variants result in differing phenotypes with a range of levels of enzymatic activity. Compromised drug efficacy due to CYP2D6 variation has been documented with a variety of agents, and this review considers a number of examples, including the 5-HT(3)-receptor antagonists, which are used in oncology supportive care for the prophylaxis of nausea and vomiting. CYP2D6 is involved in the metabolism of all of the most commonly available agents, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism. Significant interethnic differences in CYP2D6 allele frequencies have been demonstrated from studies across many countries. However, incidences of polymorphisms in the U.S. population have been challenging to characterize because of the country's wide ethnic diversity. The CYP2D6 polymorphism may become more important as robust clinical tests become widely available and as the use of multiple medications and the attendant risk for drug-drug interactions increases.

Reduced pericardial levels of endostatin correlate with collateral development in patients with ischemic heart disease.

OBJECTIVES: We investigated whether pericardial levels of a pro-angiogenic factor (vascular endothelial growth factor, VEGF) or an anti-angiogenic factor (endostatin) related to the presence of coronary collateral circulation in patients with significant coronary artery disease (CAD). BACKGROUND: Coronary collateralization favorably alters the prognosis of patients with occlusive CAD. The specific factors that mediate and maintain collateral formation in coronary vessel occlusion are yet to be identified. METHODS: Coronary angiograms from 39 patients undergoing coronary artery bypass surgery were evaluated for the absence of collaterals (n = 20) or the presence of Rentrop classification grade 3 collaterals (n = 19). Pericardial fluid samples were obtained at the time of surgery and were assayed for the VEGF and endostatin by enzyme-linked immunosorbent assay comparing the two groups of patients. RESULTS: Vascular endothelial growth factor levels were not significantly different between the groups (28.86 +/- 4.67 pg/ml vs. 24.39 +/- 3.08 pg/ml, p = 0.43). However, pericardial fluid endostatin levels were nearly 40% lower in patients with grade 3 collateralization compared with those lacking angiographic evidence of collaterals (15.17 +/- 1.87 ng/ml vs. 24.25 +/- 2.08 ng/ml, p < 0.0025). CONCLUSIONS: Pericardial fluid levels of endostatin, but not VEGF, are associated with the presence or absence of collaterals in patients with CAD. These data suggest that the angiogenesis inhibitor endostatin levels may locally modulate coronary collateral formation.