Browsing by Subject "Tamoxifen"
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Item Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort(Springer, 2009-10) Henry, N. Lynn; Rae, James M.; Li, Lang; Azzouz, Faouzi; Skaar, Todd C.; Desta, Zereunesay; Sikora, Matthew J.; Philips, Santosh; Nguyen, Anne T.; Storniolo, Anna Maria; Hayes, Daniel F.; Flockhart, David A.; Stearns, VeredWomen 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.Item BreastDefend enhances effect of tamoxifen in estrogen receptor-positive human breast cancer in vitro and in vivo(BioMed Central, 2017-02-16) Cheng, Shujie; Castillo, Victor; Welty, Matt; Alvarado, Mark; Eliaz, Isaac; Temm, Constance J.; Sandusky, George E.; Sliva, Daniel; Department of Pathology and Laboratory Medicine, IU School of MedicineBACKGROUND: Tamoxifen (TAM) has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer and its combination with other therapies is being actively investigated as a way to increase efficacy and decrease side effects. Here, we evaluate the therapeutic potential of co-treatment with TAM and BreastDefend (BD), a dietary supplement formula, in ER-positive human breast cancer. METHODS: Cell proliferation and apoptosis were determined in ER-positive human breast cancer cells MCF-7 by MTT assay, quantitation of cytoplasmic histone-associated DNA fragments and expression of cleaved PARP, respectively. The molecular mechanism was identified using RNA microarray analysis and western blotting. Tumor tissues from xenograft mouse model were analyzed by immunohistochemistry. RESULTS: Our data clearly demonstrate that a combination of 4-hydroxytamoxifen (4-OHT) with BD lead to profound inhibition of cell proliferation and induction of apoptosis in MCF-7 cells. This effect is consistent with the regulation of apoptotic and TAM resistant genes at the transcription and translation levels. Importantly, TAM and BD co-treatment significantly enhanced apoptosis, suppressed tumor growth and reduced tumor weight in a xenograft model of human ER-positive breast cancer. CONCLUSION: BD sensitized ER-positive human breast cancer cells to 4-OHT/TAM treatment in vitro and in vivo. BreastDefend can be used in an adjuvant therapy to increase the therapeutic effect of tamoxifen in patients with ER-positive breast cancer.Item CYP2D6 Genotype is Not Associated with Survival in Breast Cancer Patients Treated with Tamoxifen: Results from a Population-based Study(SpringerLink, 2017-11) Hertz, D.L.; Kidwell, K.M.; Hilsenbeck, S.G.; Oesterreich, S.; Philips, S.; Chenault, C.; Hartmaier, R.J.; Skaar, Todd C.; Sikora, M.J.; Rae, J.M.; Medicine, School of MedicinePurpose: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. Methods: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41, and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (AS = 0) phenotype were compared to patients with AS > 0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). Results: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p > 0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio 1.43, 95% confidence interval 1.00-2.04, p = 0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS > 0, were associated with superior RFS (each p = 0.0015). Conclusions: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.Item Cytochrome P450 2D6 activity predicts discontinuation of tamoxifen therapy in breast cancer patients(Springer Nature, 2009-08) Rae, J. M.; Sikora, M. J.; Henry, N. L.; Li, L.; Kim, S.; Oesterreich, S.; Skaar, Todd C.; Nguyen, A. T.; Desta, Z.; Storniolo, A. M.; Flockhart, David A.; Hayes, D. F.; Stearns, V.The selective estrogen receptor modulator tamoxifen is routinely used for treatment and prevention of estrogen-receptor-positive breast cancer. Studies of tamoxifen adherence suggest that over half of patients discontinue treatment before the recommended 5 years. We hypothesized that polymorphisms in CYP2D6, the enzyme responsible for tamoxifen activation, predict for tamoxifen discontinuation. Tamoxifen-treated women (n=297) were genotyped for CYP2D6 variants and assigned a ‘score’ based on predicted allele activities from 0 (no activity) to 2 (high activity). Correlation between CYP2D6 score and discontinuation rates at 4 months was tested. We observed a strong nonlinear correlation between higher CYP2D6 score and increased rates of discontinuation (r2=0.935, P=0.018). These data suggest that presence of active CYP2D6 alleles may predict for higher likelihood of tamoxifen discontinuation. Therefore, patients who may be most likely to benefit from tamoxifen may paradoxically be most likely to discontinue treatment prematurely.Item Disclosure and rationality: comparative risk information and decision-making about prevention(Theoretical medicine and bioethics, 2009) Schwartz, Peter H.With the growing focus on prevention in medicine, studies of how to describe risk have become increasing important. Recently, some researchers have argued against giving patients "comparative risk information," such as data about whether their baseline risk of developing a particular disease is above or below average. The concern is that giving patients this information will interfere with their consideration of more relevant data, such as the specific chance of getting the disease (the "personal risk"), the risk reduction the treatment provides, and any possible side effects. I explore this view and the theories of rationality that ground it, and I argue instead that comparative risk information can play a positive role in decision-making. The criticism of disclosing this sort of information to patients, I conclude, rests on a mistakenly narrow account of the goals of prevention and the nature of rational choice in medicine.Item Estrogen receptor genotypes influence hot flash prevalence and composite score before and after tamoxifen therapy.(ASCO, 2008-12-20) Jin, Yan; Hayes, Daniel F.; Li, Lang; Robarge, Jason D.; Skaar, Todd C.; Philips, Santosh; Nguyen, Anne; Schott, Anne; Hayden, Jill; Lemler, Suzanne; Storniolo, Anna Maria; Flockhart, David A.; Stearns, VeredPURPOSE: Hot flashes are common and frequently lead to drug discontinuation among women prescribed tamoxifen. We determined whether genetic polymorphisms in estrogen receptors (ESRs) alpha and beta (ESR1 and ESR2, respectively) are associated with tamoxifen-induced hot flashes. PATIENTS AND METHODS: We determined ESR1 PvuII and XbaI and ESR2-02 genotypes in 297 women who were initiating tamoxifen. One-week hot flash diaries were collected to calculate a hot flash score (frequency x severity) before and 1, 4, 8, and 12 months after starting tamoxifen. RESULTS: Approximately 80% of 297 participants reported hot flashes before or during the first year of tamoxifen. After 4 months of tamoxifen, premenopausal women who did not receive adjuvant chemotherapy had a four-fold increase in hot flash score (from 5.9 to 23.6; P = .003) compared with a 1.17-fold increase (from 19.6 to 23; P = .34) in those who received chemotherapy. In premenopausal women, increased number of ESR1 PvuII and XbaI CG alleles was associated with higher baseline hot flash scores compared with those who had other haplotypes (P = .0026). At 4 months, postmenopausal women with ESR1 PvuII CC and ESR2-02 GG genotypes had 4.6 times increases in hot flash scores than other postmenopausal women (56 v 12; P = .0007). Women who had the ESR2-02 AA genotype were significantly less likely to experience tamoxifen-induced hot flashes than women who carried at least one ESR-02 G allele (hazard ratio, 0.26; 95% CI, 0.10 to 0.63; P = .001). CONCLUSION: Knowledge of menopausal status, prior chemotherapy, and ESR genotype may help predict which women are most likely to suffer hot flashes during tamoxifen treatment.Item Estrogen receptor genotypes, menopausal status, and the effects of tamoxifen on lipid levels: revised and updated results.(Clinical pharmacology and therapeutics, 2010-11) Hayes, D.F.; Skaar, Todd C.; Rae, J.M.; Henry, N.L.; Nguyen, A.T.; Stearns, V.; Li, L.; Philips, S.; Desta, Z.; Flockhart, D.A.We previously reported that the ESR1 XbaI genotypes were associated with baseline and tamoxifen-induced serum lipid profiles. The analysis in that study was carried out by PCR followed by restriction-enzyme digestion. After reanalysis using more robust TaqMan assays, the findings related to ~10% of the genotypes for the ESR1 XbaI single-nucleotide polymorphism (SNP) were revised. For the other genotypes (i.e., ESR1 PvuII, ESR2, and CYP2D6), the results were nearly identical to those in the previous study. Upon reanalysis, previously reported associations between the ESR1 Xba1 genotypes and baseline triglyceride and low-density lipoprotein (LDL) cholesterol levels were no longer observed. Previously reported associations between the ESR1 XbaI genotypes and tamoxifen-induced changes in levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were also no longer observed. However, the following observations from the original report did not change: (i) the levels of circulating lipids are lower in women taking tamoxifen; (ii) there is an association between the ESR2-02 genotypes and changes in triglyceride levels; and (iii) neither ESR1 PvuII nor CYP2D6 is associated with any changes in serum lipid concentrations in patients receiving treatment with tamoxifen.Item The ethics of CYP2D6 testing for patients considering tamoxifen(BioMed Central, 2007-04-13) Hartman, Anne-Renee; Helft, Paul; Medicine, School of MedicineThe CYP2D6 gene is responsible for the majority of tamoxifen metabolism. Recent compelling, yet limited data have determined that postmenopausal women who carry a functional polymorphism in the CYP2D6 gene have a worse clinical outcome than women who have a wild-type genotype. In this commentary we discuss the level of evidence needed to change clinical practice and whether CYP2D6 genotyping is appropriate for all women considering tamoxifen as part of their adjuvant therapy.Item Lack of association between oestrogen receptor polymorphisms and change in bone mineral density with tamoxifen therapy.(Springer Nature, 2010-01-19) Henry, N. L.; Nguyen, A.; Azzouz, F.; Li, L.; Robarge, J.; Philips, S.; Cao, D.; Skaar, Todd C.; Rae, J. M.; Storniolo, A. M.; Flockhart, David A.; Hayes, D. F.; Stearns, V.BACKGROUND: Tamoxifen, a selective oestrogen receptor (ER) modulator, increases bone mineral density (BMD) in postmenopausal women and decreases BMD in premenopausal women. We hypothesised that inherited variants in candidate genes involved in oestrogen signalling and tamoxifen metabolism might be associated with tamoxifen effects in bone. METHODS: A total of 297 women who were initiating tamoxifen therapy were enrolled in a prospective multicentre clinical trial. Lumbar spine and total hip BMD values were measured using dual-energy X-ray absorptiometry (DXA) at baseline and after 12 months of tamoxifen therapy. Single-nucleotide polymorphisms (SNPs) in ESR1, ESR2, and CYP2D6 were tested for associations in the context of menopausal status and previous chemotherapy, with a mean percentage change in BMD over 12 months. RESULTS: The percentage increase in BMD was greater in postmenopausal women and in those patients who had been treated with chemotherapy. No significant associations between tested SNPs and either baseline BMD or change in BMD with 1 year of tamoxifen therapy were detected. CONCLUSION: The evaluated SNPs in ESR and CYP2D6 do not seem to influence BMD in tamoxifen-treated subjects.Item The Oral Endocrine Therapy Decision Making Process in Women with Breast Cancer(Office of the Vice Chancellor for Research, 2016-04-08) Milata, Jennifer L.; Burke Draucker, Claire; Carpenter, Janet S.Background: Oral endocrine therapy (OET) is life-saving for women with estrogen receptorpositive (ER+) breast cancer because it reduces the incidence of recurrence and mortality. An estimated 75% of women with breast cancer receive a recommendation for life-saving OET such as Tamoxifen or aromatase inhibitors. OET adherence is not a single event decision, but rather is a psychosocial process unfolding over time involving an initial decision to initiate therapy or not, and for those who do initiate OET, several additional decisions. Our understanding of OET decision making is limited, but non-adherence is a common response to OET side effects. By obtaining first-person narratives from women who have been prescribed OET and report experiencing side effects, an explanatory framework can be developed that describes their decision making processes. Purpose: The purpose of this grounded theory study is to develop an explanatory framework of decision making by women with ER+ breast cancer who report experiencing OET side effects. Aims: Specific aims are (1) describe responses to side effects among women with ER+ breast cancer, (2) identify common decisional needs of women with ER+ breast cancer who report experiencing OET side effects, (3) identify common decisional supports sought by and provided to women with ER+ breast cancer who report experiencing OET side effects, and (4) describe how women with ER+ breast cancer who report experiencing OET side effects make decisions about initiating, continuing, switching, and/or discontinuing OET. Methods: In this study, 30 women with ER+ breast cancer who report experiencing OET side effects will take part in a single, face-to-face, audio-recorded interview. Demographic and breast cancer treatment information will be collected and then analyzed using descriptive statistics. A constant comparative method of inductive and deductive processes will be used to discover common patterns and variations in the narrative data. The final products of the analysis will include typologies of responses to side effects, common decisional needs, and common decisional support as well as a framework of common trajectories of decision making related to OET in women who report experiencing side effects. Findings: Findings to date will be discussed