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Browsing by Author "Philips, S."
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Item Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects(NPG - Nature Publishing Group, 2013-10-29) Henry, N. L.; Chan, H-P; Dantzer, J.; Goswami, C. P.; Li, L.; Skaar, Todd C.; Rae, J. M.; Desta, Z.; Khouri, N.; Pinsky, R.; Oesterreich, S.; Zhou, C.; Hadjiiski, L.; Philips, S.; Robarge, J.; Nguyen, A. T.; Storniolo, A. M.; Flockhart, D. A.; Hayes, D. F.; Helvie, M. A.; Stearns, V.; Department of Medicine, School of MedicineBackground: Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy. Methods: Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment. Results: Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ⩾20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed. Conclusion: Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.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 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 Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group.(Springer, 2011-10) Yoon, H.H.; Catalano, P.; Gibson, M.K.; Skaar, Todd C.; Philips, S.; Montgomery, E.A.; Hafez, M.J.; Powell, M.; Liu, G.; Forastiere, A.A.; Benson, A.B.; Kleinberg, L.R.; Murphy, K.M.PURPOSE: Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy. METHODS: In a multicenter clinical trial (E1201), 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification. RESULTS: Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5' flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression. CONCLUSIONS: This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.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 A SNP in Steroid Receptor Coactivator-1 Disrupts a GSK3β Phosphorylation Site and Is Associated with Altered Tamoxifen Response in Bone(Oxford University Press, 2012-02) Hartmaier, R.J.; Richter, A.S.; Gillihan, R.M.; Sallit, J.Z.; McGuire, S.E.; Wang, J.; Lee, A.V.; Osborne, C.K.; O'Malley, B.W.; Brown, P.H.; Xu, J.; Skaar, Todd C.; Philips, S.; Rae, J.M.; Azzouz, F.; Li, L.; Hayden, J.; Henry, N.L.; Nguyen, A.T.; Stearns, V.; Hayes, D.F.; Flockhart, D.A.; Oesterreich, S.The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)β phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3β increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3β-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3β phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.