Browsing by Author "Henry, N. Lynn"
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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 Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover(SpringerLink, 2015-11) Oesterreich, Steffi; Henry, N. Lynn; Kidwell, Kelley M.; Van Poznak, Catherine H.; Skaar, Todd C.; Dantzer, Jessica; Li, Lang; Hangartner, Thomas N.; Peacock, Munro; Nguyen, Anne T.; Rae, James M.; Desta, Zeruesenay; Philips, Santosh; Storniolo, Anna M.; Stearns, Vered; Hayes, Daniel F.; Flockhart, David A.; Medicine, School of MedicineAdjuvant 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.Item Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer(Springer, 2017-02) Robarge, Jason D.; Desta, Zereunesay; Nguyen, Anne T.; Li, Lang; Hertz, Daniel; Rae, James M.; Hayes, Daniel F.; Storniolo, Anna M.; Stearns, Vered; Flockhart, David A.; Skaar, Todd C.; Henry, N. Lynn; Medicine, School of MedicinePURPOSE: 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 wereItem ESR1 and PGR polymorphisms are associated with estrogen and progesterone receptor expression in breast tumors(American Physiological Society, 2016-09-01) Hertz, Daniel L.; Henry, N. Lynn; Kidwell, Kelley M.; Thomas, Dafydd; Goddard, Audrey; Azzouz, Faouzi; Speth, Kelly; Li, Lang; Banerjee, Mousumi; Thibert, Jacklyn N.; Kleer, Celina G.; Stearns, Vered; Hayes, Daniel F.; Skaar, Todd C.; Rae, James M.; Medicine, School of MedicineHormone receptor-positive (HR+) breast cancers express the estrogen (ERα) and/or progesterone (PgR) receptors. Inherited single nucleotide polymorphisms (SNPs) in ESR1, the gene encoding ERα, have been reported to predict tamoxifen effectiveness. We hypothesized that these associations could be attributed to altered tumor gene/protein expression of ESR1/ERα and that SNPs in the PGR gene predict tumor PGR/PgR expression. Formalin-fixed paraffin-embedded breast cancer tumor specimens were analyzed for ESR1 and PGR gene transcript expression by the reverse transcription polymerase chain reaction based Oncotype DX assay and for ERα and PgR protein expression by immunohistochemistry (IHC) and an automated quantitative immunofluorescence assay (AQUA). Germline genotypes for SNPs in ESR1 (n = 41) and PGR (n = 8) were determined by allele-specific TaqMan assays. One SNP in ESR1 (rs9322336) was significantly associated with ESR1 gene transcript expression (P = 0.006) but not ERα protein expression (P > 0.05). A PGR SNP (rs518162) was associated with decreased PGR gene transcript expression (P = 0.003) and PgR protein expression measured by IHC (P = 0.016), but not AQUA (P = 0.054). There were modest, but statistically significant correlations between gene and protein expression for ESR1/ERα and PGR/PgR and for protein expression measured by IHC and AQUA (Pearson correlation = 0.32–0.64, all P < 0.001). Inherited ESR1 and PGR genotypes may affect tumor ESR1/ERα and PGR/PgR expression, respectively, which are moderately correlated. This work supports further research into germline predictors of tumor characteristics and treatment effectiveness, which may someday inform selection of hormonal treatments for patients with HR+ breast cancer.Item Exemestane may be less detrimental than letrozole to bone health in women homozygous for the UGT2B17*2 gene deletion(Springer, 2019-02-12) Kamdem, Landry K.; Xi, Jingyue; Clark, Brandi L.; Gregory, Bryana J.; Kidwell, Kelley M.; Storniolo, Ana-Maria; Stearns, Vered; Hayes, Daniel F.; Gersch, Christina L.; Rae, James M.; Henry, N. Lynn; Hertz, Daniel L.; Medicine, School of MedicinePurpose: UGT2B17 gene deletion (UGT2B17*2) has been reported to affect bone health as well as the pharmacokinetics of aromatase inhibitor (AI) drugs such as exemestane. The goal of this study was to assess associations between UGT2B17 gene deletion and bone health prior to and after 24 months of AI treatment in postmenopausal women with hormone receptor positive (HR+) breast cancer. Methods: Bone health in women with HR+ breast cancer enrolled on the prospective randomized Exemestane and Letrozole Pharmacogenetics (ELPh) trial was determined by measuring bone turnover markers (BTM) and bone mineral density (BMD) pre-treatment and after 3 BTM and 24 BMD months of treatment with either the steroidal AI exemestane or the nonsteroidal AI letrozole. DNA samples were genotyped for UGT2B17*2. Results: Of the 455 subjects included in the analyses, 244 (53.6%) carried at least one copy of UGT2B17*2. UGT2B17*2 was associated with lower pre-treatment BMD at the hip (P = 0.01) and spine (P = 0.0076). Letrozole treatment was associated with a greater decrease in BMD of the hip (P = 0.03) and spine (P = 0.03) than exemestane. UGT2B17 genotype was not associated with changes in BMD from 24 months of AI treatment, though in UGT2B17*2 homozygous patients, there was a trend toward greater decreases in BMD of the spine from treatment with letrozole compared with exemestane (P = 0.05). Conclusion: UGT2B17*2 may be associated with lower baseline BMD in women with HR+ breast cancer. Exemestane is less detrimental to bone health than letrozole in postmenopausal women treated with AI, and this effect may be confined to patients carrying UGT2B17*2, though this finding requires independent validation.Item Genetic Associations With Toxicity-related Discontinuation of Aromatase Inhibitor Therapy for Breast Cancer(Breast Cancer Research and Treatment, 2013-04-02) Henry, N. Lynn; Skaar, Todd C.; Dantzer, Jessica; Li, Lang; Kidwell, Kelley; Gersch, Christina; Nguyen, Anne T.; Rae, James M.; Desta, Zeruesenay; Oesterreich, Steffi; Philips, Santosh; Carpenter, Janet S.; Storniolo, Anna M.; Stearns, Vered; Hayes, Daniel F.; Flockhart, David A.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.Item Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms.(Springer, 2022-07-01) Hertz, Daniel L.; Douglas, Julie A.; Miller, Robert M.; Kidwell, Kelley M.; Gersch, Christina L.; Desta, Zeruesenay; Storniolo, Anna Maria; Stearns, Vered; Skaar, Todd C.; Hayes, Daniel F.; Henry, N. Lynn; Rae, James M.OBJECTIVE: Aromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations. METHODS: In the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR + non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk. RESULTS: Four hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p value < 5 × 10(-8)), an intronic variant (rs79048288) within CCDC148 (HR = 4.42, 95% CI: 2.67-7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR = 0.30, 95% CI: 0.20-0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR = 5.91, 95% CI: 3.16-11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts. CONCLUSIONS: Our GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR + breast cancer.Item Genome-wide association study of letrozole plasma concentrations identifies non-exonic variants that may affect CYP2A6 metabolic activity.(Wolters Kluwer, 2021-07-01) Hertz, Daniel L.; Douglas, Julie A.; Kidwell, Kelley M.; Gersch, Christina L.; Desta, Zeruesenay; Storniolo, Ana-Maria; Stearns, Vered; Skaar, Todd C.; Hayes, Daniel F.; Henry, N. Lynn; Rae, James M.OBJECTIVES: Letrozole is a nonsteroidal aromatase inhibitor used to treat hormone-receptor-positive breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism, including cytochrome P450 2A6 (CYP2A6). The objective of this genome-wide association study (GWAS) was to identify polymorphisms associated with steady-state letrozole concentrations. METHODS: The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized postmenopausal patients with hormone-receptor-positive nonmetastatic breast cancer to letrozole or exemestane treatment. Germline DNA was collected pretreatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole (and exemestane) plasma concentrations via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array (>650 000 variants) followed by imputation. The association of each germline variant with age- and BMI-adjusted letrozole concentrations was tested in self-reported white patients via linear regression assuming an additive genetic model. RESULTS: There were 228 patients who met the study-specific inclusion criteria and had both DNA and letrozole concentration data for this GWAS. The association for one genotyped polymorphism (rs7937) with letrozole concentration surpassed genome-wide significance (P = 5.26 × 10-10), explaining 13% of the variability in untransformed steady-state letrozole concentrations. Imputation around rs7937 and in silico analyses identified rs56113850, a variant in the CYP2A6 intron that may affect CYP2A6 expression and activity. rs7937 was associated with age- and BMI-adjusted letrozole levels even after adjusting for genotype-predicted CYP2A6 metabolic phenotype (P = 3.86 × 10-10). CONCLUSION: Our GWAS findings confirm that steady-state letrozole plasma concentrations are partially determined by germline polymorphisms that affect CYP2A6 activity, including variants near rs7937 such as the intronic rs56113850 variant. Further research is needed to confirm whether rs56113850 directly affects CYP2A6 activity and to integrate nonexonic variants into CYP2A6 phenotypic activity prediction systems.Item Genotyping concordance in DNA extracted from formalinfixed paraffin embedded (FFPE) breast tumor and whole blood for pharmacogenetic analyses(Wiley, 2015-11) Hertz, Daniel L.; Kidwell, Kelley M.; Thibert, Jacklyn N.; Gersch, Christina; Regan, Meredith M.; Skaar, Todd C.; Henry, N. Lynn; Hayes, Daniel F.; Van Poznak, Catherine H.; Rae, James M.; Medicine, School of MedicineBackground: Cancer pharmacogenetic studies use archival tumor samples as a DNA source when germline DNA is unavailable. Genotyping DNA from formalin-fixed paraffin embedded tumors (FFPE-T) may be inaccurate due to FFPE storage, genetic aberrations, and/or insufficient DNA extraction. Our objective was to assess the extent and source of genotyping inaccuracy from FFPE-T DNA and demonstrate analytical validity of FFPE-T genotyping of candidate single nucleotide polymorphisms (SNPs) for pharmacogenetic analyses. Methods: Cancer pharmacogenetics SNPs were genotyped by Sequenom MassARRAYs in DNA harvested from matched FFPE-T, FFPE lymph node (FFPE-LN), and whole blood leukocyte samples obtained from breast cancer patients. No- and discordant-call rates were calculated for each tissue type and SNP. Analytical validity was defined as any SNP with <5% discordance between FFPE-T and blood and <10% discordance plus no-calls. Results: Matched samples from 114 patients were genotyped for 247 SNPs. No-call rate in FFPE-T was greater than FFPE-LN and blood (4.3% vs. 3.0% vs. 0.5%, p < 0.001). Discordant-call rate between FFPE-T and blood was very low, but greater than that between FFPE-LN and blood (1.1% vs. 0.3%, p < 0.001). Samples with heterozygous genotypes were more likely to be no- or discordantly-called in either tissue (p < 0.001). Analytical validity of FFPE-T genotyping was demonstrated for 218 (88%) SNPs. Conclusions: No- and discordant-call rates were below concerning thresholds, confirming that most SNPs can be accurately genotyped from FFPE-T on our Sequenom platform. FFPE-T is a viable DNA source for prospective-retrospective pharmacogenetic analyses of clinical trial cohorts.Item Patient-Reported Outcomes and Early Discontinuation in Aromatase Inhibitor-Treated Postmenopausal Women With Early Stage Breast Cancer(Alphamed Press, 2016-05) Kadakia, Kunal C.; Snyder, Claire F.; Kidwell, Kelley M.; Seewald, Nicholas J.; Flockhart, David A.; Skaar, Todd C.; Desta, Zereunesay; Rae, James M.; Otte, Julie L.; Carpenter, Janet S.; Storniolo, Anna M.; Hayes, Daniel F.; Stearns, Vered; Henry, N. Lynn; Department of Medicine, School of MedicineBACKGROUND: Early discontinuation of aromatase inhibitors (AIs) is common and leads to poor outcomes but is challenging to predict. In the Exemestane and Letrozole Pharmacogenetics trial, a high rate of early discontinuation due to intolerance was observed. We hypothesized that early changes in patient-reported outcomes (PROs) predict AI discontinuation and that biochemical factors are associated with changes in PROs. PATIENTS AND METHODS: Postmenopausal women with early-stage breast cancer enrolled in a prospective randomized trial of exemestane versus letrozole completed questionnaires at baseline and serially over 24 months to assess overall quality of life (EuroQOL Visual Analog Scale [VAS]); mood; and multiple symptoms, including a musculoskeletal symptom cluster. A joint mixed-effects/survival model was used to estimate the effect of the change in PROs on AI discontinuation. Associations between biochemical factors and change in PROs were examined. RESULTS: A total of 490 patients were analyzed. Worsening of EuroQOL VAS and the musculoskeletal cluster were associated with the highest risk for early discontinuation (hazard ratio [HR], 2.77 [95% confidence interval (CI), 2.72-2.81; p = .015]; HR, 4.39 [95% CI, 2.40-8.02; p < .0001], respectively). Pharmacokinetics and estrogen metabolism were not consistently associated with change in PRO measures. No clinically significant differences in any PRO between AIs were observed. CONCLUSION: Changes in PROs early during AI therapy were associated with treatment discontinuation. Identification of these changes could be used to target interventions in patients at high risk for early discontinuation. IMPLICATIONS FOR PRACTICE: Early changes in patient-reported outcomes (PROs) can predict nonpersistence to aromatase inhibitor therapy. If used in clinical practice, PROs might identify women at highest risk for early discontinuation and allow for interventions to improve tolerance before significant toxicities develop. Further research is needed to improve capturing PROs in routine clinical practice.