Browsing by Subject "Aromatase inhibitor"

Now showing 1 - 6 of 6
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    The decision making process in women diagnosed with estrogen receptor-positive breast cancer experiencing side effects related to oral endocrine therapy
    (2017-02-06) Milata, Jennifer Lynn; Carpenter, Janet S.; Draucker, Claire Burke; Otte, Julie; Zimet, Greg
    Oral endocrine therapy (OET) is standard therapy for millions of estrogen receptor-positive breast cancer survivors (ER+BCS). OET reduces recurrence, mortality, and metastasis. ER+BCS often do not take their OET as recommended due to adverse side effects. The purpose of this dissertation was to develop an explanatory framework of decision making by women with ER+ breast cancer who report experiencing side effects from OET. This project was comprised of two components. The first component was a systematic review with three main findings: (1) side effects negatively impact OET non-adherence, (2) there is an absence of decisional supports provided to or available for ER+BCS who are experiencing OET side effects,, and (3) ER+BCS likely have unmet decisional needs related to OET. The second component was a grounded theory study that included 31 ER+BCS reporting OET side effects. During a single semi-structured interview, participants described the experience of OET over time. This study produced two qualitatively derived projects. First, a theoretical framework was developed that depicted four stages through which the experience of OET decision making unfolded. The stages were (1) being told what I need to do to live, (2) doing what I need to do to live, (3) enduring what I need to do to live, and (4) deciding how I want to live. Second, a typology was developed that depicted six sources of external decisional supports (healthcare providers, husbands, other breast cancer survivors, friends and family, the internet and other media sources, and God) that met four types of decisional needs (information about OET and its side effects, in-depth discussions about side effects, help in managing side effects, and emotional support). Findings can be used to develop interventions, such as decision aids, to promote quality decision making in women experiencing OET side effects.
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    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.
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    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.
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    A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β
    (Elsevier, 2016-11-01) Zhao, Li-Ming; Jin, Hai-Shan; Liu, Jinzhong; Skaar, Todd C.; Ipe, Joseph; Lv, Wei; Flockhart, David A.; Cushman, Mark; Medicine, School of Medicine
    The design and synthesis of dual aromatase inhibitors/selective estrogen receptor modulators (AI/SERMs) is an attractive strategy for the discovery of new breast cancer therapeutic agents. Previous efforts led to the preparation of norendoxifen (4) derivatives with dual aromatase inhibitory activity and estrogen receptor binding activity. In the present study, some of the structural features of the potent AI letrozole were incorporated into the lead compound (norendoxifen) to afford a series of new dual AI/SERM agents based on a symmetrical diphenylmethylene substructure that eliminates the problem of E,Z isomerization encountered with norendoxifen-based AI/SERMs. Compound 12d had good aromatase inhibitory activity (IC50 = 62.2 nM) while also exhibiting good binding activity to both ER-α (EC50 = 72.1 nM) and ER-β (EC50 = 70.8 nM). In addition, a new synthesis was devised for the preparation of norendoxifen and its analogues through a bis-Suzuki coupling strategy.,
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    Patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor therapy
    (Wiley, 2014-08-15) Kidwell, Kelley M.; Harte, Steven E.; Hayes, Daniel F.; Storniolo, Anna Maria; Carpenter, Janet; Flockhart, David A.; Stearns, Vered; Clauw, Daniel J.; Williams, David A.; Henry, N. Lynn; Department of Medicine, IU School of Medicine
    BACKGROUND: Aromatase inhibitor (AI) therapy results in substantial survival benefits for patients with hormone receptor-positive breast cancer. The rates of poor adherence and discontinuation of AI therapy are high, primarily because of treatment-related toxicities like musculoskeletal pain. Although pain-related symptoms may worsen during AI therapy, the authors hypothesized that nonpersistence with AI therapy was associated with symptoms that were present before treatment initiation. METHODS: Postmenopausal women initiating AI therapy who were enrolled in a prospective clinical trial completed questionnaires at baseline to assess sleep, fatigue, mood, and pain. Reasons for treatment discontinuation during the first year of treatment were recorded. Associations between baseline patient-reported symptoms and treatment discontinuation because of toxicity were identified using logistic regression. RESULTS: Four hundred forty-nine patients were evaluable. The odds of treatment discontinuation were higher in patients who reported a greater number of symptoms before AI initiation. Baseline poor sleep quality was associated with early treatment discontinuation, with an odds ratio (OR) of 1.91 (95% confidence interval [CI], 1.26-2.89; P = .002). Baseline presence of tired feeling and forgetfulness had similar ORs for discontinuation (tired feeling: OR, 1.76; 95% CI, 1.15-2.67; P = .009; forgetfulness: OR, 1.66; 95% CI, 1.11-2.48; P = .015). An increasing total number of baseline symptoms was associated with an increased likelihood of treatment discontinuation, with an OR of 1.89 (95% CI, 1.20-2.96; P = .006) for 3 to 5 symptoms versus 0 to 2 symptoms. CONCLUSIONS: Symptom clusters in breast cancer survivors that are present before the initiation of adjuvant AI therapy may have a negative impact on a patient's persistence with therapy. Interventions to manage these symptoms may improve breast cancer outcomes and quality of life.
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    Variable Aromatase Inhibitor Plasma Concentrations Do Not Correlate with Circulating Estrogen Concentrations in Post-Menopausal Breast Cancer Patients
    (SpringerLink, 2017-10) Hertz, Daniel L.; Speth, Kelly A.; 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.; Medicine, School of Medicine
    Purpose: The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Methods: Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. Results: Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05). Conclusions: Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.