Browsing by Subject "Receptors, Estrogen"
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Item Open Access Adherence to Adjuvant Endocrine Therapy in Insured Black and White Breast Cancer Survivors: Exploring Adherence Measures in Patient Data.(Journal of managed care & specialty pharmacy, 2019-05) Sheppard, Vanessa B; He, Jun; Sutton, Arnethea; Cromwell, Lee; Adunlin, Georges; Salgado, Teresa M; Tolsma, Dennis; Trout, Martha; Robinson, Brandi E; Edmonds, Megan C; Bosworth, Hayden B; Tadesse, Mahlet GBackground
Adjuvant endocrine therapy (AET) is a critical therapy in that it improves survival in women with hormone receptor-positive (HR+) breast cancer (BC), but adherence to AET is suboptimal. The purpose of this study was to fill scientific gaps about predictors of adherence to AET among black and white women diagnosed with BC.Objective
To assess AET adherence in black and white insured women using multiple measures, including one that uses an innovative statistical approach.Methods
Black and white women newly diagnosed with HR+ BC were identified from 2 health maintenance organizations. Pharmacy records captured the type of oral AET prescriptions and all fill dates. Multivariable logistic regression was used to identify predictors of adherence defined in terms of proportion of days covered (PDC; ≥ 80%) and medication gap of ≤ 10 days. A zero-inflated negative binomial (ZINB) regression model was used to identify variables associated with the total number of days of medication gaps.Results
1,925 women met inclusion criteria. 80% were PDC adherent (> 80%); 44% had a medication gap of ≤ 10 days; and 24% had no medication gap days. Race and age were significant in all multivariable models. Black women were less likely to be adherent based on PDC than white women (OR = 0.72, 95% CI = 0.57-0.90, P < 0.01), and they were less likely to have a medication gap of ≤ 10 days (OR = 0.65, 95% CI = 0.54-0.79, P < 0.001). Women aged 25-49 years were less likely to be PDC adherent than women aged 65-93 years (OR = 0.65, 95% CI = 0.48-0.87, P < 0.001). In the ZINB model, women were without their medication for an average of 37 days (SD = 50.5).Conclusions
Racial disparities in adherence to AET in the study highlight a need for interventions among insured women. Using various measures of adherence may help better understand this multidimensional concept. There might be benefits from using both more common dichotomous measures (e.g., PDC) and integrating novel statistical approaches to allow tailoring adherence to patterns within a specific sample.Disclosures
This research was funded by the National Institutes of Health (R01CA154848). It was also supported in part by the NIH-NCI Cancer Center Support Grant P30 CA016059, the Laboratory of Telomere Health P30 CA51008, and the TSA Award No. UL1TR002649 from the National Center for Advancing Translational Sciences. The contents of this study are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Bosworth reports grants from Sanofi, Otsuka, Johnson & Johnson, and Blue Cross/Blue Shield of NC and consulting fees from Sanofi and Otsuka. The other authors have nothing to disclose. The datasets generated during and/or analyzed during the current study are not publicly available due to privacy reasons but are available from the corresponding author on reasonable request. The author does not own these data. Data use was granted to the author as part of a data use agreement between specific agencies and organizations.Item Open Access Breast cancer as heterogeneous disease: contributing factors and carcinogenesis mechanisms.(Breast Cancer Res Treat, 2011-07) Kravchenko, Julia; Akushevich, Igor; Seewaldt, Victoria L; Abernethy, Amy P; Lyerly, H KimThe observed bimodal patterns of breast cancer incidence in the U.S. suggested that breast cancer may be viewed as more than one biological entity. We studied the factors potentially contributing to this phenomenon, specifically focusing on how disease heterogeneity could be linked to breast carcinogenesis mechanisms. Using empirical analyses and population-based biologically motivated modeling, age-specific patterns of incidence of ductal and lobular breast carcinomas from the SEER registry (1990-2003) were analyzed for heterogeneity and characteristics of carcinogenesis, stratified by race, stage, grade, and estrogen (ER)/progesterone (PR) receptor status. The heterogeneity of breast carcinoma age patterns decreased after stratification by grade, especially for grade I and III tumors. Stratification by ER/PR status further reduced the heterogeneity, especially for ER(+)/PR(-) and ER(-)/(-) tumors; however, the residual heterogeneity was still observed. The number of rate-limiting events of carcinogenesis and the latency of ductal and lobular carcinomas differed, decreasing from grade I to III, with poorly differentiated tumors associated with the least number of carcinogenesis stages and the shortest latency. Tumor grades play important role in bimodal incidence of breast carcinoma and have distinct mechanisms of carcinogenesis. Race and cancer subtype could play modifying role. ER/PR status contributes to the observed heterogeneity, but is subdominant to tumor grade. Further studies on sources of "remaining" heterogeneity of population with breast cancer (such as genetic/epigenetic characteristics) are necessary. The results of this study could suggest stratification rather than unification of breast cancer prevention strategies, risk assessment, and treatment.Item Open Access CCDC62/ERAP75 functions as a coactivator to enhance estrogen receptor beta-mediated transactivation and target gene expression in prostate cancer cells.(Carcinogenesis, 2009-05) Chen, Ming; Ni, Jing; Chang, Hong-Chiang; Lin, Chen-Yong; Muyan, Mesut; Yeh, ShuyuanHuman prostate cancer (PCa) and prostate epithelial cells predominantly express estrogen receptor (ER) beta, but not ERalpha. ERbeta might utilize various ER coregulators to mediate the E2-signaling pathway in PCa. Here, we identified coiled-coil domain containing 62 (CCDC62)/ERAP75 as a novel ER coactivator. CCDC62/ERAP75 is widely expressed in PCa cell lines and has low expression in MCF7 cells. Both in vitro and in vivo interaction assays using mammalian two-hybrid, glutathione S-transferase pull-down and coimmunoprecipitation methods proved that ERbeta can interact with the C-terminus of CCDC62/ERAP75 via the ligand-binding domain. The first LXXLL motif within CCDC62/ERAP75 is required for the interaction between ERbeta and CCDC62/ERAP75. Electrophoretic mobility shift assay showed that CCDC62/ERAP75 can be recruited by the estrogen response element-ER complex in the presence of ligand. Furthermore, a chromatin immunoprecipitation assay demonstrated the hormone-dependent recruitment of CCDC62/ERAP75 within the promoter of the estrogen-responsive gene cyclin D1. In addition, using silencing RNA (siRNA) against endogeneous CCDC62/ERAP75, we demonstrated that inhibition of endogenous CCDC62/ERAP75 results in the suppression of ERbeta-mediated transactivation as well as target gene expression in LNCaP cells. More importantly, using the tet-on overexpression system, we showed that induced expression of CCDC62/ERAP75 can enhance the E2-regulated cyclin D1 expression and cell growth in LNCaP cells. Together, our results revealed the role of CCDC62/ERAP75 as a novel coactivator in PCa cells that can modulate ERbeta transactivation and receptor function.Item Open Access E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group.(Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2021-10) Connolly, Roisin M; Zhao, Fengmin; Miller, Kathy D; Lee, Min-Jung; Piekarz, Richard L; Smith, Karen L; Brown-Glaberman, Ursa A; Winn, Jennifer S; Faller, Bryan A; Onitilo, Adedayo A; Burkard, Mark E; Budd, George T; Levine, Ellis G; Royce, Melanie E; Kaufman, Peter A; Thomas, Alexandra; Trepel, Jane B; Wolff, Antonio C; Sparano, Joseph APurpose
Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.Patients and methods
E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15.Results
Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients.Conclusion
The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.Item Open Access Early and Locally Advanced Metaplastic Breast Cancer: Presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 2010-2014.(The oncologist, 2018-04) Schroeder, Mary C; Rastogi, Priya; Geyer, Charles E; Miller, Lance D; Thomas, AlexandraBackground
Metaplastic breast cancer (MBC) is a rare disease subtype characterized by an aggressive clinical course. MBC is commonly triple negative (TN), although hormone receptor (HR) positive and human epidermal growth receptor 2 (HER2) positive cases do occur. Previous studies have reported similar outcomes for MBC with regard to HR status. Less is known about outcomes for HER2 positive MBC.Materials and methods
Surveillance, Epidemiology, and End Results Program data were used to identify women diagnosed 2010-2014 with MBC or invasive ductal carcinoma (IDC). Kaplan-Meier curves estimated overall survival (OS) and multivariate Cox models were fitted. For survival analyses, only first cancers were included, and 2014 diagnoses were excluded to allow for sufficient follow-up.Results
Our MBC sample included 1,516 women. Relative to women with IDC, women with MBC were more likely to be older (63 vs. 61 years), black (16.0% vs. 11.1%), and present with stage III disease (15.6% vs. 10.8%). HER2 positive and HER2 negative/HR positive MBC tumors represented 5.2% and 23.0% of cases. For MBC overall, 3-year OS was greatest for women with HER2 positive MBC (91.8%), relative to women with TN (75.4%) and HER2 negative/HR positive MBC (77.1%). This difference was more pronounced for stage III MBC, for which 3-year OS was 92.9%, 47.1%, and 42.2% for women with HER2 positive, TN, and HER2 negative/HR positive MBC, respectively. A multivariate Cox model of MBC demonstrated that HER2 positive tumors (relative to TN) were associated with improved survival (hazard ratio = 0.32, 95% confidence interval [CI] 0.13-0.79). In a second Cox model of exclusively HER2 positive tumors, OS did not differ between MBC and IDC disease subtypes (hazard ratio = 1.16, 95% CI 0.48-2.81).Conclusion
In this contemporary, population-based study of women with MBC, HER2 but not HR status was associated with improved survival. Survival was similar between HER2 positive MBC and HER2 positive IDC. This suggests HER2 positive MBC is responsive to HER2-directed therapy, a finding that may offer insights for additional therapeutic approaches to MBC.Implications for practice
This population-based study reports recent outcomes, by receptor status, for women with metaplastic breast cancer. Survival in metaplastic breast cancer is not impacted by hormone receptor status. To the authors' knowledge, this is the first report indicating that women with human epidermal growth receptor 2 (HER2) positive metaplastic breast cancer have survival superior to women with HER2 negative metaplastic breast cancer and survival similar to women with HER2 positive invasive ductal carcinoma. This information can be used for counseling patients diagnosed with metaplastic breast cancer. Further understanding of HER2 positive metaplastic breast cancer could offer insights for the development of therapeutic approaches to metaplastic breast cancer more broadly.Item Open Access Incidence and Survival by Human Epidermal Growth Factor Receptor 2 Status in Young Women With Stage I-III Breast Cancer: SEER, 2010-2016.(Clinical breast cancer, 2020-08) Thomas, Alexandra; Rhoads, Anthony; Suhl, Jonathan; Conway, Kristin M; Hundley, William G; McNally, Lacey R; Oleson, Jacob; Melin, Susan A; Lynch, Charles F; Romitti, Paul ABackground
Young premenopausal women with breast cancer often experience more aggressive disease biology and poorer survival than older women. Diagnostic and therapeutic advances, including human epidermal growth factor receptor 2 (HER2)-directed therapy, may lessen treatment burden and improve survival for these young women, but contemporary incidence and survival data by HER2 status are limited.Patients and methods
We identified women aged 20-49 years (n = 68,530) diagnosed with stage I-III breast cancer during 2010-2016 from the United States Surveillance, Epidemiology, and End Results 18 registries database. Age-adjusted average annual percent changes in incidence (diagnosis 2010-2016) and 5-year Kaplan-Meier survival curves (diagnosis 2010-2015) were estimated by HER2 and hormone receptor (HR) status and stratified independently by cancer stage and race/ethnicity.Results
With increasing age decade, proportions of HER2-/HR+ cancer increased, whereas proportions of HER2+/HR+, HER2+/HR-, and HER2-/HR- decreased. The greatest increases in incidence during 2010-2016 were observed for HER2+ among women aged 20-49 years and HER2-/HR- among women aged 20-29 years. Incidence decreased for HER2-/HR- among women aged 40-49 years. Five-year survival was lowest for HER2-/HR- status compared to other receptor-based subtypes among women aged 20-49 years. HER2+ status was more beneficial for 5-year survival than HR+ status among women aged 20-29 years, with the opposite observed among women aged 30-49 years, particularly those aged 40-49 years.Conclusion
HER2+ breast cancer increased among premenopausal women and was also associated with higher early survival within each HR status. HER2-/HR- cancer also increased among women aged 20-29 years and was associated with lower early survival. Our contemporary data provide important insights to help inform preventive and therapeutic strategies for premenopausal women.Item Open Access Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.(The Journal of clinical investigation, 2021-12) Chakraborty, Binita; Byemerwa, Jovita; Shepherd, Jonathan; Haines, Corinne N; Baldi, Robert; Gong, Weida; Liu, Wen; Mukherjee, Debarati; Artham, Sandeep; Lim, Felicia; Bae, Yeeun; Brueckner, Olivia; Tavares, Kendall; Wardell, Suzanne E; Hanks, Brent A; Perou, Charles M; Chang, Ching-Yi; McDonnell, Donald PImmune checkpoint blockade (ICB) therapies have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, sex-specific differences in response to ICB have been observed, with males receiving a greater benefit from ICB than females, although the mechanism or mechanisms underlying this difference are unknown. Mining published transcriptomic data sets, we determined that the response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor α (ERα) stimulated melanoma growth in murine models by skewing macrophage polarization toward an immune-suppressive state that promoted CD8+ T cell dysfunction and exhaustion and ICB resistance. This activity was not evident in mice harboring macrophage-specific depletion of ERα, confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD), decreased tumor growth, stimulated adaptive immunity, and increased the antitumor efficacy of ICBs. Further, a gene signature that determines ER activity in macrophages predicted survival in patients with melanoma treated with ICB. These results highlight the importance of E2/ER signaling as a regulator of intratumoral macrophage polarization, an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.Item Open Access Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise.(J Natl Cancer Inst, 2015-05) Betof, Allison S; Lascola, Christopher D; Weitzel, Douglas; Landon, Chelsea; Scarbrough, Peter M; Devi, Gayathri R; Palmer, Gregory; Jones, Lee W; Dewhirst, Mark WExercise has been shown to improve postischemia perfusion of normal tissues; we investigated whether these effects extend to solid tumors. Estrogen receptor-negative (ER-, 4T1) and ER+ (E0771) tumor cells were implanted orthotopically into syngeneic mice (BALB/c, N = 11-12 per group) randomly assigned to exercise or sedentary control. Tumor growth, perfusion, hypoxia, and components of the angiogenic and apoptotic cascades were assessed by MRI, immunohistochemistry, western blotting, and quantitative polymerase chain reaction and analyzed with one-way and repeated measures analysis of variance and linear regression. All statistical tests were two-sided. Exercise statistically significantly reduced tumor growth and was associated with a 1.4-fold increase in apoptosis (sedentary vs exercise: 1544 cells/mm(2), 95% CI = 1223 to 1865 vs 2168 cells/mm(2), 95% CI = 1620 to 2717; P = .048), increased microvessel density (P = .004), vessel maturity (P = .006) and perfusion, and reduced intratumoral hypoxia (P = .012), compared with sedentary controls. We also tested whether exercise could improve chemotherapy (cyclophosphamide) efficacy. Exercise plus chemotherapy prolonged growth delay compared with chemotherapy alone (P < .001) in the orthotopic 4T1 model (n = 17 per group). Exercise is a potential novel adjuvant treatment of breast cancer.Item Open Access Myocardial Function in Premenopausal Women Treated With Ovarian Function Suppression and an Aromatase Inhibitor.(JNCI cancer spectrum, 2021-08) Jordan, Jennifer H; D'Agostino, Ralph B; Ansley, Katherine; Douglas, Emily; Melin, Susan; Sorscher, Steven; Vasu, Sujethra; Park, Sung; Kotak, Anuj; Romitti, Paul A; O'Connell, Nathanial S; Hundley, William G; Thomas, AlexandraPremenopausal women with high-risk hormone receptor (HR)-positive breast cancer often receive ovarian function suppression (OFS) with aromatase inhibitor therapy; however, abrupt menopause induction, together with further decrements in estrogen exposure through aromatase inhibition, may affect cardiovascular microcirculatory function. We examined adenosine-induced changes in left ventricular (LV) myocardial T1, a potential subclinical marker of LV microcirculatory function in premenopausal women undergoing treatment for breast cancer. Twenty-one premenopausal women (14 with HR-positive breast cancer receiving OFS with an aromatase inhibitor and 7 comparator women with triple-negative breast cancer [TNBC] who had completed primary systemic therapy) underwent serial resting and adenosine cardiovascular magnetic resonance imaging measurements of LV myocardial T1 and LV volumes, mass, and ejection fraction. All statistical tests were 2-sided. After a median of 4.0 months (range = 3.1-5.7 months), the stress to resting ratio of LV myocardial T1 declined in women with HR-positive breast cancer (-1.3%, 95% confidence interval [CI] = -3.4% to 0.7%) relative to those with TNBC (3.2%, 95% CI = -1.2% to 7.6%, P = .02). After accounting for age, LV stroke volume, LV ejection fraction, diastolic blood pressure, and breast cancer subtype women with HR-positive breast cancer experienced a blunted T1 response after adenosine relative to women with TNBC (difference = -4.7%, 95% CI = -7.3% to -2.1%, Pdifference = .002). Over the brief interval examined, women with HR-positive breast cancer receiving OFS with an aromatase inhibitor experienced reductions in adenosine-associated changes in LV myocardial T1 relative to women who received nonhormonal therapy for TNBC. These findings suggest a possible adverse impact on LV myocardial microcirculatory function in premenopausal women with breast cancer receiving hormone deprivation therapy.Item Open Access Progesterone Signaling in Endometrial Epithelial Organoids.(Cells, 2022-05) Hewitt, Sylvia C; Wu, San-Pin; Wang, Tianyuan; Young, Steven L; Spencer, Thomas E; DeMayo, Francesco JFor pregnancy to be established, uterine cells respond to the ovarian hormones, estrogen, and progesterone, via their nuclear receptors, the estrogen receptor (ESR1) and progesterone receptor (PGR). ESR1 and PGR regulate genes by binding chromatin at genes and at distal enhancer regions, which interact via dynamic 3-dimensional chromatin structures. Endometrial epithelial cells are the initial site of embryo attachment and invasion, and thus understanding the processes that yield their receptive state is important. Here, we cultured and treated organoids derived from human epithelial cells, isolated from endometrial biopsies, with estrogen and progesterone and evaluated their transcriptional profiles, their PGR cistrome, and their chromatin conformation. Progesterone attenuated estrogen-dependent gene responses but otherwise minimally impacted the organoid transcriptome. PGR ChIPseq peaks were co-localized with previously described organoid ESR1 peaks, and most PGR and ESR1 peaks were in B (inactive) compartment regions of chromatin. Significantly more ESR1 peaks were assigned to estrogen-regulated genes by considering chromatin loops identified using HiC than were identified using ESR1 peak location relative to closest genes. Overall, the organoids model allowed a definition of the chromatin regulatory components governing hormone responsiveness.