The Impact of 27-Hydroxycholesterol, a Macrophage-Synthesized Estrogen Receptor Agonist, on Breast Cancer Pathophysiology

2010 ◽  
Author(s):  
Erik R. Nelson ◽  
Donald P. McDonnell
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Receptor Agonist ◽  
The Impact

Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

2016 ◽  
Vol 34 (25) ◽  
pp. 2961-2968 ◽  
Author(s):  
Charlotte Fribbens ◽  
Ben O’Leary ◽  
Lucy Kilburn ◽  
Sarah Hrebien ◽  
Isaac Garcia-Murillas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Advanced Breast Cancer ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Phase Iii ◽  
Wild Type ◽  
Estrogen Receptor Positive ◽  
Esr1 Mutations ◽  
The Impact

Purpose ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor–positive advanced breast cancer. Materials and Methods In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. Results In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). Conclusion ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.

Incidence and Predictive Factors for Recovery of Ovarian Function in Amenorrheic Women in Their 40s Treated With Letrozole

2016 ◽  
Vol 34 (14) ◽  
pp. 1594-1600 ◽  
Author(s):  
Lea K. Krekow ◽  
Beth A. Hellerstedt ◽  
Rufus P. Collea ◽  
Steven Papish ◽  
Shrinivas M. Diggikar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Ovarian Function ◽  
Follicle Stimulating Hormone ◽  
General Linear Model ◽  
Serum Estradiol ◽  
Function Recovery ◽  
Estrogen Receptor Positive ◽  
The Impact ◽  
Positive Breast Cancer

Purpose This prospective study assessed the impact of 2 years of aromatase inhibitor (AI) therapy on the incidence of ovarian function recovery (OFR) in women age 40 to 49 with estrogen receptor–positive breast cancer who were premenopausal at diagnosis and who underwent chemotherapy-induced amenorrhea during adjuvant treatment. Patients and Methods Women age 40 to 49 with estrogen receptor–positive breast cancer who had ceased menstruating with adjuvant cyclophosphamide-based chemotherapy, had postmenopausal serum estradiol (E2), and had received tamoxifen for ≥ 1 year were treated with letrozole (2.5 mg) daily for ≥ 2 years. Serum follicle-stimulating hormone (FSH) and E2 were measured at baseline and over 2 years. A general linear model was used to assess serial FSH by OFR. Logistic regression was used to assess baseline predictors and OFR. Results The study enrolled 177 women (145 women age 45 to 49 years and 32 women age 40 to 44 years). Of 173 evaluable patients, 67 (39%; 95% CI, 31% to 46%) regained ovarian function; 11 of these patients (6%; 95% CI, 3% to 10%) resumed menses, and 56 of these patients (32%; 95% CI, 25% to 39%) developed premenopausal E2 without menses. Among AI-naïve patients, serial FSH significantly increased over time (P < .001), did not vary significantly by OFR status (P = .55), but showed mild evidence of a decrease after month 12 for those who resumed menses (P = .0989). Age less than 45 years and inhibin B were significant multivariable baseline predictors of OFR. Conclusion These results emphasize the challenge in determining definitive menopause in women with chemotherapy-induced amenorrhea. The risk of OFR during treatment with AIs in amenorrheic women in their 40s is high, and AI therapy should be avoided in these patients.

scholarly journals Prognostic Impact of Pregnancy After Breast Cancer According to Estrogen Receptor Status: A Multicenter Retrospective Study

2013 ◽  
Vol 31 (1) ◽  
pp. 73-79 ◽  
Author(s):  
Hatem A. Azim ◽  
Niels Kroman ◽  
Marianne Paesmans ◽  
Shari Gelber ◽  
Nicole Rotmensz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Pregnancy Outcome ◽  
Estrogen Receptor Status ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Er Positive ◽  
The Impact ◽  
Disease Free ◽  
Er Status

Purpose We questioned the impact of pregnancy on disease-free survival (DFS) in women with history of breast cancer (BC) according to estrogen receptor (ER) status. Patients and Methods A multicenter, retrospective cohort study in which patients who became pregnant any time after BC were matched (1:3) to patients with BC with similar ER, nodal status, adjuvant therapy, age, and year of diagnosis. To adjust for guaranteed time bias, each nonpregnant patient had to have a disease-free interval at least equal to the time elapsing between BC diagnosis and date of conception of the matched pregnant one. The primary objective was DFS in patients with ER-positive BC. DFS in the ER-negative cohort, whole population, and overall survival (OS) were secondary objectives. Subgroup analyses included DFS according to pregnancy outcome and BC–pregnancy interval. With a two-sided α = 5% and β = 20%, 645 ER-positive patients were required to detect a hazard ratio (HR) = 0.65. Results A total of 333 pregnant patients and 874 matched nonpregnant patients were analyzed, of whom 686 patients had an ER-positive disease. No difference in DFS was observed between pregnant and nonpregnant patients in the ER-positive (HR = 0.91; 95% CI, 0.67 to 1.24, P = .55) or the ER-negative (HR = 0.75; 95% CI, 0.51 to 1.08, P = .12) cohorts. However, the pregnant group had better OS (HR = 0.72; 95% CI, 0.54 to 0.97, P = .03), with no interaction according to ER status (P = .11). Pregnancy outcome and BC–pregnancy interval did not seem to impact the risk of relapse. Conclusion Pregnancy after ER-positive BC does not seem to reduce the risk of BC recurrence.

scholarly journals Analysis of the TP53 Deleterious Single Nucleotide Polymorphisms Impact on Estrogen Receptor Alpha-p53 Interaction: A Machine Learning Approach

2019 ◽  
Vol 20 (12) ◽  
pp. 2962 ◽  
Author(s):  
Kumaraswamy Naidu Chitrala ◽  
Mitzi Nagarkatti ◽  
Prakash Nagarkatti ◽  
Suneetha Yeguvapalli
Keyword(s):  
Breast Cancer ◽  
Machine Learning ◽  
Risk Factors ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Large Deviation ◽  
The Other ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
The Impact

Breast cancer is a leading cancer type and one of the major health issues faced by women around the world. Some of its major risk factors include body mass index, hormone replacement therapy, family history and germline mutations. Of these risk factors, estrogen levels play a crucial role. Among the estrogen receptors, estrogen receptor alpha (ERα) is known to interact with tumor suppressor protein p53 directly thereby repressing its function. Previously, we have studied the impact of deleterious breast cancer-associated non-synonymous single nucleotide polymorphisms (nsnps) rs11540654 (R110P), rs17849781 (P278A) and rs28934874 (P151T) in TP53 gene on the p53 DNA-binding core domain. In the present study, we aimed to analyze the impact of these mutations on p53–ERα interaction. To this end, we, have modelled the full-length structure of human p53 and validated its quality using PROCHECK and subjected it to energy minimization using NOMAD-Ref web server. Three-dimensional structure of ERα activation function-2 (AF-2) domain was downloaded from the protein data bank. Interactions between the modelled native and mutant (R110P, P278A, P151T) p53 with ERα was studied using ZDOCK. Machine learning predictions on the interactions were performed using Weka software. Results from the protein–protein docking showed that the atoms, residues and solvent accessibility surface area (SASA) at the interface was increased in both p53 and ERα for R110P mutation compared to the native complexes indicating that the mutation R110P has more impact on the p53–ERα interaction compared to the other two mutants. Mutations P151T and P278A, on the other hand, showed a large deviation from the native p53-ERα complex in atoms and residues at the surface. Further, results from artificial neural network analysis showed that these structural features are important for predicting the impact of these three mutations on p53–ERα interaction. Overall, these three mutations showed a large deviation in total SASA in both p53 and ERα. In conclusion, results from our study will be crucial in making the decisions for hormone-based therapies against breast cancer.

scholarly journals Obesity-Altered Adipose Stem Cells Promote Radiation Resistance of Estrogen Receptor Positive Breast Cancer through Paracrine Signaling

2020 ◽  
Vol 21 (8) ◽  
pp. 2722 ◽  
Author(s):  
Rachel A. Sabol ◽  
Vidal A. Villela ◽  
Alexandra Denys ◽  
Benjamin T. Freeman ◽  
Alifiani B. Hartono ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Estrogen Receptor ◽  
Notch Signaling ◽  
Radiation Resistance ◽  
Adipose Stem Cells ◽  
Stromal Component ◽  
Estrogen Receptor Positive ◽  
The Impact ◽  
Positive Breast Cancer

Obesity is associated with poorer responses to chemo- and radiation therapy for breast cancer, which leads to higher mortality rates for obese women who develop breast cancer. Adipose stem cells (ASCs) are an integral stromal component of the tumor microenvironment (TME). In this study, the effects of obesity-altered ASCs (obASCs) on estrogen receptor positive breast cancer cell’s (ER+BCCs) response to radiotherapy (RT) were evaluated. We determined that BCCs had a decreased apoptotic index and increased surviving fraction following RT when co-cultured with obASCs compared to lnASCs or non-co-cultured cells. Further, obASCs reduced oxidative stress and induced IL-6 expression in co-cultured BCCs after radiation. obASCs produce increased levels of leptin relative to ASCs from normal-weight individuals (lnASCs). obASCs upregulate the expression of IL-6 compared to non-co-cultured BCCs, but BCCs co-cultured with leptin knockdown obASCs did not upregulate IL-6. The impact of shLeptin obASCs on radiation resistance of ER+BCCs demonstrate a decreased radioprotective ability compared to shControl obASCs. Key NOTCH signaling players were enhanced in ER+BBCs following co-culture with shCtrl obASCs but not shLep obASCs. This work demonstrates that obesity-altered ASCs, via enhanced secretion of leptin, promote IL-6 and NOTCH signaling pathways in ER+BCCs leading to radiation resistance.

Prospective study of the impact of using the 21-gene recurrence score assay on clinical decision making in women with estrogen receptor-positive, HER2-negative, early-stage breast cancer in France.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 568-568 ◽  
Author(s):  
Joseph Gligorov ◽  
Xavier B. Pivot ◽  
Herve L. Naman ◽  
William Jacot ◽  
Dominique Spaeth ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Early Stage ◽  
Recurrence Score ◽  
Oncotype Dx ◽  
Early Stage Breast Cancer ◽  
Treatment Recommendation ◽  
Endocrine Treatment ◽  
Estrogen Receptor Positive ◽  
The Impact

568^ Background: The 21-gene Oncotype DX Recurrence Score (RS) is a validated assay to help inform the appropriate treatment of estrogen receptor-positive (ER+), early stage breast cancer in the adjuvant setting. Treatment traditions regarding choice of adjuvant treatment vary significantly in different countries. This prospective multicenter study is the first to assess the impact of using the Oncotype DX assay in the French clinical setting. Methods: A total of 100 consecutive patients with ER+, HER2-negative, node negative or pN1 (mi) breast cancer were enrolled. Overall treatment recommendation change, change from chemoendocrine to endocrine alone and change from endocrine alone to chemoendocrine treatment were recorded. Medical oncologists completed questionnaires regarding their confidence in their recommendation before and after knowing the patient’s RS. A preliminary analysis was conducted on the first 92 evaluable patients with data available at the time of abstract submission. Final data will be presented at the meeting. Results: Prior to Oncotype DX 49% of patients were recommended chemoendocrine treatment and 51% endocrine treatment alone. After having the RS, 26% were recommended chemoendocrine treatment and 74% endocrine treatment alone. The overall reduction in chemotherapy recommendation from 49% to 26% was significant (p<0.001). Of patients originally recommended chemoendocrine treatment, 58% were changed to endocrine treatment alone after having the RS. Of patients originally recommended endocrine treatment, 11% were changed to chemoendocrine treatment after receiving the RS. There was a significant improvement in physician confidence in treatment recommendations (p=0.002) when using Oncotype DX. Conclusions: These are the first prospective data regarding the impact of using Oncotype DX in France. Using Oncotype DX was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use. The data are consistent with those presented from Germany, Spain, the UK and the US.

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