Understanding resistance to hormonal therapy in estrogen avid breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 566-566
Author(s):  
H. M. Linden ◽  
S. Stekhova ◽  
J. M. Link ◽  
R. B. Livingston ◽  
J. R. Gralow ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Hormonal Therapy ◽  
Objective Response ◽  
Response To Therapy ◽  
Serum Estradiol ◽  
Tumor Spread ◽  
Imaging Protocol ◽  
Estradiol Levels ◽  
Er Expression

566 Background: The estrogen receptor (ER) is an essential target for endocrine therapy in breast cancer. We, and others, have tested an in vivo assay of ER function, [F-18]-16α-fluoroestradiol (FES) PET, which allows assessment of all sites of tumor spread and predicts response to hormonal therapy. However, not all patients with tumors bearing functional ER respond to therapy, suggesting the presence of mechanisms of resistance other than ER loss. Methods: 65 postmenopausal female patients with known ER+ metastatic (mostly bone and soft tissue dominant) breast cancer treated with aromatase inhibitors underwent PET FDG and FES imaging on an institutional imaging protocol (majority in second-line therapy). Hormone levels were assayed at the time of imaging, and biopsy specimens from either the primary tumor or metastasis were analyzed for expression of ER, PR, AR, PSA, HER2neu, and TopoIIα. Results: 49 (75%) patients had at least modest levels of retained ER expression, indicated by an average FES SUV > 1.5 at the tumor sites. We found serum estradiol, or estrone, levels >30pg/ml in 30% of patients. We found the majority of patients had PR, or AR expression, but few had EGFR or TopoIIα expression. FES SUV > 1.5 predicted response to therapy (p=.0006); no patient with an FES SUV < 1.5 had an objective response. Only 18/49 patients with SUV >1.5 responded to AI therapy. In the subset with FES SUV > 1.5, factors predicting lack of response to AI included PR negativity (p=.038) and/or detectable serum estradiol levels (p=.05). Conclusions: Quantitative PET FES predicts response to hormonal therapy. Estrogen levels may not be completely suppressed in patients on long-term AI therapy. Estradiol levels > 30pg/ml and lack of PR expression predict resistance to endocrine therapy in patients with tumors bearing functional ER expression. Efforts to monitor and reduce estradiol levels may offer therapeutic benefit to patients. No significant financial relationships to disclose.

scholarly journals Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer

2020 ◽  
Vol 21 (11) ◽  
pp. 4068 ◽  
Author(s):  
Annamaria Salvati ◽  
Valerio Gigantino ◽  
Giovanni Nassa ◽  
Valeria Mirici Cappa ◽  
Giovanna Maria Ventola ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Target Genes ◽  
Acquired Resistance ◽  
Biological Significance ◽  
Response To Therapy ◽  
Term Survival ◽  
Tumor Spread ◽  
Long Term Survival

Breast cancer (BC) is a heterogeneous disease characterized by different biopathological features, differential response to therapy and substantial variability in long-term-survival. BC heterogeneity recapitulates genetic and epigenetic alterations affecting transformed cell behavior. The estrogen receptor alpha positive (ERα+) is the most common BC subtype, generally associated with a better prognosis and improved long-term survival, when compared to ERα-tumors. This is mainly due to the efficacy of endocrine therapy, that interfering with estrogen biosynthesis and actions blocks ER-mediated cell proliferation and tumor spread. Acquired resistance to endocrine therapy, however, represents a great challenge in the clinical management of ERα+ BC, causing tumor growth and recurrence irrespective of estrogen blockade. Improving overall survival in such cases requires new and effective anticancer drugs, allowing adjuvant treatments able to overcome resistance to first-line endocrine therapy. To date, several studies focus on the application of loss-of-function genome-wide screenings to identify key (hub) “fitness” genes essential for BC progression and representing candidate drug targets to overcome lack of response, or acquired resistance, to current therapies. Here, we review the biological significance of essential genes and relative functional pathways affected in ERα+ BC, most of which are strictly interconnected with each other and represent potential effective targets for novel molecular therapies.

Immunocytochemical assay for estrogen receptor in patients with breast cancer: relationship to a biochemical assay and to outcome of therapy.

1986 ◽  
Vol 4 (8) ◽  
pp. 1171-1176 ◽  
Author(s):  
R A McClelland ◽  
U Berger ◽  
L S Miller ◽  
T J Powles ◽  
R C Coombes
Keyword(s):  
Breast Cancer ◽  
Monoclonal Antibody ◽  
Endocrine Therapy ◽  
Objective Response ◽  
Staining Intensity ◽  
Response To Therapy ◽  
Immunoperoxidase Technique ◽  
Breast Cancer Patients ◽  
Intensity Index ◽  
Immunocytochemical Assay

We developed an immunoperoxidase technique using a monoclonal antibody to the estradiol receptor (ER) to identify immunoreactive ER (iER) in breast carcinomas and compared this with the conventional dextran-coated charcoal (DCC) steroid binding assay. We also examined the relationship between the iER and response to therapy in patients with advanced breast cancer. We found iER-positive cells in 60 of 90 carcinomas (66.7%); this correlated with the DCC assay (r = 0.76; P less than .001). Of these, 56 patients were found to be assessable for response to endocrine therapy. Twenty-two showed an objective response to some form of endocrine manipulation, and all these had positively stained carcinomas. By deriving a staining intensity index (SII) we observed that 21 of 22 responders (95%) had an SII of greater than or equal to 0.5, whereas only 8 of 34 nonresponders (24%) had an SII of greater than or equal to 0.5. This difference is highly significant (P less than .001). None of the 17 patients with negatively stained carcinomas responded to endocrine therapy. We conclude that the monoclonal antibody to ER can help identify breast cancer patients who may respond to endocrine therapy.

Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer.

1995 ◽  
Vol 13 (5) ◽  
pp. 1123-1128 ◽  
Author(s):  
C L Vogel ◽  
J Schoenfelder ◽  
I Shemano ◽  
D F Hayes ◽  
R A Gams
Keyword(s):  
Breast Cancer ◽  
Disease Progression ◽  
Retrospective Analysis ◽  
Hormonal Therapy ◽  
Bone Scan ◽  
Large Scale ◽  
Response To Therapy ◽  
X Rays ◽  
Cancer Trial ◽  
Radiology Reports

PURPOSE Scintigraphic flare in association with response to therapy has been well described in the medical literature. During the course of a recent breast cancer trial, it became apparent that several patients with worsening bone scan but no other clinical evidence of disease progression might have potentially benefited from continued therapy, but had therapy discontinued. A retrospective analysis of this issue was performed to assess the magnitude and scope of this problem. MATERIALS AND METHODS A total of 648 patients with hormone receptor-positive or unknown advanced breast cancer were treated as part of a large-scale trial of first-line hormonal therapy. Patients were assessed for response to therapy, including response duration, progression-free interval (PFI), overall survival, and quality of life. The retrospective analysis presented here was performed to assess whether patients with a possible scintigraphic flare within the first 16 weeks of therapy might have had therapy discontinued prematurely due to a worsening bone scan attributable to tumor flare, rather than due to disease progression. RESULTS Analysis of the hormonal trial showed that of 376 assessable patients 108 (29%) with bone disease had a possible scintigraphic flare by week 8 or 16 of the trial, based on data on the case report forms and radiology reports (bone scans and x-rays). Of these, 69 patients (64%) were continued on study therapy, which resulted in clinical benefit in 50 (72%) of those patients. In contrast, 39 patients (36%) with possible scintigraphic flare were removed from the trial. CONCLUSION We conclude that changes in bone scintigraphy that mimic progressive disease early in the course of hormonal treatment of patients with breast cancer metastatic to bone may represent scintigraphic flare associated with response. Thus, clinicians must be cognizant of the phenomenon of scintigraphic flare to avoid premature discontinuation of a potentially beneficial treatment.

Circulating Ca 15.3 Levels in Breast Cancer. Our Present Experience

1986 ◽  
Vol 1 (2) ◽  
pp. 89-92 ◽  
Author(s):  
Ramon Colomer ◽  
Alvaro Ruibal ◽  
Matilde Navarro ◽  
Gloria Encabo ◽  
Luis Alfonso Sole ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Objective Response ◽  
Stage Iv ◽  
Distant Metastases ◽  
Response To Therapy ◽  
Breast Cancer Patients ◽  
Benign Diseases ◽  
Ca 15.3 ◽  
Stage Iv Breast Cancer

CA 15.3 is an antigen expressed by human breast carcinoma cells, and defined by two monoclonal antibodies, 115D8 and DF3. We used IRMA to determine the circulating serum levels of CA 15.3 in 1178 subjects with breast cancer, non-breast malignancies, benign diseases and controls. A threshold level of 40 U/ml was established with 140 healthy controls and 650 patients with benign diseases (respectively 0% subjects and 1.5% patients had abnormal antigen levels). Elevated CA 15.3 was found in 12 of 184 patients with malignancies different from breast cancer (6.5%), either epithelial carcinomas with distant metastases, mainly in the liver, or primary liver tumors. Breast cancer patients (n=204) were analysed by prior therapy, UICC stage and WHO response to therapy. Eight of 134 (5.9%) patients with stage II or III breast cancer at presentation and no evidence of disease (NED) had elevated CA 15.3. All of 22 patients with stage IV breast cancer not responding to therapy (SD and PD) had antigen levels > 40 U/ml, as did 10 of 34 (29.4%) stage IV patients in objective response (CR+PR). Three of 14 pretreatment patients had abnormal marker levels, and they later proved to have distant metastases. Serum CA 15.3 values were statistically different (p < 0.01) in NED (20.6 ± 11.2 U/ml), CR+PR (33.5 ± 24.0 U/ml), stable disease (98.8 ± 50.4 U/ml) and progressive disease (> 200 U/ml) breast cancer patients. Our results suggest that circulating CA 15.3 antigen levels agree with the stage of breast cancer and with the response to therapy.

scholarly journals Effects of Vaginal Estrogens on Serum Estradiol Levels in Postmenopausal Breast Cancer Survivors and Women at Risk of Breast Cancer Taking an Aromatase Inhibitor or a Selective Estrogen Receptor Modulator

2012 ◽  
Vol 8 (3) ◽  
pp. 144-148 ◽  
Author(s):  
Shannon Wills ◽  
Anita Ravipati ◽  
Padmaja Venuturumilli ◽  
Cynthia Kresge ◽  
Elizabeth Folkerd ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Survivors ◽  
Aromatase Inhibitor ◽  
Breast Cancer Survivors ◽  
Postmenopausal Breast Cancer ◽  
Serum Estradiol ◽  
Estradiol Treatment ◽  
Receptor Modulator ◽  
Estradiol Levels

The authors conclude that intravaginal estradiol treatment, regardless of type, results in elevated circulating E2 levels in this population and should be used with caution.

scholarly journals Endocrine Therapy Toxicity: Management Options

2014 ◽  
pp. e25-e30 ◽  
Author(s):  
N. Lynn Henry
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Response To Therapy ◽  
Management Options ◽  
Hormone Receptor Positive ◽  
Research Investment ◽  
Positive Breast Cancer

Treatment with adjuvant endocrine therapy, including tamoxifen and the aromatase inhibitors, has resulted in notable improvements in disease-free and overall survival for patients with hormone receptor-positive breast cancer. Despite their proven benefit, however, adherence to and persistence with the medications is poor in part because of bothersome side effects that can negatively affect quality of life. Retrospective analyses have identified possible predictors of development of toxicity. Reports have also suggested that development of toxicity may be a biomarker of better response to therapy. In addition, there has been considerable research investment into the management of these side effects, which may lead to improved adherence and persistence with therapy. However, although notable advances have been made, much more remains to be done to provide patients with truly personalized therapy for hormone receptor-positive breast cancer.

scholarly journals Impact of systemic therapy on circulating leukocyte populations in patients with metastatic breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Anna-Maria Larsson ◽  
Anna Roxå ◽  
Karin Leandersson ◽  
Caroline Bergenfelz
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Natural Killer ◽  
Endocrine Therapy ◽  
Immune Cells ◽  
Systemic Therapy ◽  
Immune Cell ◽  
Metastatic Breast ◽  
Response To Therapy ◽  
Cell Populations

Abstract Tumors affect the immune system, locally and systemically. The frequencies of specific circulating immune cell populations correlate with disease progression as well as prognosis of the patients. Although largely neglected, conventional antitumoral therapies often possess immunomodulatory properties and affect the levels of specific immune cell populations. Most information, however, derive from animal or in vitro studies. As this could impact prognosis as well as response to therapy, further studies of the effects of treatment on circulating immune cells in patients are warranted. In this pilot study, we evaluated a wide panel of circulating immune cells over time (up to six months) in ten patients with metastatic breast cancer receiving standard antitumoral regimens. Overall, endocrine therapy tends to enrich for natural killer (NK) and natural killer T (NKT) cells in the circulation, whereas both chemotherapy and endocrine therapy reduce the levels of circulating monocytic myeloid-derived suppressor cells (Mo-MDSCs). This indicates that the systemic immunosuppressive profile observed in patients tends to revert over the course of systemic therapy and holds promise for future combination treatment with standard antitumoral agents and immunotherapy.

scholarly journals Preclinical Imaging Evaluation of miRNAs’ Delivery and Effects in Breast Cancer Mouse Models: A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6020
Author(s):  
Francesca Maria Orlandella ◽  
Luigi Auletta ◽  
Adelaide Greco ◽  
Antonella Zannetti ◽  
Giuliana Salvatore
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Mouse Models ◽  
Data Extraction ◽  
Response To Therapy ◽  
Mice Model ◽  
Imaging Evaluation ◽  
Preclinical Imaging ◽  
Imaging Protocol

Background: We have conducted a systematic review focusing on the advancements in preclinical molecular imaging to study the delivery and therapeutic efficacy of miRNAs in mouse models of breast cancer. Methods: A systematic review of English articles published in peer-reviewed journals using PubMed, EMBASE, BIOSIS™ and Scopus was performed. Search terms included breast cancer, mouse, mice, microRNA(s) and miRNA(s). Results: From a total of 2073 records, our final data extraction was from 114 manuscripts. The most frequently used murine genetic background was Balb/C (46.7%). The most frequently used model was the IV metastatic model (46.8%), which was obtained via intravenous injection (68.9%) in the tail vein. Bioluminescence was the most used frequently used tool (64%), and was used as a surrogate for tumor growth for efficacy treatment or for the evaluation of tumorigenicity in miRNA-transfected cells (29.9%); for tracking, evaluation of engraftment and for response to therapy in metastatic models (50.6%). Conclusions: This review provides a systematic and focused analysis of all the information available and related to the imaging protocols with which to test miRNA therapy in an in vivo mice model of breast cancer, and has the purpose of providing an important tool to suggest the best preclinical imaging protocol based on available evidence.

scholarly journals NEOADJUVANT ENDOCRINE THERAPY FOR PATIENTS WITH ESTROGEN-RECEPTOR-POSITIVE BREAST CANCER

2018 ◽  
Vol 17 (3) ◽  
pp. 11-19
Author(s):  
V. F. Semiglazov ◽  
V. V. Semiglazov ◽  
G. A. Dashyan ◽  
P. V. Krivorotko ◽  
V. G. Ivanov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Neoadjuvant Chemotherapy ◽  
Endocrine Therapy ◽  
Locally Advanced ◽  
Response To Therapy ◽  
Neoadjuvant Endocrine Therapy ◽  
Receive Hormone Therapy ◽  
Study Results ◽  
Estrogen Receptor Positive

More than 70 % of patients with breast cancer have estrogen-receptor-positive tumors (ER+) and are considered hormone- sensitive. That is why a vast majority of patients with early operable  tumors receive adjuvant endocrine therapy. Patients with metastatic  ER+ breast cancer also receive hormone therapy as first-line  treatment. Patients with ER+/PR+ locally advanced breast cancer  including potentially operable cases (cT2N1, cT3N0M0) are still a  subject to neoadjuvant chemotherapy in most of the oncology  centers in Russia and worldwide. More than 10 years ago, several  trials evaluating the efficacy of neoadjuvant endocrine therapy were  conducted in the Petrov Research Institute of Oncology (aromatase  inhibitors vs tamoxifen, neoadjuvant endocrine therapy vs  neoadjuvant chemotherapy, etc.) The primary endpoint was the  evaluation of pathologic complete/partial response to therapy and  the frequency of breast-conserving surgeries following neoadjuvant  treatment. We now represent 10-year long-term follow-up data on  comparison of neoadjuvant chemotherapy with neoadjuvant  endocrine therapy after retrospective determination of IHC- phenotypes of 239 patients with ER+ breast cancer. The study  results show tendency to better 10-year disease-free survival in  patients with luminal-A breast cancer who received endocrine  therapy compared to neoadjuvant chemotherapy (72.8 % vs 53.9  %, respectively, p=0.062) There were no statistically significant  differences in DFS rates among patients with the luminal B breast  cancer subtype (41 % vs 40 %) The discovery of biomarkers of  potential resistance to endocrine therapy (cycline-dependant kinase  activity [cdk 4/6], estrogenreceptor mutation [ESR1], mTOR  signaling pathway activity, co-expression of the ER and HER2neu  [ER+/ HER2neu3+]) and ways to inhibit the activity of the resistance pathways (palbocyclib, everolimus, etc.) have expanded the  armamentarium of endocrine-therapy for not only metastatic and  locally-advanced but also operable cases of ER+ breast cancer.

scholarly journals Inhibitors of cyclin-dependent kinases 4/6 for breast cancer patients with different somatic mutations of the PIK3CA gene

2020 ◽  
pp. 40-46
Author(s):  
A. F. Nasretdinov ◽  
N. I. Sultanbaeva ◽  
Sh. I. Musin ◽  
O. N. Lipatov ◽  
A. A. Izmailov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Therapy ◽  
Endocrine Therapy ◽  
Anticancer Agents ◽  
Pik3ca Mutation ◽  
Breast Tumors ◽  
Response To Therapy ◽  
Breast Cancer Patients ◽  
Adjuvant Hormone Therapy ◽  
Pik3ca Gene

Introduction. Breast cancer is the leader in cancer incidence in theRussian Federation. The tumor is considered extremely heterogeneous and the luminal subtypes of breast tumors occupy a special place, since they are considered relatively favorable in therapy and control of the disease.Drug therapy for hormone-positive cancer has undergone significant evolution and new anticancer agents have appeared in the arsenal of the oncologist and have shown promising results compared to classical therapy. The search for predictive markers of the effectiveness of new therapy has become of great importance. This marker turned out to be a mutation in the PIK3CA gene – one of the most frequent genetic disorders in breast cancer cells. According to the literature, the presence of this mutation negatively effects on endocrine therapy for breast tumors.The aim of this study was to analyze the frequency of mutations in the PIK3CA gene among patients with hormone-positive tumors, and the effectiveness of therapy with CDK4/6 inhibitors in this group of patients.Materials and methods. The material for the study of the mutation in the PIK3CA gene was tumor biopsies of 31 patients and clinical data on the response to therapy with CDK4/6 inhibitors and classical hormone therapy.Results and discussion. The results of the work showed a high incidence of the PIK3CA mutation among hormone-positive tumors (45%). The mutation resulted in a decrease in both the median time to progression after radical surgery (from 48.4 ± 7.8 months to 30.1 ± 6.0 months) in patients receiving adjuvant hormone therapy and progression-free survival in patients receiving therapy with CDK4 /6 inhibitors (4.2 months versus 9 months). This confirmed the theory that the PIK3CA mutation negatively affects the outcome of hormone therapy.Conclusions. PIK3CA is an important predictive marker in endocrine therapy for hormone-positive tumors. Its presence not only determines the relatively worse results of treatment, but can also serve as an indication for the appointment of a special series of drugs – inhibitors of this mutation.

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