Endocrine Treatment Of Breast Cancer Research Articles

Hormone therapy for breast cancer, with an emphasis on the pure antiestrogen fulvestrant: mode of action, antitumor efficacy and effects on bone health

Breast cancer is a major health problem in women of developed Western countries. Whereas estrogen receptor (ER) may be involved in many cases in breast carcinogenesis, its expression in breast tumors may predict a favorable response to hormone therapy. In this review, we report the role played by ER in breast cancer and compare the effects and mechanisms of action of partial (tamoxifen) and pure (fulvestrant) antiestrogens, as well as of aromatase inhibitors. Moreover, as ER also has a critical role in bone metabolism, we review the beneficial and adverse effects of breast cancer hormone therapy on bone health, with a particular emphasis on fulvestrant, the only pure antiestrogen recently approved by the FDA for Phase III clinical trials. We conclude that, because of its therapeutic efficacy and its seemingly minimal effect on bone integrity, fulvestrant represents a new option for the hormonal treatment of breast cancer that deserves further clinical evaluation.

Functional identification of genes causing estrogen independence of human breast cancer cells

Endocrine treatment of breast cancer is widely applied and effective. However, in advanced disease cases, the tumors will eventually progress into an estrogen-independent and therapy-resistant phenotype. To elucidate the molecular mechanisms underlying this endocrine therapy failure, we applied retroviral insertion mutagenesis to identify the main genes conferring estrogen independence to human breast cancer cells. Estrogen-dependent ZR-75-1 cells were infected with replication-defective retroviruses followed by selection with the anti-estrogen 4-hydroxy-tamoxifen. In the resulting panel of 79 tamoxifen-resistant cell lines, the viral integrations were mapped within the human genome. Genes located in the immediate proximity of the retroviral integration sites were characterized for altered expression and their capacity to confer anti-estrogen resistance when transfected into breast cancer cells. Out of 15 candidate BCAR (breast cancer anti-estrogen resistance) genes, seven (AKT1, AKT2, BCAR1, BCAR3, EGFR, GRB7, and TRERF1/BCAR2) were shown to directly underlie estrogen independence. Our results show that insertion mutagenesis is a powerful tool to identify BCAR loci, which may provide insights into the molecular and cellular mechanisms of breast tumor progression and therapy resistance thereby offering novel targets for the development of tailor-made therapeutical and prevention strategies.

Oestrogen receptors α and β show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer

Aims:The majority of all breast cancers are hormone responsive, traditionally defined by the expression of oestrogen receptor (ER) α and/or progesterone receptors. In contrast to ERα, the clinical significance of...

ERBB2 status and outcome of endocrine treatment

Until recently, tamoxifen was the standard endocrine treatment for breast cancer, used in millions of women worldwide, and was suggested to be a factor in the improved survival noted in patients with breast cancer.1 However, the use of tamoxifen in postmenopausal women is now challenged by findings from the use of third-generation aromatase inhibitors (anastrozole, exemestane, and letrozole). Large randomised clinical trials for breast cancer have shown clinical benefit in favour of these aromatase inhibitors over tamoxifen.

Current NCI-sponsored Cooperative Group trials of endocrine therapies in breast cancer

Over several decades, investigators working through National Cancer Institute-sponsored Cooperative Groups have contributed to major advances in the endocrine treatment of breast cancer. Accomplishments include the benefit of tamoxifen therapy for early stage invasive and noninvasive breast cancer, the benefit of raloxifene and tamoxifen for prevention of breast cancer, the improved efficacy of tamoxifen after chemotherapy as opposed to concurrent administration, and the ability of letrozole administered after 5 years of tamoxifen to improve disease-free survival. Most recently, Cooperative Group studies have contributed to the development of a molecular profiling test, Oncotype Dx, which identifies women who have an excellent prognosis with hormonal therapy alone. Ongoing phase 3 clinical trials address the following questions: Is prolonged duration of aromatase inhibitor (AI) therapy beneficial? What is the efficacy and toxicity of steroidal versus nonsteroidal AIs in adjuvant treatment? Is combination hormonal therapy with an estrogen receptor down-regulator (fulvestrant) and an AI superior to an AI alone in the treatment of metastatic breast cancer? Does ovarian suppression offer superior benefit to standard therapy in the treatment of premenopausal breast cancer? What is the role of chemotherapy for early stage breast cancer selected via molecular profiling analysis? How can targeted therapies be used effectively in combination? Studies in subsets of patients defined by molecular profiling will be necessary to fully define breast cancer subtypes and realize the promise of personalized medicine. Close research partnerships that promote large-scale translational research are essential to the continuation of rapid achievements in this field.

Recent Advances in the Hormonal Treatment of Breast Cancer

Recent Advances in the Hormonal Treatment of Breast Cancer

The oestrogen-dependent biology of breast cancer. Sensitivity and resistance to aromatase inhibitors revisited: a molecular perspective

Endocrine treatment of breast cancer was the first molecular targeted anti-cancer therapy to reach clinical practice. Among the several options that share the common denomination of hormonal treatment, aromatase inhibitors (AIs) in the postmenopausal setting show the highest efficacy rates. These drugs have become the standard of care both in the advanced and adjuvant scenarios. Nevertheless resistance to AIs either upfront or after initial clinical response is almost a universal feature whenever tumour excision is not possible. Multiple reports have established the role of alternative pro-growth signalling pathways in the acquisition of resistance to the oestradiol deprivation that AIs produce. However the first clinical trials addressing the double blockade of both the oestrogen and other growing factor pathways raise some concerns on the efficacy of this approach. This review presents the evidence on the molecular events underpinning the response and resistance to AIs and suggests some key issues to consider when designing clinical research projects in this context.

Anomalies utérines chez la femme non ménopausée sous tamoxifène en traitement adjuvant du cancer du sein

Objective To elaborate a strategy of endometrial follow-up for premenopausal women treated with Tamoxifen as adjuvant hormonal treatment of breast cancer. Patients and methods Retrospective study of 152 premenopausal patients treated with Tamoxifen in Nantes Comprehensive Cancer Center for a breast cancer from January 2003 to December 2005. Vaginal sonography was used in the follow-up of 70 of them. Results Endometrial hypertrophy was found in 26 patients. Sonohysterography and hysteroscopy allowed to find 11 polyps and three hyperplasias in the 19 women who were investigated. In our study, endometrial pathology was found in 20% of premenopausal women treated with Tamoxifen (polyps or hyperplasia). Uterine bleeding was found in half patient of this group. Discussion and conclusion Vaginal sonography monitoring could be proposed to premenopausal women treated with Tamoxifen among whom endometrial pathology is usual.

Choices and challenges in endocrine treatment for breast cancer

Choices and challenges in endocrine treatment for breast cancer

Controversies of adjuvant endocrine treatment for breast cancer and recommendations of the 2007 St Gallen conference

Endocrine treatment for breast cancer was introduced more than a century ago. The discovery of hormone receptors has allowed targeting of endocrine treatment to patients whose primary tumours express these receptors. In the adjuvant setting, different approaches are used in premenopausal or postmenopausal women. In premenopausal patients, suppression of ovarian function and the use of tamoxifen are the most important therapeutic options, even though questions on timing, duration, and combination of these compounds remain unanswered. The use of aromatase inhibitors in combination with ovarian-function suppression is currently under investigation in the premenopausal setting. In postmenopausal patients, aromatase inhibitors given after 2-3 years or 5 years of tamoxifen have shown a significant benefit over tamoxifen alone. However, questions on this treatment also remain unanswered. For example, whether all patients should receive an aromatase inhibitor or whether some subgroups of patients might be optimally treated by tamoxifen alone is yet to be established. In this paper we review the published work on adjuvant endocrine treatment in breast cancer and provide recommendations from the 2007 St Gallen International Conference on Primary Therapy of Early Breast Cancer.

Ear acupuncture for hot flushes—The perceptions of women with breast cancer

Hot flushes and night sweats are a major problem for women having adjuvant hormonal treatment for breast cancer. We explored using a standardised ear acupuncture protocol delivered in small group clinics as an option to manage these side effects. Qualitative research aimed to elicit the opinions of women who received this treatment. Sixteen women took part in three focus groups, and discussed a range of topics including reasons for joining the study, experience of having acupuncture, effects of the treatment, the possible reasons for these, and their experience of group treatments. Transcripts of the groups were analysed using grounded techniques. The women, who had all been experiencing chronic multiple flushes and sweats, found the acupuncture helpful and relaxing. Many reported reductions in hot flush frequency, as well as improvements in overall emotional and physical well being. The group setting for treatment was regarded as supportive and encouraging.

Does the addition of COX-2 inhibitors alter the resistance to aromatase inhibitors?

11511 Background: This study aimed to investigate whether the addition of COX-2 inhibitor to aromatase inhibitor alter the resistance to aromatase inhibitor, developed during first or second line hormonal treatment of estrogen (ER) and/or progesterone receptor (PR) positive metastatic breast cancer cases. Methods: ER and/or PR positive breast cancer patients with known high baseline CA 15–3 levels due to the tumor and receiving a first or second line (after first line tamoxifen) aromatase inhibitor due to soft tissue (lymphatic tissue, skin) or bone metastasis were evaluated in this study. A recurrent increase in CA 15–3 levels without tumor progression following an initial decrease in CA 15–3 levels was observed in 7 patients and this was considered as resistance to the aromatase inhibitor. For this reason, a COX- 2 inhibitor was added to either letrozole (5/7) or anastrozole (2/7) treatment. The aromatase inhibitor and COX-2 inhibitor combination (celecoxib 200 mg bid, 5/7 cases; rofecoxib 50 mg od, 2/7 cases) was used for 3 months. CA 15–3 levels and tumor response of these 7 cases was re- evaluated at the end of 3 months. Results: None of the seven cases had a decrease in CA 15–3 levels following the 3 months of aromatase inhibitor plus COX-2 inhibitor combination treatment, instead all cases had their levels increased. In addition, none of the 7 cases had clinical or radiological tumor response, all had tumor progression. Treatment was continued by either third line hormone treatment (4/7) or chemotherapy (3/7). Conclusions: COX-2 inhibitors are suggested to potentiate endocrine treatment since the overexpression of COX-2 contributes to the increased expression of aromatase in the breast tumor tissue. Thus, the combination of an aromatase inhibitor and a COX-2 inhibitor may be useful in the hormonal treatment of breast cancer. However, present study failed to demonstrate alteration of the developed aromatase resistance by the addition of a COX-2 inhibitor. No significant financial relationships to disclose.

Anastrozole therapy for postmenopausal women with early breast cancer

Although tamoxifen was the standard endocrine treatment for breast cancer for more than 30 years, aromatase inhibitors such as anastrozole now have an important therapeutic role in postmenopausal women. Anastrozole gained initial acceptance for use in advanced breast cancer, but subsequent studies have shown that, in early breast cancer, anastrozole is superior to tamoxifen as initial adjuvant therapy for newly diagnosed patients, while patients already receiving treatment benefit from switching to anastrozole rather than continuing with tamoxifen or from extending therapy with anastrozole after 5 years of tamoxifen. Additionally, in the neoadjuvant setting, anastrozole may reduce tumor size in patients with locally advanced disease. Current studies are focusing on possible uses of anastrozole in breast cancer prevention and combination treatments.

Quantitative measures of oestrogen receptor and ERBB2 expression

In 1896, Beatson described clinical improvement after ovariectomy in young women with breast cancers. 1 Beatson GT On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet. 1896; 2: 104-107 Crossref Google Scholar These findings established widespread use of endocrine treatment for this disease, which persists to this day. In the 1960s, the discovery of the oestrogen receptor by Jensen 2 Jensen EV Jacobson HI Smith S et al. The use of estrogen antagonists in hormone receptor studies. Gynecol Invest. 1972; 3: 108-123 Crossref PubMed Scopus (52) Google Scholar led to investigations by McGuire and colleagues 3 McGuire WL Estrogen receptors in human breast cancer. J Clin Invest. 1973; 52: 73-77 Crossref PubMed Scopus (180) Google Scholar that showed that this molecule could be used to guide endocrine treatment of breast cancer. It is now clear that patients with oestrogen-receptor-positive breast cancer gain substantial benefit from the selective oestrogen receptor modulator, tamoxifen, but patients whose cancers are oestrogen-receptor negative do not. 4 Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005; 365: 1687-1717 Summary Full Text Full Text PDF PubMed Scopus (6339) Google Scholar Consequently, standard recommendations now call for the use of oestrogen receptors to identify patients who should not receive endocrine treatment. 5 Bast Jr, RC Ravdin P Hayes DF et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001; 19: 1865-1878 Crossref PubMed Google Scholar Determination of oestrogen-receptor status and ERBB2 status of breast carcinoma: a gene-expression profiling studyAmounts of ESR1 and ERBB2 mRNA as measured by the Affymetrix GeneChip reliably and reproducibly establish oestrogen-receptor status and ERBB2 status, respectively. Full-Text PDF

Evolution of aromatase inhibitors as an endocrine treatment for breast cancer

Evolution of aromatase inhibitors as an endocrine treatment for breast cancer

TGF‐Beta Signaling in Breast Cancer

The antiestrogen tamoxifen is one of the most successful drugs in the endocrine treatment of breast cancer and significantly reduces the risk of recurrence and death. Antiestrogens act by inhibiting the production of growth-stimulatory factors as well as by activating peptides with growth-inhibitory effects like transforming growth factor- beta (TGF-beta). In hormone-responsive breast cancer cells treatment with antiestrogens leads to the conversion of TGF-beta1 into a biologically active form. Expression of TGF-beta2 and TGF-beta receptor (TbetaR) II is induced via a transcriptional mechanism involving p38 MAP kinase. Inhibition of p38 abolishes antiestrogen-dependent growth inhibition. However, the role of TGF-beta in breast cancer progression is ambiguous, as it was shown to display both tumor-suppressing and -enhancing effects. A polymorphism in the promoter of TGF-beta2 that enhances expression of the protein was associated with lymph node metastasis in breast cancer patients, pointing to a role of TGF-beta2 in the process of invasion. An immunohistochemical study on TbetaRI and TbetaRII expression in breast cancer tissues indicates that the estrogen receptor (ER) status of a tumor is an important marker and a potential mediator of the transition of TGF-beta from tumor suppressor to tumor promoter. In ER-negative tumors, expression of TbetaRII was associated with a subset of tumors that appeared to be highly aggressive, leading to strongly reduced overall survival times. Further characterization of the influence of ER expression on TGF-beta signal transduction shows that ER-alpha plays a crucial role in TGF-beta signaling.

Megestrol acetate after aromatase inhibitor failure in metastatic breast cancer

10572 Background: As aromatase inhibitors (AI) are now an essential component of the adjuvant hormonal treatment in breast cancer, it is important to define strategies after progression. Progestational agents have significant activity in endocrine-responsive breast cancer. This is the first report of megestrol acetate (MA) after AI failure. Methods: We have retrospectively reviewed the charts of all patients treated with MA for the last 2 years at the Instituto Nacional de Câncer, in Brazil. All the patients were postmenopausal and had metastatic breast cancer. The treatment sequence was as follows: tamoxifen ⋄ AI ⋄ MA. MA was given at a dose of 160 mg PO daily. Results: A total of 27 postmenopausal patients were treated between December 2003 and December 2005. Median age was 71 years (37–93). Seven patients had visceral metastases and 20 had bone, soft tissue or pleural disease. Eight patients are still on treatment. Median time to disease progression was 16 weeks (4–81), with no difference between those with or without visceral metastases: 17 and 16 weeks, respectively. Treatment was well tolerated and no patient discontinued therapy due to toxicity. There was no report of venous thromboembolism. Conclusions: Despite the limitations of a retrospective analysis, our results compare favorably with exemestane and high-dose estrogens in a similar setting. These agents have been studied in phase II trials (Lonning PE. JCO 18: 2234, 2000 and BCRT 67: 111, 2001) and showed time to progression of 15 and 18 weeks, respectively. A prospective trial of MA after AI failure is warranted. No significant financial relationships to disclose.

Semi-quantitative scoring of potentially predictive markers for endocrine treatment of breast cancer: a comparison between whole sections and tissue microarrays

Aim: To assess whether immunohistochemically stained tissue microarrays (TMA) of 2 mm cores from paraffin embedded tumour tissue may replace whole sections in semi-quantitative evaluation of selected potential markers for...

Optimising adjuvant endocrine treatment of breast cancer with aromatase inhibitors

There is mounting evidence that aromatase inhibitors (AIs) are superior to tamoxifen as adjuvant treatment for postmenopausal women with oestrogen receptor positive breast cancer. Nevertheless, tamoxifen still remains a useful and relatively nontoxic treatment, and further work is necessary to determine which patients need an AI. In terms of cost-effectiveness, letrozole has been estimated to be superior to tamoxifen. Anastrozole, letrozole and exemestane have not been compared directly in an adjuvant setting but letrozole proved superior to anastrozole in patients with advanced breast cancer. Although tumour receptor phenotype may be useful in selection for tamoxifen or AI, the evidence is mixed. Optimal sequencing and duration of treatment have yet to be determined. If nationally funded and organised trials could be instigated, these would give timely and reliable data, so that adjuvant endocrine treatment of breast cancer could be tailored to needs of the individual patient.

Quantitative Fluoroestradiol Positron Emission Tomography Imaging Predicts Response to Endocrine Treatment in Breast Cancer

In breast cancer, [(18)F]fluoroestradiol (FES) positron emission tomography (PET) correlates with estrogen receptors (ER) expression and predicts response to tamoxifen. We tested the ability of FES-PET imaging to predict response to salvage hormonal treatment in heavily pretreated metastatic breast cancer patients, predominantly treated with aromatase inhibitors. Initial FES uptake measurements in 47 patients with ER-positive tumors were correlated with subsequent tumor response to 6 months of hormonal treatment. Most patients had bone dominant disease and prior tamoxifen exposure. Response was compared to initial FES-PET uptake, measured qualitatively and quantitatively using standardized uptake value (SUV) and estradiol-binding flux. Eleven of 47 patients (23%) had an objective response. While no patients with absent FES uptake had a response to treatment, the association between qualitative FES-PET results and response was not significant (P = .14). However, quantitative FES uptake and response were significantly associated; zero of 15 patients with initial SUV less than 1.5 responded to hormonal therapy, compared with 11 of 32 patients (34%) with SUV higher than 1.5 (P < .01). In the subset of patients whose tumors did not overexpress HER2/neu, 11 of 24 patients (46%) with SUV higher than 1.5 responded. Quantitative FES-PET can predict response to hormonal therapy and may help guide treatment selection. Treatment selection using quantitative FES-PET in our patient series would have increased the rate of response from 23% to 34% overall, and from 29% to 46% in the subset of patients lacking HER2/neu overexpression. A multi-institutional collaborative trial would permit definitive assessment of the value of FES-PET for therapeutic decision making.