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This large randomized trial compared the standard adjuvant treatment for early breast cancer in postmenopausal women, five years of therapy with tamoxifen (an inhibitor of the estrogen receptor), with two to three years of tamoxifen followed by therapy with exemestane, an aromatase inhibitor, for the balance of the five-year period. Disease-free survival was significantly better in the exemestane group than in the tamoxifen group. Sequential use of antiestrogen compounds with different mechanisms may obviate the problem of resistance to tamoxifen. Breast cancer is estrogen-dependent in many cases, and reducing the estrogen levels by means of ovariectomy can cause regression of established disease, 1 especially if the tumor is rich in estrogen receptors. 2 The selective estrogen-receptor modulator tamoxifen blocks the action of estrogen by binding to one of the activating regions of the estrogen receptor. 3 , 4 When given to women with estrogen-receptor–positive breast cancer for five years after surgery, tamoxifen reduces the risk of recurrence by 47 percent and the risk of death by 26 percent. 5 The risk–benefit ratio of using tamoxifen for longer than five years remains unclear, 6 , 7 and trials . . .

Some oestrogen-receptor (ER) positive breast cancers express epidermal growth factor receptor (EGFR), but whether inhibition of EGFR can suppress proliferation of breast cancer cells and ER function is not known. In a double-blind, placebo-controlled randomised trial of 56 postmenopausal patients with ER-positive and EGFR-positive primary breast cancer, 27 women were randomly assigned to the tyrosine-kinase inhibitor of EGFR gefitinib (250 mg given orally once a day) and the aromatase inhibitor anastrozole (1 mg given orally once a day), and 29 women to gefitinib (250 mg given orally once a day) and placebo of identical appearance to anastrozole given orally once a day, all given for 4–6 weeks before surgery. Primary outcome was inhibition of tumour-cell proliferation, as measured by Ki67 antigen labelling index. Secondary outcomes were reduction in EGFR phosphorylation at Tyr 845, reduction in ER phosphorylation at Ser 118, tumour size, and toxic effects. Analyses were by intention to treat. Patients assigned gefitinib and anastrozole had a greater reduction from pretreatment values in proliferation-related Ki67 labelling index than did those assigned gefitinib alone (mean % reduction 98·0 [95% CI 96·1–98·9] vs 92·4 [85·1–96·1]; difference between groups 5·6% [5·1–6·0], p=0·0054). Tumour size was reduced by 30–99% (partial response) in 14 of 28 patients assigned gefitinib and anastrozole and in 12 of 22 assigned gefitinib, as assessed by ultrasonography. Reduction in phosphorylation of ER at Ser 118 was similar for both groups. Treatment was well tolerated and much the same for both groups. Single-agent gefitinib and gefitinib combined with anastrozole are well-tolerated and effective treatments for reducing the size of breast tumours and levels of ER phosphorylation when given as neoadjuvant therapy.

Key Points Breast cancer is the most common cancer of women in the western world. In most cases, breast cancer is oestrogen dependent, and treatment with oestrogen antagonists that inhibit oestrogen receptor (ER) action, particularly tamoxifen, has contributed to a dramatic reduction in breast cancer mortality. However, a substantial proportion of patients presenting with localized disease, and all of the patients with metastatic disease, become resistant to endocrine therapies. In most cases, the ER is present in resistant tumours, and in many of these its activity continues to regulate tumour growth. Resistance to endocrine therapy potentially arises by: ER activation in the absence of oestrogen; hypersensitivity of ER to low levels of circulating oestrogens; or ER activation, rather than inhibition, by oestrogen antagonists. At the molecular level, mechanisms responsible for resistance include: ER mutations that result in increased sensitivity to ligand and/or co-activator recruitment, and a resultant increase in ER activity. Post-translational modifications that result in ligand-independent activation of the ER. These modifications can be triggered by the oncogenic activation of growth-factor signalling pathways. Increased expression of the co-activator proteins that mediate ER activity. By contrast, downregulation of corepressor activity reduces the inhibitory potential of tamoxifen. Mitogenic and anti-apoptotic effects can be mediated by non-genomic effects of the ER, through direct interaction with key components of several signal-transduction pathways. Altered activity of these pathways could contribute to resistance. By understanding which of these pathways could be involved in mediating resistance, we might be able to develop strategies for overcoming or bypassing such resistance. Deaths from breast cancer have fallen markedly over the past decade due, in part, to the use of endocrine agents that reduce the levels of circulating oestrogens or compete with oestrogen for binding to its receptor. However, many breast tumours either fail to respond or become resistant to endocrine therapies. By understanding the mechanisms that underlie this resistance, we might be able to develop strategies for overcoming or bypassing it.

The role of estrogen receptor (ER) α as a target in treatment of breast cancer is clear, but those of ERβ1 and ERβ2 in the breast remain unclear. We have examined expression of all three receptors in surgically excised breast samples from two archives: (i): 187 invasive ductal breast cancer from a Japanese study; and (ii) 20 lobular and 24 ductal cancers from the Imperial College. Samples contained normal areas, areas of hyperplasia, and in situ and invasive cancer. In the normal areas, ERα was expressed in not more than 10% of epithelium, whereas approximately 80% of epithelial cells expressed ERβ. We found that whereas ductal cancer is a highly proliferative, ERα-positive, ERβ-negative disease, lobular cancer expresses both ERα and ERβ but with very few Ki67-positive cells. ERβ2 was expressed in 32% of the ductal cancers, of which 83% were postmenopausal. In all ERβ2-positive cancers the interductal space was filled with dense collagen, and cell nuclei expressed hypoxia-inducible factor 1α. ERβ2 expression was not confined to malignant cells but was strong in stromal, immune, and endothelial cells. In most of the high-grade invasive ductal cancers neither ERα nor ERβ was expressed, but in the high-grade lobular cancer ERβ was lost and ERα and Ki67 expression were abundant. The data show a clear difference in ER expression between lobular and ductal breast cancer and suggest (i) that tamoxifen may be more effective in late than in early lobular cancer and (ii) a potential role for ERβ agonists in preventing in situ ductal cancers from becoming invasive.

In a pooled analysis of nine clinical trials involving almost 5000 women with breast cancer who underwent examination of the bone marrow for metastatic cancer cells, the presence of metastases in the bone marrow at the time of diagnosis of breast cancer was associated with a poor prognosis. In trials involving almost 5000 women with breast cancer, the presence of micrometastases in the bone marrow at the time of diagnosis of breast cancer was associated with a poor prognosis. Data from experiments in animals 1 performed in the 1960s and from more recent immunocytochemical 2 , 3 and molecular 4 , 5 studies suggest that lymph-node involvement does not accurately predict hematogenous dissemination of cancer cells, nor is hematogenous dissemination necessarily associated with lymph-node involvement. 6 , 7 During the past two decades, several studies have assessed the prevalence and prognostic value of hematogenous dissemination of tumor cells in patients with node-positive and node-negative breast cancer. 3 , 8 – 15 The influence of the presence of micrometastasis in the bone marrow on prognosis has been shown in patients with identical stages of breast cancer, as defined by tumor . . .

A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast Cancer Original Article, N Engl J Med 2004:350;1081-1092.. On page 1083, in Figure 1, the number of patients who were assigned to receive two to three years of tamoxifen therapy should have read 2380, rather than 2362, as printed, and the number of patients assigned to receive exemestane therapy should have read 2362, rather than 2380, as printed.

In this study, we investigated the regulation of FOXM1 expression by estrogen receptor α (ERα) and its role in hormonal therapy and endocrine resistance. FOXM1 protein and mRNA expression was regulated by ER-ligands, including estrogen, tamoxifen (OHT) and fulvestrant (ICI182780; ICI) in breast carcinoma cell lines. Depletion of ERα by RNA interference (RNAi) in MCF-7 cells downregulated FOXM1 expression. Reporter gene assays showed that ERα activates FOXM1 transcription through an estrogen-response element (ERE) located within the proximal promoter region. The direct binding of ERα to the FOXM1 promoter was confirmed in vitro by mobility shift and DNA pull-down assays and in vivo by chromatin immunoprecipitation (ChIP) analysis. Our data also revealed that upon OHT treatment ERα recruits histone deacetylases to the ERE site of the FOXM1 promoter, which is associated with a decrease in histone acetylation and transcription activity. Importantly, silencing of FOXM1 by RNAi abolished estrogen-induced MCF-7 cell proliferation and overcame acquired tamoxifen resistance. Conversely, ectopic expression of FOXM1 abrogated the cell cycle arrest mediated by the anti-estrogen OHT. OHT repressed FOXM1 expression in endocrine sensitive but not resistant breast carcinoma cell lines. Furthermore, qRT–PCR analysis of breast cancer patient samples revealed that there was a strong and significant positive correlation between ERα and FOXM1 mRNA expression. Collectively, these results show FOXM1 to be a key mediator of the mitogenic functions of ERα and estrogen in breast cancer cells, and also suggest that the deregulation of FOXM1 may contribute to anti-estrogen insensitivity.

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE 100 C or endocrine therapy: letrozole 2.5 mg, daily for 18–23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95 % CI 57–81) were randomised. 12 (54.5, 95 % CI 32.2–75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95 % CI 36.4–79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2–4 and at surgery [fold change: 0.24 (95 % CI 0.12–0.51) and 0.24; (95 % CI 0.15–0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95 % CI 1.47–3.00), letrozole 1.47(95 % CI 0.98–2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95 % CI 1.56–4.41), letrozole 0.95 (95 % CI 0.71–1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

Tamoxifen preserves bone in postmenopausal women, but non-steroidal aromatase inhibitors accelerate bone loss and increase fracture risk. We aimed to study the effect on bone health in a subgroup of women included in the Intergroup Exemestane Study (IES), a large randomised trial that compared the switch to the steroidal aromatase inhibitor exemestane with continuation of tamoxifen in the adjuvant treatment of postmenopausal breast cancer. Results were analysed from 206 evaluable patients from the IES, in which postmenopausal women with histologically confirmed and completely resected unilateral breast cancer (that was oestrogen-receptor positive or of unknown status), who were disease-free after 2–3 years of treatment with tamoxifen were randomised to continue oral tamoxifen 20 mg/day or switch to oral exemestane 25 mg/day to complete a total of 5 years of adjuvant endocrine therapy. The primary endpoint was change in bone-mineral density (BMD) assessed by dual energy X-ray absorptiometry. Changes in biochemical markers of bone turnover were also analysed in this substudy, and the incidence of fractures in the entire study reported. The IES is registered on the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN11883920. Within 6 months of switching to exemestane, BMD was lowered by 0·051 g/cm 3 (2·7%; 95% CI 2·0–3·4; p<0·0001) at the lumbar spine and 0·025 g/cm 3 (1·4%; 0·8–1·9; p<0·0001) at the hip compared with baseline. BMD decreases were only 1·0% (0·4–1·7; p=0·002) and 0·8% (0·3–1·4; p=0·003) in year 2 at the lumbar spine and hip, respectively. No patient with BMD in the normal range at trial entry developed osteoporosis. Bone resorption and formation markers increased at all time points in women receiving exemestane (p<0·001). With a median follow-up in all IES participants (n=4274) of 58 months, 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio 1·45 [1·13–1·87]; p=0·003). These results indicate that the increase in survival shown previously with the IES switch strategy is achieved at the expense of some detriment to skeletal health, so the risk-benefit ratio to women needs to be individually assessed.

Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2–3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. After a median follow-up of 55·7 months (range 0–89·7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0·76 (95% CI 0·66–0·88, p=0·0001) in favour of exemestane, absolute benefit 3·3% (95% CI 1·6–4·9) by end of treatment (ie, 2·5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0·85 (95% CI 0·71–1·02, p=0·08), 0·83 (0·69–1·00, p=0·05) when 122 patients with oestrogen-receptor-negative disease were excluded. Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2–3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.