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Background Therapies targeting estrogenic stimulation in estrogen receptor-positive (ER+) breast cancer (BC) reduce mortality, but resistance remains a major clinical problem. Molecular studies have shown few high-frequency mutations to be associated with endocrine resistance. In contrast, expression profiling of primary ER+ BC samples has identified several promising signatures/networks for targeting. Methods To identify common adaptive mechanisms associated with resistance to aromatase inhibitors (AIs), we assessed changes in global gene expression during adaptation to long-term estrogen deprivation (LTED) in a panel of ER+ BC cell lines cultured in 2D on plastic (MCF7, T47D, HCC1428, SUM44 and ZR75.1) or in 3D on collagen (MCF7) to model the stromal compartment. Furthermore, dimethyl labelling followed by LC-MS/MS was used to assess global changes in protein abundance. The role of target genes/proteins on proliferation, ER-mediated transcription and recruitment of ER to target gene promoters was analysed. Results The cholesterol biosynthesis pathway was the common upregulated pathway in the ER+ LTED but not the ER– LTED cell lines, suggesting a potential mechanism dependent on continued ER expression. Targeting the individual genes of the cholesterol biosynthesis pathway with siRNAs caused a 30–50 % drop in proliferation. Further analysis showed increased expression of 25-hydroxycholesterol (HC) in the MCF7 LTED cells. Exogenous 25-HC or 27-HC increased ER-mediated transcription and expression of the endogenous estrogen-regulated gene TFF1 in ER+ LTED cells but not in the ER– LTED cells. Additionally, recruitment of the ER and CREB-binding protein (CBP) to the TFF1 and GREB1 promoters was increased upon treatment with 25-HC and 27-HC. In-silico analysis of two independent studies of primary ER+ BC patients treated with neoadjuvant AIs showed that increased expression of MSMO1 , EBP , LBR and SQLE enzymes, required for cholesterol synthesis and increased in our in-vitro models, was significantly associated with poor response to endocrine therapy. Conclusion Taken together, these data provide support for the role of cholesterol biosynthesis enzymes and the cholesterol metabolites, 25-HC and 27-HC, in a novel mechanism of resistance to endocrine therapy in ER+ BC that has potential as a therapeutic target.

Aromatase inhibitors (AIs) reduce recurrences and mortality in postmenopausal patients with oestrogen receptor positive (ER+) breast cancer (BC), but >20% of patients will eventually relapse. Given the limited understanding of intrinsic resistance in these tumours, here we conduct a large-scale molecular analysis to identify features that impact on the response of ER + HER2- BC to AI. We compare the 15% of poorest responders (PRs, n  = 177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant AI to good responders (GRs, n  = 190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In this work, low ESR1 levels are associated with poor response, high proliferation, high expression of growth factor pathways and non-luminal subtypes. PRs having high ESR1 expression have similar proportions of luminal subtypes to GRs but lower plasma estradiol levels, lower expression of estrogen response genes, higher levels of tumor infiltrating lymphocytes and immune markers, and more TP53 mutations. Aromatase inhibitors are an effective treatment for ER+ breast cancer, but response is variable. Here, the authors undertake molecular analyse of response from the POETIC trial and identify several factors associated with response.

Understanding the complex relationship between obesity and breast cancer is fundamental to our knowledge of the etiology of this malignancy; changes in the composition of the hormonal milieu are implicit in this process. Estrogens are synthesized from androgens by aromatase in the gonads and in peripheral tissues, principally, adipose tissue. Obesity in women, regardless of their age, leads to more aromatase and more extra-glandular estrogen production. In postmenopausal women, in whom ovarian estrogen production is absent, the increased incidence of breast cancer in women with high body mass index has been attributed to the relatively high plasma levels of estradiol from subcutaneous fat. In contrast, obesity in premenopausal women is associated with a previously unexplained reduced incidence of breast cancer. In obese premenopausal women, the cumulative effect of higher levels of estrogens synthesized in the peripheral tissues, together with ovarian estrogen production, results in a negative feedback on the hypothalamic pituitary controlled release of gonadotrophins and a resultant diminution in ovarian steroid production. As a consequence, the normal balance of estrogen and progesterone levels is disrupted: while estrogen levels are normalized, progesterone production is markedly decreased. Progesterone is a promoter of proliferation in the breast. The low levels of progesterone in obese premenopausal women are consistent with, and we propose, are responsible for, the reduction in breast cancer incidence in these women.

Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ~1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint β = -0.126; joint P = 2.09 × 10(-16)), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P<10(-5)), several were located at the CYP19A1 gene locus. Overall results were similar in secondary meta-analyses that included ~900 NHS current postmenopausal hormone users. No variant associated with estradiol, testosterone, or SHBG at P<10(-5) was associated with postmenopausal breast cancer risk among CGEMS participants. Our results suggest that the small magnitude of difference in hormone levels associated with common genetic variants is likely insufficient to detectably contribute to breast cancer risk.

Background: Recurrent epithelial ovarian cancer (EOC) remains difficult to treat, with an urgent need for more therapy options. Androgens bind to the androgen receptor (AR), commonly expressed in EOC. CYP17 inhibitor abiraterone irreversibly inhibits androgen biosynthesis. The Cancer of the Ovary Abiraterone (CORAL) trial was designed to evaluate the clinical activity of abiraterone in EOC. Patients & Methods: CORAL was a multi-centre, open-label, non-randomised, 2-stage phase II clinical trial. Eligible patients had progression within 12 months of last systemic therapy and no prior hormonal anti-cancer agents. Patients received abiraterone 1000 mg daily plus 5 mg prednisone until progression. The primary endpoint was objective response rate (ORR) according to combined Response Evaluation Criteria in Solid Tumours/Gynaecological Cancer Intergroup (RECIST/GCIG) criteria at 12 weeks. Secondary endpoints included clinical benefit rate (CBR) at 12 weeks. Results: A total of 42 patients were recruited; median age 65 (range 34–85) years; 37 (88.1%) had high-grade serous tumours; 20 (48%) had at least three prior lines of therapy; 29/40 (72.5%) were AR+. In stage 1, 1/26 response was observed (in an AR+, low-grade serous EOC); response lasted 47 weeks. Overall, 12 week ORR was 1/42 (2%), CBR was 11/42 (26%) (8/29 (28%) in AR+ patients). Disease control was ⩾6 months for 4/29 (14%). One patient (AR+, low-grade serous) had a RECIST response at 82 weeks. Four (10%) had grade ⩾3 hypokalaemia; 11 (26%) had dose delays. Conclusions: CORAL represents the first trial of an AR targeted agent in ovarian cancer. While responses were rare, a subset of patients achieved sustained clinical benefit. Targeting AR in EOC including low-grade serous cancer warrants further investigation. Trial registration: CORAL is registered on the ISRCTN registry: ISRCTN63407050; http://www.isrctn.com/ISRCTN63407050

Sex steroids have an important role in bone health, however previous studies on fracture risk have been carried out in older populations. The EPIC-Oxford study is a prospective cohort of men and women living in the UK. Five years after recruitment, participants self-reported previous fractures. Sex steroid concentrations (plasma estradiol, testosterone and sex hormone binding globulin) were measured in 436 cases (155 men, 46 premenopausal women and 235 postmenopausal women) with an incident fracture and 868 matched controls. Fracture risk was inversely related to concentrations of estradiol among men (RR for a doubling of estradiol 0.35, 95% CI 0.44-0.96) but there was no association between fracture risk and testosterone levels. There were no clear associations between fracture risk and hormone levels among postmenopausal women, however there was suggestion of an inverse association for both estradiol and testosterone as the RR in the highest compared with the lowest tertile for estradiol was 0.74 (95% CI 0.46, 1.18) and testosterone was 0.75 (95% CI 0.49, 1.16). Among premenopausal women fracture risk was inversely associated with levels of testosterone (RR for doubling of testosterone 0.46, 95% CI 0.26-0.81), with no association between estradiol and fracture risk. SHBG was not associated with risk of fracture among either men or women. In summary, this study finds evidence of an inverse association between endogenous estradiol and risk of fracture in men, and between endogenous testosterone and risk of fracture in premenopausal women but no clear associations among postmenopausal women.

The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen fulvestrant in combination with continued oestrogen deprivation. In a composite, multicentre, phase 3 randomised controlled trial done in the UK and South Korea, postmenopausal women with hormone-receptor-positive breast cancer (oestrogen receptor [ER] positive, progesterone receptor [PR] positive, or both) were eligible if they had relapsed or progressed with locally advanced or metastatic disease on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months). Additionally, patients had to have adequate organ function and a WHO performance status of 0–2. Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). Randomisation was done with computer-generated permuted blocks, and stratification was by centre and previous use of an NSAI as adjuvant treatment or for locally advanced or metastatic disease. Participants and investigators were aware of assignment to fulvestrant or exemestane, but not of assignment to anastrozole or placebo. The primary endpoint was progression-free survival (PFS). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, numbers NCT00253422 (UK) and NCT00944918 (South Korea). Between March 26, 2004, and Aug 6, 2010, 723 patients underwent randomisation: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4·4 months (95% CI 3·4–5·4) in patients assigned to fulvestrant plus anastrozole, 4·8 months (3·6–5·5) in those assigned to fulvestrant plus placebo, and 3·4 months (3·0–4·6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (hazard ratio 1·00, 95% CI 0·83–1·21; log-rank p=0·98), or between those assigned to fulvestrant plus placebo and exemestane (0·95, 0·79–1·14; log-rank p=0·56). 87 serious adverse events were reported: 36 in patients assigned to fulvestrant plus anastrozole, 22 in those assigned to fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3–4 adverse events were rare; the most frequent were arthralgia (three in the group assigned to fulvestrant plus anastrozole; seven in that assigned to fulvestrant plus placebo; eight in that assigned to exemestane), lethargy (three; 11; 11), and nausea or vomiting (five; two; eight). After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane. Cancer Research UK and AstraZeneca.

Up to 50 % of women receiving aromatase inhibitor (AI) complain of AI-associated musculoskeletal symptoms (AIMSS) and 15 % discontinue treatment. We conducted a randomized, sham-controlled trial to evaluate whether acupuncture improves AIMSS and to explore potential mechanisms. Postmenopausal women with early stage breast cancer, experiencing AIMSS were randomized to eight weekly real or sham acupuncture sessions. We evaluated changes in the Health Assessment Questionnaire Disability Index (HAQ-DI) and pain visual analog scale (VAS) following the intervention compared to baseline. Serum estradiol, β-endorphin, and proinflammatory cytokine concentrations were measured pre and post-intervention. We enrolled 51 women of whom 47 were evaluable, including 23 randomized to real and 24 to sham acupuncture. Baseline characteristics were balanced between groups with the exception of a higher HAQ-DI score in the real acupuncture group ( p  = 0.047). We did not observe a statistically significant difference in reduction of HAQ-DI ( p  = 0.30) or VAS ( p  = 0.31) between the two groups. Following eight weekly treatments, we observed a statistically significant reduction of IL-17 ( p  ≤ 0.009) in both groups. No significant modulation was seen in estradiol, β-endorphin, or other proinflammatory cytokine concentrations in either group. We did not observe a significant difference in AIMSS changes between real and sham acupuncture. As sham acupuncture used in this study may not be equivalent to placebo, further studies with a non-acupuncture arm may be required to establish whether acupuncture is beneficial for the treatment of AIMSS.

BackgroundResistance to endocrine therapy remains a major clinical problem in the treatment of oestrogen-receptor positive (ER+) breast cancer. Studies show androgen-receptor (AR) remains present in 80–90% of metastatic breast cancers providing support for blockade of AR-signalling. However, clinical studies with abiraterone, which blocks cytochrome P450 17A1 (CYP17A1) showed limited benefit.MethodsIn order to address this, we assessed the impact of abiraterone on cell-viability, cell-death, ER-mediated transactivation and recruitment to target promoters. together with ligand-binding assays in a panel of ER+ breast cancer cell lines that were either oestrogen-dependent, modelling endocrine-sensitive disease, or oestrogen-independent modelling relapse on an aromatase inhibitor. The latter, harboured wild-type (wt) or naturally occurring ESR1 mutations.ResultsSimilar to oestrogen, abiraterone showed paradoxical impact on proliferation by stimulating cell growth or death, depending on whether the cells are hormone-dependent or have undergone prolonged oestrogen-deprivation, respectively. Abiraterone increased ER-turnover, induced ER-mediated transactivation and ER-degradation via the proteasome.ConclusionsOur study confirms the oestrogenic activity of abiraterone and highlights its differential impact on cells dependent on oestrogen for their proliferation vs. those that are ligand-independent and harbour wt or mutant ESR1. These properties could impact the clinical efficacy of abiraterone in breast cancer.

Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had completed all planned treatment of a prior stage 0–III breast cancer received simvastatin 40 mg orally daily for 24–28 weeks. At baseline and end-of-study, we measured circulating concentrations of high-sensitivity C-reactive protein (hsCRP), estrogens, and fasting lipids; breast density on contralateral breast mammogram; and quality of life by Rand Short Form 36-Item health survey. Fifty women were enrolled with a median age of 53 years. Total cholesterol, LDL cholesterol, triglyceride, and hsCRP fell significantly during the study ( P values < 0.001, <0.001, 0.003, and 0.05, respectively). Estrone sulfate concentrations decreased with simvastatin treatment ( P  = 0.01 overall), particularly among post-menopausal participants ( P  = 0.006). We did not observe a significant change in circulating estradiol or estrone concentrations, contralateral mammographic breast density, or reported physical functioning or pain scores. This study demonstrates the feasibility of short-term biomarker modulation studies using the contralateral breast of high-risk women. Simvastatin appears to modulate estrone sulfate concentrations and its potential chemopreventive activity in breast cancer warrants further investigation.