Publications by authors named "Elizabeth Folkerd"

55 Publications

Abiraterone in patients with recurrent epithelial ovarian cancer: principal results of the phase II Cancer of the Ovary Abiraterone (CORAL) trial (CRUK - A16037).

Ther Adv Med Oncol 2020 29;12:1758835920975352. Epub 2020 Dec 29.

Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.

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.
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http://dx.doi.org/10.1177/1758835920975352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013695PMC
December 2020

Menstrual cycle associated changes in hormone-related gene expression in oestrogen receptor positive breast cancer.

NPJ Breast Cancer 2019 15;5:42. Epub 2019 Nov 15.

1The Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, Fulham Road, London, UK.

The major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used. Plasma hormone measurements were used to assign tumours to one of three pre-defined menstrual cycle windows: W1 (days 27-35 and 1-6; low oestradiol and low progesterone), W2 (days 7-16; high oestradiol and low progesterone) and W3 (days 17-26; intermediate oestradiol and high progesterone). RNA expression of 50 genes, including 27 ERGs, 11 putative PRGs and seven PAGs was measured. The AvERG (geomean of , , and ) was used as a composite measure of ERG expression and showed significant changes between the three windows of the menstrual cycle increasing over 2.2-fold between W1 and W2 and decreasing between W2 and W3 and between W3 and W1. Proliferation gene expression also varied significantly, following the same pattern of changes as ERG expression, but the changes were of lower magnitude (1.4-fold increase between W1 and W2). Significant changes in the expression of eight individual ERGs, including , and , and two PAGs were observed between W1 and either W2 or W3 with all genes showing higher levels in W2 or W3 (1.3-2.4-fold; FDR 0.016-0.05). The AvProg, a composite measure of PRG expression, increased significantly (1.5-fold) in W3 compared to W1 or W2 but no significant changes were observed for individual PRGs. In conclusion, we observed significant changes in ERG, PRG and PAG expression in ER+ breast tumours during the menstrual cycle that may affect the assessment and interpretation of prominent biomarkers (e.g. PgR) and commonly used multigene prognostic signatures in premenopausal ER+ breast cancer.
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http://dx.doi.org/10.1038/s41523-019-0138-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858333PMC
November 2019

Circulating Growth and Sex Hormone Levels and Breast Tissue Composition in Young Nulliparous Women.

Cancer Epidemiol Biomarkers Prev 2018 12 18;27(12):1500-1508. Epub 2018 Sep 18.

Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom.

Background: Endogenous hormones are associated with breast cancer risk, but little is known about their role on breast tissue composition, a strong risk predictor. This study aims to investigate the relationship between growth and sex hormone levels and breast tissue composition in young nulliparous women.

Methods: A cross-sectional study of 415 young (age ∼21.5 years) nulliparous women from an English prebirth cohort underwent a MRI examination of their breasts to estimate percent-water (a proxy for mammographic percent density) and provided a blood sample to measure plasma levels of growth factors (insulin-like growth factor-I, insulin-like growth factor-II, insulin growth factor-binding protein-3, growth hormone) and, if not on hormonal contraception ( = 117) sex hormones (dehydroepiandrosterone, androstenedione, testosterone, estrone, estadiol, sex hormone-binding globulin, prolactin). Testosterone ( = 330) and sex hormone-binding globulin ( = 318) were also measured at age 15.5 years. Regression models were used to estimate the relative difference (RD) in percent-water associated with one SD increment in hormone levels.

Results: Estradiol at age 21.5 and sex hormone-binding globulin at age 21.5 were positively associated with body mass index (BMI)-adjusted percent-water [RD (95% confidence interval (CI)): 3% (0%-7%) and 3% (1%-5%), respectively]. There was a positive nonlinear association between androstenedione at age 21.5 and percent-water. Insulin-like growth factor-I and growth hormone at age 21.5 were also positively associated with BMI-adjusted percent-water [RD (95% CI): 2% (0%-4%) and 4% (1%-7%), respectively].

Conclusions: The findings suggest that endogenous hormones affect breast tissue composition in young nulliparous women.

Impact: The well-established associations of childhood growth and development with breast cancer risk may be partly mediated by the role of endogenous hormones on breast tissue composition.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0036DOI Listing
December 2018

Abiraterone shows alternate activity in models of endocrine resistant and sensitive disease.

Br J Cancer 2018 08 11;119(3):313-322. Epub 2018 Jul 11.

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK.

Background: Resistance 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.

Methods: In 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.

Results: Similar 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.

Conclusions: Our 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.
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http://dx.doi.org/10.1038/s41416-018-0158-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068155PMC
August 2018

Molecular changes in premenopausal oestrogen receptor-positive primary breast cancer in Vietnamese women after oophorectomy.

NPJ Breast Cancer 2017 27;3:47. Epub 2017 Nov 27.

The Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, Fulham Road, London, UK.

For premenopausal women with primary ER + breast cancer, oophorectomy (OvX) is an evidence-based cost-effective option and is standard treatment in many countries. However, there is virtually no data describing the effects of OvX on breast tumour biology. We therefore, characterised the endocrine and genome-wide transcriptional impact of OvX in 56 premenopausal women with ER + breast cancer for 2 weeks prior to mastectomy. Plasma estradiol concentrations decreased from 406 ± 41 to 20.7 ± 2.6 pmol/l (mean ± sem) 24 h after OvX, and to 8.1 ± 0.8 pmol/l 2 weeks later at mastectomy. Ki67 decreased in 33/36 (91.7%) tumours. The expression of 655 genes changed significantly (FDR < 1%) with an absolute mean fold-change (FC) ≥ 1.25 (257 up, 398 down). Archetypal oestrogen-regulated genes (TFF1, GREB1, PGR and PDZK1) showed large decreases in expression (FC = 0.20-0.69;  < 1e-6-1e-7). Proliferation-associated genes (e.g. TOP2A, AURKA and UBE2C) were also strongly downregulated (FC = 0.38-0.56;  < 1e-7) along with putative progesterone-regulated genes (e.g. FKBP4, MYB; FC = 0.64-0.68;  < 1e-4-1e-7). The gene expression changes did not differ according to HER2 status and correlated strongly with the changes reported previously after aromatase inhibitor (AI) treatment in postmenopausal women (rho = 0.55,  < 1e-04). However, after OvX the mean FC was significantly higher compared to AI ( < 1e-04). In conclusion, changes in tumoural gene expression after OvX were largely similar, but of a greater magnitude to those observed after AI in postmenopausal patients; however, OvX appeared to have a greater effect on progesterone-regulated genes than AI.
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http://dx.doi.org/10.1038/s41523-017-0049-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703856PMC
November 2017

Palbociclib Combined with Fulvestrant in Premenopausal Women with Advanced Breast Cancer and Prior Progression on Endocrine Therapy: PALOMA-3 Results.

Oncologist 2017 09 26;22(9):1028-1038. Epub 2017 Jun 26.

Royal Marsden Hospital and Institute of Cancer Research, London, UK.

Background: The efficacy and safety of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, combined with fulvestrant and goserelin was assessed in premenopausal women with advanced breast cancer (ABC) who had progressed on prior endocrine therapy (ET).

Patients And Methods: One hundred eight premenopausal endocrine-refractory women ≥18 years with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC were among 521 women randomized 2:1 (347:174) to fulvestrant (500 mg) ± goserelin with either palbociclib (125 mg/day orally, 3 weeks on, 1 week off) or placebo. This analysis assessed whether the overall tolerable safety profile and significant progression-free survival (PFS) improvement extended to premenopausal women. Potential drug-drug interactions (DDIs) and ovarian suppression with goserelin were assessed via plasma pharmacokinetics and biochemical analyses, respectively. (ClinicalTrials.gov identifier: NCT01942135) RESULTS: Median PFS for premenopausal women in the palbociclib ( = 72) versus placebo arm ( = 36) was 9.5 versus 5.6 months, respectively (hazard ratio, 0.50, 95% confidence interval: 0.29-0.87), and consistent with the significant PFS improvement in the same arms for postmenopausal women. Any-grade and grade ≤3 neutropenia, leukopenia, and infections were among the most frequent adverse events reported in the palbociclib arm with concurrent goserelin administration. Hormone concentrations were similar between treatment arms and confirmed sustained ovarian suppression. Clinically relevant DDIs were not observed.

Conclusion: Palbociclib combined with fulvestrant and goserelin was an effective and well-tolerated treatment for premenopausal women with prior endocrine-resistant HR+/HER2- ABC. Inclusion of both premenopausal and postmenopausal women in pivotal combination ET trials facilitates access to novel drugs for young women and should be considered as a new standard for clinical trial design.

Implications For Practice: PALOMA-3, the first registrational study to include premenopausal women in a trial investigating a CDK4/6 inhibitor combined with endocrine therapy, has the largest premenopausal cohort reported in an endocrine-resistant setting. In pretreated premenopausal women with hormone receptor-positive advanced breast cancer, palbociclib plus fulvestrant and goserelin (luteinizing hormone-releasing hormone [LHRH] agonist) treatment almost doubled median progression-free survival (PFS) and significantly increased the objective response rate versus endocrine monotherapy, achieving results comparable to those reported for chemotherapy without apparently interfering with LHRH agonist-induced ovarian suppression. The significant PFS gain and tolerable safety profile strongly support use of this regimen in premenopausal women with endocrine-resistant disease who could possibly delay chemotherapy.
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http://dx.doi.org/10.1634/theoncologist.2017-0072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599195PMC
September 2017

Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer.

Breast Cancer Res 2016 06 1;18(1):58. Epub 2016 Jun 1.

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.

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.
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http://dx.doi.org/10.1186/s13058-016-0713-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888666PMC
June 2016

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer.

Endocr Relat Cancer 2016 Feb 16;23(2):77-91. Epub 2015 Nov 16.

Department of Public Health and Primary CareCentre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, Cambridge CB1 8RN, UKDepartment of Genetics and Computational BiologyQIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, AustraliaWellcome Trust Centre for Human GeneticsUniversity of Oxford, Oxford OX3 7BN, UKAcademic Department of BiochemistryRoyal Marsden Hospital, London SW3 6JJ, UKDepartment of Clinical GeneticsSt George's Hospital Medical School, London SW17 0RE, UKDepartment of OncologyCentre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UKDepartment of Medical Epidemiology and BiostatisticsKarolinska Institutet, Stockholm SE-171 77, SwedenDepartment of MedicineDivision of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USADepartment of Gynecology and ObstetricsUniversity Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, GermanyInstitute of Human GeneticsUniversity Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, GermanyGynaecology Research UnitHannover Medical School, Hannover 30625, GermanyClinics of Gynaecology and ObstetricsHannover Medical School, Hannover 30625, GermanyDepartment of GynaecologyJena University Hospital - Friedrich Schiller University, Jena 07743, GermanyVesalius Research CenterLeuven 3000, BelgiumLaboratory for Translational GeneticsDepartment of Oncology, University Hospitals Leuven, Leuven 3000, BelgiumDepartment of Obstetrics and GynecologyDivision of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Leuven 3000, BelgiumDepartment of Health Sciences ResearchMayo Clinic, Rochester, Minnesota 55905, USADepartment of BiostatisticsUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USADepartment of Obstetrics and GynecologyDivision of G

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
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http://dx.doi.org/10.1530/ERC-15-0386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697192PMC
February 2016

Reduced progesterone levels explain the reduced risk of breast cancer in obese premenopausal women: a new hypothesis.

Breast Cancer Res Treat 2015 Jan 21;149(1):1-4. Epub 2014 Nov 21.

Academic Department of Biochemistry, Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK.

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.
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http://dx.doi.org/10.1007/s10549-014-3211-4DOI Listing
January 2015

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study.

Breast Cancer Res 2014 May 26;16(3):R51. Epub 2014 May 26.

Department of Obstetrics and Gynecology, University of Heidelberg, Vosstrasse 9, 69115, Heidelberg, Germany.

Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.

Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.

Results: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29).

Conclusions: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
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http://dx.doi.org/10.1186/bcr3662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522594PMC
May 2014

Interpreting plasma estrogen levels in breast cancer: caution needed.

J Clin Oncol 2014 May 14;32(14):1396-400. Epub 2014 Apr 14.

The Institute of Cancer Research; Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.

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http://dx.doi.org/10.1200/JCO.2013.53.9411DOI Listing
May 2014

Reproducibility of estradiol and testosterone levels in postmenopausal women over 5 years: results from the breakthrough generations study.

Am J Epidemiol 2014 May 30;179(9):1128-33. Epub 2014 Mar 30.

Prospective cohort studies examining sex hormones in relation to cancer risk have generally collected blood samples at 1 time point, with an assumption that hormone levels measured in these samples will be reliable markers of true levels at other times. In postmenopausal women, body fat is a major source of estradiol; therefore, changes in adiposity may affect the correlation of single measurements to more relevant long-term averages. To estimate the intraclass correlation coefficient (ICC) for estradiol and testosterone, we collected repeat blood samples from 119 postmenopausal women (average age = 59.4 (standard deviation, 4.7) years) from the United Kingdom during 2004-2005 and again during 2010-2011. The ICCs (adjusted for assay variation) were 0.73 (95% confidence interval: 0.63, 0.82) for total estradiol and 0.59 (95% confidence interval: 0.47, 0.72) for total testosterone. The ICCs were 3%-5% larger after adjustment for change in body mass index (weight (kg)/height (m)(2)) or leptin, which are 2 markers of change in adiposity. There was no increase in ICCs after adjustment for change in age, alcohol consumption, smoking, exercise, time between waking and blood collection, or season. The results suggest that other factors account for within-woman variation in these sex hormones.
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http://dx.doi.org/10.1093/aje/kwu027DOI Listing
May 2014

Sex hormones and breast cancer risk and prognosis.

Breast 2013 Aug;22 Suppl 2:S38-43

The Academic Department of Biochemistry, The Royal Marsden NHS Foundation Trust, Wallace Wing, Fulham Road, London SW3 6JJ, UK. Electronic address:

The study of large prospective collections of plasma samples from women prior to the development of breast cancer has firmly established certain sex steroids as being significantly associated with risk. The strongest associations have been found in postmenopausal women in whom the within person variability of most hormones is markedly reduced but some positive associations have also been seen in premenopausal women. Plasma estrogens show the strongest correlations with risk and these are strengthened by measurement or calculation of the proportion of estradiol that circulates free of sex hormone binding globulin (SHBG), consistent with this being the most active fraction. The relationships have been reported to potentially explain virtually all of the association of breast cancer with body mass index in postmenopausal women; this is likely to be due to non-ovarian estrogen synthesis being prominent in subcutaneous fat. These strong relationships have led to plasma and urine estrogen levels being used as intermediate end-points in the search for genes that affect breast cancer risk via their role in steroid disposition. Plasma androgen levels also show a relationship with breast cancer risk that is weakened but not eliminated by 'correction' for estrogen levels. This has been argued to be evidence of the local production of estrogens being important in the etiology of breast cancer. Given that plasma steroid levels do not correlate closely with mammographic density, which is strongly associated with risk, the opportunity exists to combine the two factors in assessing breast cancer risk but the low availability of suitable estrogen assays is a major impediment to this. In established breast cancer, plasma estrogens have been found to correlate with gene expression of estrogen dependent genes and the expression of these varies across the menstrual cycle of premenopausal women. There is infrequently a need for routine measurement of plasma estrogen levels but it has been important in the comparative pharmacology and dose-related effectiveness of aromatase inhibitors. Measurement may be needed to identify residual ovarian function in women who have amenorrhea subsequent to cytotoxic chemotherapy indicating their unsuitability for aromatase inhibitor treatment. Use of highly sensitive assays has also revealed that the association between BMI and plasma estrogen levels persists in patients on 3rd generation aromatase inhibitors and that measurable increments in plasma estrogen levels occur with some vaginal estrogen preparations that are of concern in relation to treatment efficacy.
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http://dx.doi.org/10.1016/j.breast.2013.07.007DOI Listing
August 2013

Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial.

Lancet Oncol 2013 Sep 29;14(10):989-98. Epub 2013 Jul 29.

Royal Marsden NHS Foundation Trust, London, UK.

Background: 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.

Methods: 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).

Findings: 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).

Interpretation: 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.
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http://dx.doi.org/10.1016/S1470-2045(13)70322-XDOI Listing
September 2013

Changes in estradiol and testosterone levels in postmenopausal women after changes in body mass index.

J Clin Endocrinol Metab 2013 Jul 10;98(7):2967-74. Epub 2013 May 10.

Division of Genetics and Epidemiology, The Institute of Cancer Research, University of London, Sutton SM2 5NG and London SW3 6JB, United Kingdom.

Context: Endogenous sex hormones are risk factors for postmenopausal breast cancer. A potential route for favorable hormonal modification is weight loss.

Objective: The objective of the study was to measure change in plasma estradiol and testosterone levels in postmenopausal women in relation to change in body mass index (BMI) and plasma leptin.

Setting: The setting was a cohort study of over 100,000 female volunteers from the general population, United Kingdom.

Participants: The participants were a sample of 177 postmenopausal women aged over 45 years who provided blood samples during 2004-2005 and again during 2010-2011.

Main Outcome Measure: Outcomes were percentage change in plasma estradiol and testosterone levels per 1 kg/m² change in BMI and per 1 ng/mL change in plasma leptin.

Results: Among women with reduction in BMI, estradiol decreased 12.7% (95% confidence interval: [6.4%, 19.5%]; P < .0001) per kg/m² and among women with increased BMI estradiol increased 6.4% [0.2%, 12.9%] (P = .042). The corresponding figures for testosterone were 10.7% [3.0%, 19.0%] (P = .006) and 1.9% [-5.4%, 9.7%] (P = .61) per kg/m². For women with decreases and increases in leptin, estradiol decreased by 3.6% [1.3%, 6.0%] (P = .003) per ng/mL and increased by 1.7% [-0.3%, 3.6%] (P = .094), respectively. The corresponding figures for testosterone were 4.8% [2.0%, 7.8%] (P = .009) and 0.3% [-2.0%, 2.6%] (P = .82) per ng/mL.

Conclusions: In postmenopausal women, changes in BMI and plasma leptin occurring over several years are associated with changes in estradiol and testosterone levels. The results suggest that fat loss by an individual can result in substantial decreases in postmenopausal estradiol and testosterone levels and provides support for weight management to lessen breast cancer risk.
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http://dx.doi.org/10.1210/jc.2013-1588DOI Listing
July 2013

A dual-center randomized controlled double blind trial assessing the effect of acupuncture in reducing musculoskeletal symptoms in breast cancer patients taking aromatase inhibitors.

Breast Cancer Res Treat 2013 Feb 8;138(1):167-74. Epub 2013 Feb 8.

University of Maryland Greenebaum Cancer Center, Baltimore, MD 20201, USA.

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.
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http://dx.doi.org/10.1007/s10549-013-2427-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594526PMC
February 2013

The heritability of mammographic breast density and circulating sex-hormone levels: two independent breast cancer risk factors.

Cancer Epidemiol Biomarkers Prev 2012 Dec 16;21(12):2167-75. Epub 2012 Oct 16.

Department of Public Heath and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.

Background: Mammographic breast density and endogenous sex-hormone levels are both strong risk factors for breast cancer. This study investigated whether there is evidence for a shared genetic basis between these risk factors.

Methods: Using data on 1,286 women from 617 families, we estimated the heritabilities of serum estradiol, testosterone, and sex-hormone binding globulin (SHBG) levels and of three measures of breast density (dense area, nondense area, and percentage density). We tested for associations between hormone levels and density measures and estimated the genetic and environmental correlations between pairs of traits using variance and covariance components models and pedigree-based maximum likelihood methods.

Results: We found no significant associations between estradiol, testosterone, or SHBG levels and any of the three density measures, after adjusting for body mass index (BMI). The estimated heritabilities were 63%, 66%, and 65% for square root-transformed adjusted percentage density, dense area, and nondense area, respectively, and 40%, 25%, and 58% for log-transformed-adjusted estradiol, testosterone, and SHBG. We found no evidence of a shared genetic basis between any hormone levels and any measure of density, after adjusting for BMI. The negative genetic correlation between dense and nondense areas remained significant even after adjustment for BMI and other covariates (ρ = -0.34; SE = 0.08; P = 0.0005).

Conclusions: Breast density and sex hormones can be considered as independent sets of traits.

Impact: Breast density and sex hormones can be used as intermediate phenotypes in the search for breast cancer susceptibility loci.
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http://dx.doi.org/10.1158/1055-9965.EPI-12-0789DOI Listing
December 2012

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.

J Oncol Pract 2012 May 7;8(3):144-8. Epub 2012 Feb 7.

William Beaumont Hospital, Royal Oak; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; and The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom.

Background: Intravaginal estradiols (VE) have been proposed as safe alternatives to systemic estrogen therapy in breast cancer survivors.

Patients And Methods: Postmenopausal women with estrogen receptor-positive breast cancer or at high risk for breast cancer (n = 24) who were taking an aromatase inhibitor (AI) or a selective estrogen receptor modulator (SERM) and VE for ≥ 90 days for atrophic vaginitis and 24 controls taking AI only participated in the study. Serum samples were drawn from VE ring patients before insertion and 30 and 60 days postinsertion, from VE tablet patients the morning before insertion and approximately 12 hours postinsertion, and once from controls. Samples were assayed for E2 concentrations by using highly sensitive radioimmunoassay after ether extraction.

Results: Mean E2 levels in controls were 3.72 pmol/L (range, < 3.0-7.7 pmol/L); mean E2 levels preinsertion and 12 weeks postinsertion in the VE ring patients were significantly greater than controls (P < .001 for each comparison). Mean preinsertion E2 levels in patients using VE tablets were not significantly different than those of controls (P = .48), and postinsertion levels were 76 pmol/L higher than preinsertion (P < .001).

Conclusion: VE treatment increased E2 levels. Preinsertion levels for patients receiving VE tablets were not elevated compared with those of controls, suggesting that E2 elevations with this preparation may not be continuously sustained. We conclude that VE treatment, regardless of type, results in elevated circulating E2 levels in this population and should be used with caution.
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http://dx.doi.org/10.1200/JOP.2011.000352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396801PMC
May 2012

Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer.

J Clin Oncol 2012 Aug 16;30(24):2977-80. Epub 2012 Jul 16.

Royal Marsden Hospital, London, United Kingdom.

Purpose: To investigate whether suppression of plasma estradiol and estrone sulfate levels by the aromatase inhibitors (AIs) anastrozole and letrozole is related to body mass index (BMI) in postmenopausal women with early estrogen receptor (ER) -positive breast cancer. Recent studies have reported that the AI anastrozole has lower effectiveness than tamoxifen in women with high BMI. This effect with high BMI might hypothetically be a result of reduced inhibition of aromatase and suppression of plasma estrogen levels and might be overcome by the use of an increased dose of anastrozole or, alternatively, the use of a more potent AI such as letrozole.

Patients And Methods: Plasma estradiol and estrone sulfate levels from a highly sensitive radioimmunoassay were available for 44 postmenopausal patients who received anastrozole (1 mg per day) for 3 months followed by letrozole (2.5 mg per day) for 3 months or the opposite sequence. Correlations between the estrogen suppression by each AI and BMI were assessed.

Results: Baseline values of estradiol and estrone sulfate were significantly correlated with BMI (r = 0.57; P < .001, and r = 0.38; P = .006, respectively). Levels of estrogen in patients receiving treatment were greater at higher levels of BMI with both AIs, but although this was significant with letrozole (r = 0.35; P = .013, and r = 0.30; P = .035 for estradiol and estrone sulfate, respectively), it was not with anastrozole. Suppression of both estrogen types was greater with letrozole across the full range of BMIs in this study.

Conclusion: The suppressed levels of plasma estradiol and estrone sulfate in postmenopausal women with early ER-positive breast cancer treated with the AIs anastrozole and letrozole are related to BMI.
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http://dx.doi.org/10.1200/JCO.2012.42.0273DOI Listing
August 2012

Genome-wide association study of circulating estradiol, testosterone, and sex hormone-binding globulin in postmenopausal women.

PLoS One 2012 4;7(6):e37815. Epub 2012 Jun 4.

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366971PMC
October 2012

CYP3A variation, premenopausal estrone levels, and breast cancer risk.

J Natl Cancer Inst 2012 May 3;104(9):657-69. Epub 2012 Apr 3.

The Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London, UK.

Background: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women.

Methods: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided.

Results: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82).

Conclusions: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.
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http://dx.doi.org/10.1093/jnci/djs156DOI Listing
May 2012

Testosterone, SHBG and differential white blood cell count in middle-aged and older men.

Maturitas 2012 Mar 4;71(3):274-8. Epub 2012 Jan 4.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.

Objective: Low-grade chronic inflammation is increasingly being implicated in cardiovascular disease (CVD) etiology and may represent an alternative pathway through which testosterone and sex hormone-binding globulin (SHBG) influence CVD risk. We examined the associations between endogenous testosterone, SHBG and total and differential white blood cell (WBC) counts in men.

Methods: Cross-sectional study of 2418 men aged 40-78 years from the Norfolk population of European Prospective Investigation into Cancer (EPIC-Norfolk) who had no history of CVD or cancer and complete data on sex hormones (total testosterone (TT), SHBG and free testosterone (FT)) and WBC counts. Associations between sex hormones and WBC counts were assessed using linear regression models.

Results: Higher SHBG and TT levels were associated with lower WBC counts. After adjustment for age, BMI, smoking, physical activity and diabetes status, total WBC count decreased by 0.163 (95% CI -0.236; -0.091) and 0.102 (-0.170; -0.034) per standard deviation (SD) increase in SHBG and TT respectively. Associations of SHBG and TT with total WBC count were mainly accounted for by a lower granulocyte count (β coefficient=-0.132 (-0.194; -0.070) per SD increase in SHBG and β coefficient=-0.104 (-0.161; -0.046) per SD increase in TT). No associations between FT and total and differential WBC counts were found.

Conclusions: Endogenous TT and SHBG levels are inversely associated with total WBC and granulocyte count in middle-aged and older men. Even though the underlying mechanism and causal directionality requires further exploration, these results support a link between hormonal status and low-grade inflammation.
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http://dx.doi.org/10.1016/j.maturitas.2011.12.007DOI Listing
March 2012

Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer.

J Clin Endocrinol Metab 2012 Feb 14;97(2):507-16. Epub 2011 Dec 14.

The Institute of Cancer Research, Sutton, Surrey SM2 5PT, UK.

Context: Abiraterone acetate is a small-molecule cytochrome P450 17A1 (CYP17A1) inhibitor that is active in castration-resistant prostate cancer.

Objective: Our objective was to determine the impact of abiraterone with and without dexamethasone treatment on in vivo steroidogenesis.

Design And Methods: We treated 42 castrate, castration-resistant prostate cancer patients with continuous, daily abiraterone acetate and prospectively collected blood and urine before and during abiraterone treatment and after addition of dexamethasone 0.5 mg daily.

Results: Treatment with single-agent abiraterone acetate was associated with accumulation of steroids with mineralocorticoid properties upstream of CYP17A1. This resulted in side effects, including hypertension, hypokalemia, and fluid overload, in 38 of 42 patients that were generally treated effectively with eplerenone. Importantly, serum and urinary androgens were suppressed by more than 90% from baseline. Urinary metabolites of 17-hydroxypregnenolone and 17-hydroxyprogesterone downstream of 17α-hydroxylase remained unchanged. However, 3α5α-17-hydroxypregnanolone, which can be converted via the backdoor pathway toward 5α-dihydrotestosterone, increased significantly and correlated with levels of the major 5α-dihydrotestosterone metabolite androsterone. In contrast, urinary metabolites of 11-deoxycortisol and active glucocorticoids declined significantly. Addition of dexamethasone to abiraterone acetate significantly suppressed ACTH and endogenous steroids, including 3α5α-17-hydroxypregnanolone.

Conclusion: CYP17A1 inhibition with abiraterone acetate is characterized by significant suppression of androgen and cortisol synthesis. The latter is associated with a rise in ACTH that causes raised mineralocorticoids, leading to side effects and incomplete 17α-hydroxylase inhibition. Concomitant inhibition of 17,20-lyase results in diversion of 17-hydroxyprogesterone metabolites toward androgen synthesis via the backdoor pathway. Addition of dexamethasone reverses toxicity and could further suppress androgens by preventing a rise in substrates of backdoor androgen synthesis.
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http://dx.doi.org/10.1210/jc.2011-2189DOI Listing
February 2012

A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.

Breast Cancer Res Treat 2012 Feb 11;131(3):915-24. Epub 2011 Nov 11.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRBI, Room 144, Baltimore, MD 21231, USA.

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.
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http://dx.doi.org/10.1007/s10549-011-1858-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536477PMC
February 2012

Changes in breast density and circulating estrogens in postmenopausal women receiving adjuvant anastrozole.

Cancer Prev Res (Phila) 2011 Dec 1;4(12):1993-2001. Epub 2011 Sep 1.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Factors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: -16%, 95% CI: -30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: -93%, 95% CI: -94 to -91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes.
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http://dx.doi.org/10.1158/1940-6207.CAPR-11-0154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700336PMC
December 2011

Cigarette smoking and endogenous sex hormones in postmenopausal women.

J Clin Endocrinol Metab 2011 Oct 10;96(10):3184-92. Epub 2011 Aug 10.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 CA Utrecht, The Netherlands.

Context: Sex hormones play a key role in women's health, but little is known about lifestyle factors that influence their levels.

Objective: The objective of the study was to investigate the relationship between cigarette smoking habits and endogenous sex hormone levels in postmenopausal women.

Design And Participants: This was a cross-sectional study among 2030 postmenopausal women aged 55-81 yr from the Norfolk population of the European Prospective Investigation into Cancer. All women were at least 1 yr postmenopausal and not currently using hormone replacement therapy. General linear models were used to examine the relationship between smoking habits and sex hormone levels.

Results: Among current smokers, the daily number of cigarettes smoked was associated with increased levels of testosterone (19-37%), free testosterone (19-34%), 17-hydroxprogesterone (17-22%), androstenedione (2-23%), SHBG (6-10%), and estradiol (-2 to 15%). Stratified analysis for body mass index revealed an interaction such that the association with SHBG was restricted to lean women, whereas a smoking-related increase in free estradiol was found only in overweight women. No clear dose-response relationship was observed for estrone, although its levels were highest in heavy smokers. Current smoking habit was associated with a larger difference in sex hormone levels than lifetime cigarette exposure as measured by pack-years. Among former smokers, sex hormones were at levels of never smokers within 1-2 yr of smoking cessation.

Conclusions: Cigarette smoking is associated with higher circulating levels of androgens, estrogens, 17-hydroxprogesterone, and SHBG in postmenopausal women. The almost immediate lower levels with smoking cessation may indicate that hormone related disease risks could potentially be modified by changing smoking habits.
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http://dx.doi.org/10.1210/jc.2011-1165DOI Listing
October 2011

Associations of endogenous testosterone and SHBG with glycated haemoglobin in middle-aged and older men.

Clin Endocrinol (Oxf) 2011 May;74(5):572-8

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: Low circulating levels of testosterone and sex-hormone-binding globulin (SHBG) are associated with increased cardiovascular risk in men. This association may be partially mediated through changes in glucose metabolism, but relatively few data are available on the relationship between sex hormones and markers of long-term glycaemia. We assessed the associations of endogenous testosterone and SHBG with glycated haemoglobin (HbA(1c) ) in men.

Design And Subjects: Cross-sectional study of 1292 men from the Norfolk population of European Prospective Investigation into Cancer (EPIC-Norfolk).

Measurements: Glycated haemoglobin, total testosterone (TT) and SHBG levels were measured, and free testosterone (FT) levels were calculated. Multiple linear regression models were used to assess the associations of TT, SHBG and FT with HbA(1c).

Results: Men with diabetes had lower testosterone and SHBG levels. In non-diabetic men, HbA(1c) levels were inversely associated with TT and calculated FT independently of age, body mass index, smoking, alcohol consumption and physical activity. The adjusted change in HbA(1c) was 0·055 (95% CI 0·025; 0·085) per standard deviation (SD) decrease in TT and 0·041 (95% CI 0·010; 0·073) per SD decrease in calculated FT, respectively. SHBG levels were inversely associated with HbA(1c) after multivariable adjustment (β = 0·038 per SD decrease (95% CI 0·004; 0·071)).

Conclusions: In middle-aged and older men, low endogenous testosterone and SHBG levels are associated with glycaemia, even below the threshold for diabetes. Further studies are needed to determine the effects of interventions that raise testosterone levels in men having increased HbA(1c) and subnormal testosterone levels.
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http://dx.doi.org/10.1111/j.1365-2265.2010.03951.xDOI Listing
May 2011

Influence of sex hormones on cancer progression.

J Clin Oncol 2010 Sep 19;28(26):4038-44. Epub 2010 Jul 19.

The Academic Department of Biochemistry, the Royal Marsden NHS Foundation Trust, Fulham Rd, London, SW3 6JJ, United Kingdom.

To review the influence of sex hormones on the progression of breast, prostate, gynecologic, and colorectal cancer. The literature was reviewed in an informal manner utilizing the authors' prior knowledge to collate the current evidence for the involvement of sex hormones, particularly estrogens and androgens in the progression of a range of hormonally responsive cancers. In particular, the effect of treatment involving hormone withdrawal treatment was considered strong evidence for involvement. The impact of basal levels of endogenous steroids was considered. Data from clinical trials indicate the efficacy of therapeutic interventions that result in ablation or antagonism of host steroids for a range of cancers. Demonstration of the correlation of the completeness of withdrawal with clinical outcome together with direct evidence of progression from studies looking at the influence of tissue and circulating levels of sex hormones more recently in conjunction with gene expression profiles all provide compelling evidence for the involvement of steroids in the progression of disease. The involvement of steroids in the progression of cancer in hormone-sensitive tissues is well established and an important target for therapy.
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http://dx.doi.org/10.1200/JCO.2009.27.4290DOI Listing
September 2010

Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women.

J Clin Oncol 2010 Mar 1;28(7):1161-7. Epub 2010 Feb 1.

Academic Department of Biochemistry, Royal Marsden Hospital, Fulham Rd, London, SW3 6JJ, United Kingdom.

PURPOSE To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)-positive breast cancers in postmenopausal women. Materials and METHODS Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. Results The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = -0.179; P = .05; and r = -0.389; P = .0005, respectively). CONCLUSION Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.
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http://dx.doi.org/10.1200/JCO.2009.23.9616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834467PMC
March 2010