Previous Hormone Replacement Therapy Research Articles

Abstract P3-09-03: Single nucletotide polymorphisms of aromatase gene (CYP19A1) and toxicity of adjuvant aromatase inhibitors: A translational, prospective study

Abstract Background: Extending adjuvant endocrine treatment (ET) with aromatase inhibitors (AI) to 7-10 years decreases the risk of relapse in hormone receptor-positive (HR+) breast cancer (BC). However, such benefit comes at the price of higher incidence of skeletal and cardiovascular (CV) events. Biomarkers predicting such toxicities might help clinicians in tailoring adjuvant ET to patient’s needs. We conducted a prospective study to assess whether SNPs in the gene encoding for the aromatase enzyme (CYP19A1) affect the risk of skeletal and CV events in HR+ early BC patients enrolled in the GIM4 trial. Methods: The GIM4 trial randomized HR+ BC postmenopausal patients who had been already treated with 2-3 years of adjuvant tamoxifen to either 3-2 years or 5 years of adjuvant letrozole. Four SNPs of CYP19A1 were evaluated: rs10046, rs4646, rs479292 and rs727479. SNPs were genotyped through PCR on DNA obtained from patients’ peripheral blood samples. Skeletal and CV events were assessed from randomization in the GIM4 trial to last follow-up, disease recurrence or death. Skeletal events were defined as the onset of osteoporosis or bone fractures. CV events were defined as the onset of thrombosis, embolism, stroke, myocardial infarction, hearth failure, or arrythmia. Univariate and multivariate logistic regressions were performed to evaluate the association between SNPs and skeletal and CV events. Bonferroni correction for multiplicity was used for univariate SNPs association tests, with a corrected alpha of 0.012. Only associations with an alpha level <0.012 were considered significant and included in multivariate models.Multivariate models’ covariates included: treatment arm (5 vs 3-2 years letrozole), (neo)adjuvant chemotherapy, previous hormone replacement therapy, age, BMI, previous biphosphonates, hypercholesterolemia and hypertension at baseline. SNPs were tested for Hardy–Weinberg equilibrium (HWE) and linkage disequilibrium (LD). Interaction between SNPs of interest and treatment arm was also investigated. Results: Of 2,056 patients enrolled in the GIM4 trial, 647 entered this translational study. All SNPs were in HWE. The CT and TT variants of rs10046 were less associated to skeletal events compared to variant CC, suggesting a dominant effect of the minor T allele (odds ratio [OR]: 0.47,. 95% confidence interval [CI]: 0.28-0.79, p=0.005). The association was independent from the other covariates (adjusted OR [aOR]: 0.43, p=0.002). Patients with rs10046-TT had no significant differences in the odd of skeletal events according to treatment arm. Conversely, in patients with rs10046-CC, skeletal events were more likely with 5-year letrozole (interaction p=0.043). Compared to rs10046-CC, rs10046-TT/CT was also less associated with CV events at both univariate (OR: 0.46 95% CI: 0.27-077, p=0.003) and multivariate analysis (aOR: 0.41, p<0.001).The rs727479—GG variant was associated with more CV events compared to the GT and TT variants (OR: 2.30, 95%CI: 1.27-4.15, p=0.009), suggesting a recessive effect of the minor G allele. The association remained significant at multivariate analysis (aOR: 2.30, p=0.010). No significant interaction was observed among treatment arms, rs10046 or rs272479 variants (interaction p=0.070 and 0.061). Rs10046-CC and rs727479-GG variants were in high LD (D’=0.92, haplotype-CG frequency: 39%). Hence, the association between genotype rs10046-CC/rs727479-GG and CV events was investigated. The association was significant at the multivariate analysis (aOR: 2.79, p=0.002). With such genotype, the odd of CV events was significantly increased with the 5-year letrozole (interaction p=0.046). Conclusions: SNPs of CYP19A1 could be useful biomarkers of long-term toxicity in HR+ BC patients who are candidates for adjuvant AI. Citation Format: Benedetta Conte, Chiara Molinelli, Giancarlo Bisagni, Antonio Durando, Giovanni Sanna, Stefania Gori, Ornella Garrone, Stefano Tamberi, Sabino De Placido, Francesco Schettini, Antonio Pazzola, Riccardo Ponzone, Filippo Montemurro, Gianluigi Lunardi, Rosario Notaro, Anna Turletti, Claudia Bighin, Francesca Poggio, Giulia Buzzatti, Matteo Lambertini, Luca Boni, Lucia Del Mastro. Single nucletotide polymorphisms of aromatase gene (CYP19A1) and toxicity of adjuvant aromatase inhibitors: A translational, prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-03.

Hydatid Cyst of the Breast: A Review and Update of the Literature

Hydatid cyst of the breast is a rare infection of the breast that tends to be reported sporadically in Echinococcus infection endemic areas; nevertheless, because of increasing global travel hydatid cyst of the breast may be encountered in a non-endemic area of the world where clinicians may not be familiar with the manifestation and biological behaviour of the disease. Hydatid cyst of the breast has been reported sporadically in females whose ages have ranged between 16 years and 87 years and these cases only represent 0.27% of all cases of hydatid cyst encountered globally. Hydatid cyst of the breast does present as a lump/mass in the breast which quite often tends to be painless but it could be associated with pain/discomfort. Hydatid cyst of the breast tends to present insidiously and the lump tends to be present for a long time before attention is sought by the patient because it had behaved innocuously and had either been growing slowly with a recent noticeable increase in size over a few months. A history of previous contact with dogs and sheep as well as present or previous residence in an echinococcus endemic area tends to be helpful in alerting the clinician to the possibility of the diagnosis of hydatid cyst. A past history of treatment for echinococcal infection elsewhere in the body would also be helpful in alerting the clinician to the diagnosis of the disease. There tends to be no family history of breast cancer, and no history of previous hormone replacement therapy. The general and systematic examinations of most of the patients tend to be normal unless they have other non-related medical conditions. Clinical examination usually tends to reveal a swelling that tends to be well-circumscribed with clear margin that may be non-tender but at times there may be tenderness associated with the lump. The clinical examination findings tend to be non-specific and would usually mimic fibroadenoma, phyllodes tumour, or intra-cystic carcinoma of the breast. Usually the results of routine haematology and haematology blood tests would tend to be normal unless there is a non-related disease but there could be eosinophilia. Echinococcus hemagglutination test and Elisa test for Echinococcal IgE test would tend to be positive in cases of hydatid cyst of the breast. Various radiology imaging modalities tend to be utilized to assess hydatid cyst of the breast including mammogram, ultrasound scan of the breast, computed tomography (CT) scan of the breast, thorax, and abdomen, magnetic resonance imaging (MRI) scan of breast, thorax, and abdomen. Diagnosis of hydatid cyst of the breast tends to be diagnosed by undertaking fine needle aspiration biopsy of the breast lesion for cytology/histopathology examination or histopathology examination of excised hydatid cysts of the breast. Successful treatment of hydatid cyst of the breast requires complete excision without spillage of the hydatid cyst and additionally to minimise recurrence of disease Albendazole medication tends to be given. When there is spillage of the hydatid cyst or rupture of the hydatid cyst during the process of the excision, a thorough lavage of the operating field and excision of the surrounding tissue to ensure any possible residual daughter cysts are completely removed and utilization of Albendazole medicament would help to minimize or avoid development of recurrence. Because of the possibility of recurrence of disease a period of follow-up assessment with clinical examination and radiology imaging assessment as well as echinococcus hemagglutination tests would be recommended.

Hormone Replacement Therapy, Breast Cancer Risk Factors, and Breast Cancer Risk: A Nationwide Population-Based Cohort.

Hormone replacement therapy (HRT) increases the risk of breast cancer, but the association may vary according to patient factors. We investigated the association between HRT and breast cancer in a nationwide cohort with risk stratification according to risk factors for breast cancer. Using the Korean National Health Insurance Service database, 4,558,376 postmenopausal women who underwent breast cancer screening and regular health checkups from 2009 to 2014 were analyzed. A total of 696,084 (15.3%) women reported current or previous HRT use. Breast cancer was newly diagnosed in 26,797 (0.6%) women during a median follow-up of 5.35 years. The HR of the risk of breast cancer in HRT users was 1.25 [95% confidence interval (CI), 1.22-1.29] compared with HRT nonusers. The risk of breast cancer increased according to HRT duration [adjusted HR = 1.08; 95% CI, 1.04-1.12, for <2 years; adjusted HR = 1.33; 95% CI, 1.25-1.40, for 2 to <5 years; and adjusted HR = 1.72; 95% CI, 1.63-1.82, for ≥5 years). The effects of HRT on breast cancer risk applied to both invasive and in situ cancer. The HRT-related risk of breast cancer was higher in women who were leaner and those who had dense breasts. This nationwide population-based study confirms the association between HRT use and breast cancer risk. The risk increased proportionally with duration of HRT and differed according to body weight and breast density. Risk stratification would be useful when deciding whether to apply HRT for relief of menopausal symptoms.

Influence des facteurs hormonaux sur le pronostic des cancers du sein triple négatifs

ObjectivesTriples negative breast cancer defined by the absence of expression of the hormone receptors and HER2 protein, are considered as aggressive tumours with bad outcome in comparison to the hormone sensitive tumours. The aim of the study was to evaluate the link between hormone factors and prognostic factors of triple-negative tumours. MethodsAll patients managed for a triple-negative breast cancer between January, 2009 and December, 2013 were included. For every patient, collected data were the clinical, histological, adjuvant or neoadjuvant treatments, as well as survival data. Results and conclusionDuring the study period, 1682 patients were operated for a breast cancer, among which 1444 presented at least an invasive tumour. One hundred and fifty-five women (10.7%) had a negative triple tumour. The average age of diagnosis was 56.4years, is significantly younger than for patients with other types of tumours, P=0.0001. For women with a triple-negative tumour, the parity was the only hormonal factor identified as an independent factor for axillary lymph node involvement (OR=1.53; 95% CI [1.10–2.25] P=0.02) and previous hormone replacement therapy as an independent factor of locoregional recurrence (OR=0.13 [0.005–0.64] P=0.001). We did not find any hormonal factor predictive of distant metastasis. We did not find any difference in overall survival according to the parity (P=0.72), the Body mass index (P=0.62) or the use of HRT (P=0.49). ConclusionHormone factors seem to have a prognostic implication for triple-negative despite the absence of hormone receptors expression.

Abstract 4216: Adiponectin, leptin and breast cancer in high risk postmenopausal women: Results from a nested case-control study

Abstract Introduction: Obesity is a risk factor for postmenopausal breast cancer (BC) and evidence supports the pivotal role of adipokines in the association between obesity and BC. In the present study, we aim to investigate the role of adiponectin and leptin as independent risk markers for postmenopausal BC in a prospective nested case-control study within the cohort of women from the International Breast cancer Intervention prevention Study II (IBIS-II). Methods and Results: In the IBIS-II Prevention trial, 3864 healthy postmenopausal women at increased risk for BC were randomized to receive 1 mg/day oral anastrozole or matching placebo for 5 years. We measured serum adiponectin and leptin at baseline and 12-months in 119 cases and 336 controls in the placebo arm, and 57 cases and 165 controls in the anastrozole arm. We performed the adipokines measurements on the automated immunoassay platform ELLA (ProteinSimple, Biotechne). Baseline characteristics (age, body mass index (BMI), smoking status, and oophorectomy) were not different between cases and controls in both trial arms, except for hormone replacement therapy (HRT) use (38.7% of cases vs 51.5% of controls) and hysterectomy (25.2% of cases vs 37.5% of controls) in the placebo arm. We did not observe any statistically significant difference in adiponectin and leptin at baseline between cases and controls in both trial arms. When we considered the change in adiponectin levels between baseline and 12-months of follow-up, we observed a borderline significant higher proportion of BC cases in subjects with a decrease in adiponectin (36.4%) compared to subjects with an increase in adiponectin (25.7%). The multivariate Cox model indicated that women on placebo with a decrease in adiponectin between baseline and 12-months had a 36% significant increased risk in BC (HR=0.64; CI 0.42-0.98; adjusted for age, BMI, previous HRT use, smoking, oophorectomy, hysterectomy). Changes in leptin were not significantly associated with BC incidence overall. However, the multivariate Cox model for the anastrozole arm, indicated a significant higher BC risk for women with the highest increase (&amp;gt;10 ng/ml) vs the lowest decrease (&amp;lt;-10 ng/ml) in leptin: HR=4.45; CI 1.08-18.30; adjusted for age, BMI, previous HRT use, smoking, oophorectomy, hysterectomy. Conclusion: Our results did not support a prognostic role of baseline adiponectin and leptin levels in postmenopausal BC development. However, we observed an increased BC risk in women with a 12-month adiponectin decrease and leptin increase. These data suggest further investigations of changes of adiponectin and leptin levels as attractive targets for BC prevention in postmenopausal women at high risk for BC. Citation Format: Debora Macis, Ivana Sestak, Valentina Aristarco, Harriet Johansson, Aliana Guerrieri-Gonzaga, Andrea Decensi, Bernardo Bonanni, Jack Cuzick, Sara Gandini. Adiponectin, leptin and breast cancer in high risk postmenopausal women: Results from a nested case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4216.

Adiposity and breast cancer risk in postmenopausal women: Results from the UK Biobank prospective cohort.

Body size is an important modifiable risk factor for postmenopausal breast cancer. However, it remains unclear whether direct measures of fat mass are better indicators of risk than anthropometric measures, or whether central adiposity may contribute to risk beyond overall adiposity. We analyzed data from 162,691 postmenopausal women in UK Biobank followed from 2006 to 2014. Body size was measured by trained technicians. Multivariable‐adjusted Cox regression was used to estimate relative risks. Analyses were stratified by age at recruitment, region and socioeconomic status, and adjusted for family history of breast cancer, age at menarche, age at first birth, parity, age at menopause, previous hormone replacement therapy use, smoking, alcohol intake, height, physical activity and ethnicity. We observed 2,913 incident invasive breast cancers during a mean 5.7 years of follow‐up. There was a continuous increase in risk of postmenopausal breast cancer with increasing adiposity, across all measures. The point estimate, comparing women in the top (median 37.6 kg) to bottom (median 17.6 kg) quartile of body fat mass was 1.70 (95% confidence interval 1.52–1.90). The magnitudes of the associations between per SD increase in BMI and body fat mass with breast cancer risk were similar, suggesting impedance measures of fat were not substantially better indicators of risk than anthropometric measures. After adjusting for body fat mass, the associations between anthropometric measures of central adiposity and breast cancer risk were attenuated. The magnitude of risk, across all measures of adiposity, was greater in women who had been postmenopausal for 12 or more years.

The use and discontinuation of hormone replacement therapy in women in South China

Objective: The use of hormone replacement therapy (HRT) started later in China than in European countries. The purpose of the present study was to investigate HRT patterns and reasons for the initiation and discontinuation of HRT among women in South China.Methods: A telephone survey about menopausal status, the use of HRT, reasons for HRT discontinuation and duration of HRT treatment was conducted in 2014.Results: A total of 825 telephone surveys were carried out, and 217 previous HRT users and 390 current users were recruited for this study. Among these 607 subjects, 50.7% of the women sought out HRT for hot flushes, 41.6% for fatigue and 41.5% for sleeplessness. Approximately one-third (35.9%) of the patients abandoned HRT during the following year. The reasons for stopping HRT were mainly fear of breast and uterine cancer (28.4%), reduced menopausal symptoms (22.9%) and the inconvenience of taking pills or seeing a doctor (17.9%). The factors related to HRT discontinuation were the age when HRT was initiated (odds ratio 1.59, 95% confidence interval 1.19–2.13) and education level (odds ratio 0.78, 95% confidence interval 0.62–0.98).Conclusions: The duration of HRT use in women in south China was short, and a high proportion of the women discontinued HRT. Given the high discontinuation rate and the low medical compliance, Chinese health-care providers still have much to do to let women know about the advantages and disadvantages of HRT and to encourage the use of HRT appropriately.

PP.23.09] HEART, ARTERIES AND WOMEN, A HEALTHCARE PATHWAY FOR WOMEN AT CARDIOVASCULAR RISK

Objective: Cardiovascular diseases remain the primary cause of death in women. Assessment of cardiovascular risk in women is specific and should take into account hormonal factors. Preventive measures must be implemented and diagnosis and therapeutic approaches improved. In order to upgrade women's health, a coordinated healthcare pathway, Heart, arteries and women, was initiated at the Lille University Hospital. The objective was to assess the relevance of the healthcare pathway at two years to improve prevention, diagnosis and treatment in women at cardiovascular risk. Design and method: We undertook a retrospective and consecutive observational study based on a cohort of post-menopausal women followed through the healthcare pathway “Heart, arteries and women”, at the Lille University Hospital, between January 1st, 2013 and December 31st, 2015. Clinical presentation, medical management and follow-up were assessed. Results: Of the 201 women included, with a mean age of 62 years, 64 (32%) were at high cardiovascular risk and 136 (68%) at very high risk. Arterial hypertension was present in 188 (94%) and diabetes in 88 (44%). Sixty-one women (30, 3%) had experienced high blood pressure or diabetes during pregnancy. Only eight women had current or previous hormone replacement therapy. Among the 91 women screened for obstructive sleep apnea syndrome by night polygraphy or polysomnography, 66 (73%) were positive. Among the 90 women who had a ischemic stress test, 11 (12%) were positive. Three women were diagnosed with peripheral arterial disease and 16 with a significant renal arterial stenosis. Medical therapies were optimized especially for women with atheroma in which 14.5% to 27% were properly treated (p < 0.05). Coordination between cardiologists and gynaecologists was improved: 20.4% of the gynecologists received conclusive reports versus 12% in the one year evaluation. Conclusions: At two years, our healthcare pathway, “Heart, arteries and women”, allowed optimizing medical therapy and clinical management of women. Coordination between cardiologists and gynaecologists should continue to improve.

Efficacy and safety of drospirenone 2 mg/17β-estradiol 1 mg hormone therapy in Korean postmenopausal women.

This regulatory post-marketing surveillance study aimed to evaluate the therapeutic efficacy and safety of drospirenone (DRSP) 2 mg/estradiol (E2) 1 mg tablet in Korean postmenopausal women. A total of 4,149 patients were enrolled and the study was conducted at 207 clinical research centers. The patients' source data was collected between November 2006 and November 2012. More than 85% of patients experienced improvement of menopausal symptoms. The most frequently reported adverse events were vaginal bleeding and breast pain; most of the women suffering from these symptoms fully recovered. The incidence of adverse event was higher in patients of younger age (20 to 39 years), in patients with concomitant diseases, previous hormone replacement therapy in medical history, those treated with DRSP 2 mg/E2 1 mg for shorter duration (3 years or less) and in patients using concomitant medication. In conclusion, the results from this large post-marketing surveillance study confirm the efficacy and safety of DRSP 2 mg/E2 1 mg tablet in Korean postmenopausal women.

Clinical Effects of Isoflavones and Berberine (Estromineral Lipid) in Menopausal Women with Borderline Dyslipimia

Objective: During the menopause, oestrogen deficiency brings about changes in the lipid profile which increase the cardiovascular (CV) risk. The use of food supplements together with a healthy lifestyle and a varied, balanced diet is a logical approach for improving CV disease prevention. A combination of nutraceuticals (EL) based on berberine (a natural extract that reduces total cholesterol and triglycerides), soya isoflavones (SI), Lactobacillus sporogenes and vitamin D3 was compared with the same formulation without berberine (E) in menopausal women with borderline dyslipidaemia. Method: Randomised, controlled, parallel-group multicenter study in menopausal women with Tot-C >200 and <260 mg/dl on a controlled low-fat diet or not on treatment with lipid-lowering agents. The study treatments were: 1 tablet of EL (Estromineral Lipid) or E (Estromineral®) daily by mouth for 3 months. Typical menopausal symptoms, CV and metabolic parameters were evaluated at baseline and at the end of treatment. Results: Fifty-nine gynecology centers treated 535 women, 287 with EL and 248 with E; mean age 53.8 years and body mass index 25.4 kg/m2, in the menopause for 3.8 years, 6.7% with previous hormone replacement therapy use. After 3 months, EL significantly reduced Tot-C (-9.2% vs. -4.9%; p<0.01), LDL-C (-16.7% vs. -9.9%; p<0.05) and triglycerides (-13.3% vs. -6.3%; p<0.06) compared with E. Hot flushes, night sweats, palpitations, decrease in libido and vaginal dryness decreased significantly compared with baseline with both treatments (p<0.0001). Three cases with EL (dyspepsia, gastric pain and erythema) and 1 case with E (gastric pain) experienced nonserious adverse events. Conclusion: Berberine in EL and the SI in both formulations significantly improved, respectively, the lipid profile and vasomotor symptoms in menopausal women. EL has the rationale for a complete prevention of menopausal risk: osteoporosis (vitamin D3, calcium and folic acid), genitourinary dystrophy (SI) and CV diseases (berberine).

Increased risk of heart failure in women with symptoms of sleep-disordered breathing

BackgroundAn association between obstructive sleep apnea and the incidence of heart failure has been reported in men but not in women. The aim of this study was to investigate whether a combination of snoring and excessive daytime sleepiness, the two main symptoms of obstructive sleep apnea syndrome, was able to predict incident heart failure in a population-based sample of women. MethodsThe population-based cohort study Sleep and Health in Women (SHE; n = 5990 women born between 1901 and 1980) was used, with baseline questionnaire data from April 2000 relating to snoring, excessive daytime sleepiness, and covariates. Using data retrieved from the Swedish National Patient Register and Cause of Death Register, the follow-up of incident heart failure continued until 31 December 2011. ResultsAmong women with both snoring and excessive daytime sleepiness at baseline, 5.3% developed heart failure during follow-up compared with 0.9% in the reference group with neither snoring nor excessive daytime sleepiness. After adjustment for age, waist circumference, smoking, alcohol, hypertension, diabetes, previous myocardial infarction, physical inactivity, depressive symptoms, menopausal status, and hormone replacement therapy, women with the combination of snoring and excessive daytime sleepiness had a twofold increase in the risk of incident heart failure (hazard ratio [HR] 2.2 95% confidence interval [CI] 1.1–4.4). ConclusionSymptoms of obstructive sleep apnea, that is, the combination of snoring and excessive daytime sleepiness, are associated with an increased risk of developing heart failure in women.

Abstract 864: Body size and composition, physical activity and breast cancer risk in UK Biobank

Abstract Background: Body size and physical activity are two important modifiable risk factors for breast cancer. Many previous studies are limited by the use of body mass index (BMI), which is unable to distinguish between fat and lean mass. Questions also remain over the role of vigorous compared to lower intensity physical activity in relation to breast cancer risk. We investigate the associations between BMI, body fat percentage, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), total and vigorous physical activity and both premenopausal and postmenopausal breast cancer. Methods: We analyzed data from 48,713 premenopausal and 127,850 postmenopausal women followed from 2006 through 2012. We observed 443 premenopausal and 1,422 postmenopausal incident invasive breast cancers during a mean 3.84 years of follow-up. Current users of hormone replacement therapy (HRT) were excluded from the analyses. Multivariable-adjusted Cox regression was used. All analyses were stratified by age, geographical region, and socioeconomic status. Analyses were adjusted for family history of breast cancer, previous HRT use, height, parity, age at first birth, smoking, age at menarche, alcohol intake frequency, and age at menopause (for postmenopausal women only). This research has been conducted using the UK Biobank Resource, a nationwide study of approximately 500,000 UK adults between ages 40-70 at recruitment. Results: All measures of adiposity were positively associated with increased breast cancer risk in postmenopausal but not in premenopausal women. Compared with postmenopausal women in the lowest quartile of body fat percentage (16.8-32.9%; median, 29.6%), women in the highest quartile (41.9-54.3%; 44.8%) had an increased risk of breast cancer (HR, 1.47; 95% confidence interval, 1.24-1.74; ptrend &amp;lt;0.001). Vigorous physical activity was associated with decreased breast cancer risk in postmenopausal but not in premenopausal women. Postmenopausal women who participated in an average of 17.5 MET-h/week of vigorous physical activity had a 15% decreased risk of breast cancer (HR 0.85; 0.74-0.98; ptrend = 0.025). This association was no longer significant after adjusting for body fat percentage (HR 0.88, 0.77-1.02, ptrend = 0.084). Higher levels of total physical activity were associated with non-statistically significant breast cancer risk reductions in both premenopausal and postmenopausal women. Conclusion: In postmenopausal women, breast cancer risk is strongly associated with greater adiposity while it moderately decreased with greater vigorous physical activity. Adjusting for body fat percentage attenuated the association between vigorous physical activity and breast cancer risk. Longer follow-up is needed to clarify associations, particularly in premenopausal women. We also plan to extend these analyses by subdividing cancers by hormone receptor status. Citation Format: Wenji Guo, Gillian K. Reeves, Timothy J. Key. Body size and composition, physical activity and breast cancer risk in UK Biobank. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 864. doi:10.1158/1538-7445.AM2015-864

Abstract PD4-1: Timing, severity and risk factors for arthralgia in the IBIS-II trial: A retrospective and exploratory analysis

Abstract Background: Arthralgia is a well known side effect of aromatase inhibitors and low oestrogen levels and postmenopausal status are associated with this event. Anastrozole reduced the incidence of oestrogen receptor positive, invasive breast cancer by 58% in the IBIS-II trial. However, timing, severity and risk factors for arthralgia have not been assessed in detail in this trial. Methods: The IBIS-II trial randomised postmenopausal women at high risk to receive 1mg anastrozole or matching placebo for 5 years. Date of occurrence of arthralgia along with severity (mild, moderate, severe) were recorded at each yearly follow-up visit. Age, body mass index (BMI), and previous hormone replacement therapy (HRT) were investigated as potential risk factors for arthralgia. All analyses were done by the use of logistic regression. Results: 3864 postmenopausal women (anastrozole: 1920, placebo: 1944) were enrolled in the IBIS-II trial. 58.5% of women randomised to anastrozole reported arthralgia at any time during the trial compared with 52.8% on placebo (OR=1.26 (1.11-1.43), P=0.0004). The majority of arthralgias were reported within the first 18 months of randomisation, with a decline thereafter (Table). 17.5% of women who reported arthralgia withdrew from the trial compared to 13.9% without any of these symptoms (OR=1.31 (1.10-1.57)), and the withdrawal was significantly greater for those with severe symptoms compared to mild (OR=5.97 (4.27-8.33)). Women who used HRT before trial entry had a significant higher risk of developing arthralgia than their counterparts irrespective of allocated treatment (OR=1.45 (1.27-1.64), P&amp;lt;0.001). Increasing BMI (lowest vs. highest BMI group: OR=1.30 (1.11-1.53)) and age (lowest vs. highest age group: OR=1.23 (1.01-1.50)) were also significant risk factors for arthralgia. HRT and BMI remained highly significant in a multivariate model. Conclusion: Arthalgia was common in the IBIS-II trial irrespective of treatment. However it increased in severity in the active treatment arm mainly in the 18 month period after randomisation. Severe arthralgia led to significantly more withdrawals from the trial than mild symptoms irrespective of treatment. Major risk factors for arthralgia in both arms were previous HRT use and obesity. Number and percentages (%) of arthralgia of any severity according to treatment allocation and time point.Overall0-18 months18-30 months30-42 months42-54 months&amp;gt;54 monthsAnastrozoleWomen at risk19201150842673543401Number with arthralgia1123770170865344Percentage (%)58.567.020.212.89.811.0PlaceboWomen at risk19441294979782618481Number with arthralgia10266501531096945Percentage (%)52.850.315.613.911.29.4OR (95% CI) (A vs. P)1.26 (1.11-1.43)1.33 (1.17-1.52)1.29 (1.01-1.65)0.92 (0.67-1.25)0.87 (0.59-1.29)1.17 (0.74-1.86) Citation Format: Ivana Sestak, Anthony Howell, John F Forbes, Patrick Neven, Jack Cuzick. Timing, severity and risk factors for arthralgia in the IBIS-II trial: A retrospective and exploratory analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD4-1.

Polymorphisms in CYP17, COMT, and ESR1 genes in women after menopause and association with bone mineral density.

In this study, we evaluated genetic factors related to the mineral density during post-menopause. We evaluated 110 women in the first 5 years post-menopause, without previous hormone replacement therapy. Cytochrome P450 17 (CYP17) (rs743572), catechol-O-methyl transferase (COMT) (rs4680), and estrogen receptor 1 (ESR1) (rs9322331) were examined for the presence of polymorphisms. Clinical data were collected by anamnesis; all patients had the osseous densitometry examined using a lunar instrument to determine mineral osseous densitometry in the lumbar column (L2-L4). CYP17, COMT, and ESR1 genotyping was carried out by polymerase chain reaction with DNA collected from buccal swabs. The average age was 51.96 years. The average weights of the patients in control and osteopenia groups were 70.25 ± 12.00 and 62.45 ± 11.64, respectively (P = 0.001) and body mass index (P = 0.006; control: 29.43 ± 5.25; osteopenia: 26.72 ± 4.57). Related to CYP17 polymorphisms, 28.18% of women were TT (wild-type homozygous), 60% were TC (heterozygous), and 11.82% were CC (mutated homozygous). Related to COMT polymorphisms, 53.64% of women were GG (wild-type homozygous), 37.27% were GA (heterozygous), and 9.09% were AA (mutated homozygous). Related to ESR1, 53.64% of women were CC (wild-type homozygous), 40.91% were CT (heterozygous), and 5.45% were TT (mutated homozygous). The ESR1 variant allele was significantly higher in the osteopenia group when compared with women in the normal group (P = 0.02). ESR1 may be associated with low mineral osseous densitometry, while CYP17 and COMT gene polymorphisms were not associated with mineral osseous densitometry.

Hormone replacement therapy and prognosis in ovarian cancer patients

Estrogen exposure has at least a moderate effect on the risk for ovarian cancer, and antiestrogen therapy may be helpful in treating the disease. It is known from breast cancer that previous hormone replacement therapy (HRT) may influence the molecular profile and prognostic behavior of these tumors. The aim of this study was therefore to investigate the influence of previous HRT on the prognosis in a cohort of patients with invasive epithelial ovarian cancer. Among 547 patients who were treated for ovarian malignancies at a single institution from 1995 to 2008, a total of 244 postmenopausal patients with epithelial cancer and under the age of 75 were identified for whom information about HRT before the onset of the disease was available. HRT was correlated with tumor and patient characteristics. Analyses of overall survival and progression-free survival were carried out using Cox proportional hazards models. Age, tumor stage, and resection status correlated significantly with HRT in the univariate analysis. Patients with previous HRT were more likely to have a lower stage, to be younger, and to have optimal debulking. With regard to survival, HRT had a positive effect on overall survival, specifically in the subgroup of patients with optimal debulking. No correlation was seen in relation to progression-free survival. Sex hormone exposure through HRT may influence the behavior of ovarian cancers after the onset of the disease. This study supports the hypothesis that ovarian cancer is a hormonally influenced tumor.

Joint Disorders Frequency and Structural Changes during Anastrozole Adjuvant Treatment in Early Breast Cancer: A Prospective Trial (D5392L00013).

Abstract Background:Aromatase inhibitors (AIs) are standard adjuvant endocrine-therapy in postmenopausal women with hormone-sensitive breast cancer. However, main side effects reported are musculoskeletal symptoms. The pathogenic and anatomic features of AI-induced arthralgia have not been clearly defined. The objective of the study was to describe the joint symptoms and structural joint changes in women received adjuvant anastrozoleMethods: Postmenopausal women with hormone receptor positive early breast cancer were enrolled in this open, multicentre trial. Anastrozole was administrated 1mg/day p.o. All of them were naïve of AI and tamoxifen treatment. Patients were followed one year with clinical examination every 3 months, ultrasound (US) examination every 6 months, measurements of inflammation biomarkers and cartilage biomarkers of degradation U-CTX-II (urinary C-terminal crosslinked telopeptide of type II collagen) every 6 months and X-rays at baseline and 12 monthsResults: From June 2006 to December 2007, one hundred and fourteen patients (114) were included and 106, with a median age of 61.5 (49-79) years, were followed-up for 1 year.Overall, 33% of patients were previously treated by chemotherapy, (anthracyclines 97%, taxanes 63 %) and 40.6% were receiving hormone replacement therapy (HRT) at tumour diagnosis. The prevalences of arthralgia were 40.6, 59.1 and 60.6 % at baseline, 6 months and 12 months respectively.Among the 63 (59.4%) patients without arthralgia at baseline, 37 patients presented with arthralgia during treatment (26 between baseline and M6, 11 between M6 and M12) with median time to onset of 4 months.In univariate logistic analysis, significant determinant factors of joint disorders at 12 months were previous osteoarthritis and personal history of arthralgia but not the previous HRT or previous adjuvant chemotherapy with taxanes. In multivariate analysis, none of those factors were significant.Clinical examination by rheumatologist and US examination did not show any significant changes of the number of synovitis and tenosynovitis over 12 months.There were no significant changes of the U-CTX-II levels and of joint damages assessed by radiographs. Inflammation biomarkers did not significantly change over 12 months.Conclusion: This prospective study with a systematic rheumatologist follow up of the patients showed that arthralgia occurs early after the beginning of anastrozole therapy (first 6 months); and suggest that joint disorders were not associated with any cartilage degradation after 1 year of treatment. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 801.

Modelling Bone Mineral Density in Swiss Breast Cancer Patients Treated with Letrozole, Tamoxifen and Sequences of Letrozole and Tamoxifen in the BIG 1-98 Study (SAKK 21/07).

Abstract Background: Bone health is a concern when treating early stage breast cancer patients with adjuvant aromatase inhibitors. Early detection of patients (pts) at risk of osteoporosis and fractures may be helpful for starting preventive therapies and selecting the most appropriate endocrine therapy schedule. We present statistical models describing the evolution of lumbar and hip bone mineral density (BMD) in pts treated with tamoxifen (T), letrozole (L) and sequences of T and L.Methods: Available dual-energy x-ray absorptiometry exams (DXA) of pts treated in trial BIG 1-98 were retrospectively collected from Swiss centers. Treatment arms: A) T for 5 years, B) L for 5 years, C) 2 years of T followed by 3 years of L and, D) 2 years of L followed by 3 years of T. Pts without DXA were used as a control for detecting selection biases. Patients randomized to arm A were subsequently allowed an unplanned switch from T to L. Allowing for variations between DXA machines and centres, two repeated measures models, using a covariance structure that allow for different times between DXA, were used to estimate changes in hip and lumbar BMD (g/cm2) from trial randomization. Prospectively defined covariates, considered as fixed effects in the multivariable models in an intention to treat analysis, at the time of trial randomization were: age, height, weight, hysterectomy, race, known osteoporosis, tobacco use, prior bone fracture, prior hormone replacement therapy (HRT), bisphosphonate use and previous neo-/adjuvant chemotherapy (ChT). Similarly, the T-scores for lumbar and hip BMD measurements were modeled using a per-protocol approach (allowing for treatment switch in arm A), specifically studying the effect of each therapy upon T-score percentage.Results: A total of 247 out of 546 pts had between 1 and 5 DXA; a total of 576 DXA were collected. Number of DXA measurements per arm were; arm A 133, B 137, C 141 and D 135. The median follow-up time was 5.8 years. Significant factors positively correlated with lumbar and hip BMD in the multivariate analysis were weight, previous HRT use, neo-/adjuvant ChT, hysterectomy and height. Significant negatively correlated factors in the models were osteoporosis, treatment arm (B/C/D vs. A), time since endocrine therapy start, age and smoking (current vs. never).Modeling the T-score percentage, differences from T to L were -4.199% (p = 0.036) and -4.907% (p = 0.025) for the hip and lumbar measurements respectively, before any treatment switch occurred.Conclusions: Our statistical models describe the lumbar and hip BMD evolution for pts treated with L and/or T. The results of both localisations confirm that, contrary to expectation, the sequential schedules do not seem less detrimental for the BMD than L monotherapy. The estimated difference in BMD T-score percent is at least 4% from T to L. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5037.

Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial

BackgroundTo compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial. MethodsWe evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. ResultsThe incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy. ConclusionsConsistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.

Modeling bone mineral density (BMD) evolution in postmenopausal patients treated by letrozole (L), tamoxifen (T), and sequences of T and L (SAKK 21/07)

545 Background: Osteoporosis and fractures are long term complications of aromatase inhibitor use in the adjuvant therapy of breast cancer. Early detection of patients (pts) at risk of treatment-induced osteoporosis may allow preventive therapy and selection of the most appropriate endocrine therapy. We developed a statistical model describing the evolution of BMD in pts treated with T, L and sequences of T and L. Methods: Available dual-energy x-ray absorptiometry exams (DXA) of pts treated in trial BIG 1–98 were retrospectively collected from Swiss centers. Treatment arms: A) T for 5 years; B) L for 5 years; C) 2 years of T followed by 3 years of L; and D) 2 years of L followed by 3 years of T. Pts without DXA were used as a control for detecting selection bias. A repeated measures model using the first-order autoregressive covariance structure to allow for different times between DXA was used to model BMD (g/cm2) since trial randomisation. Prospectively defined covariates were considered as fixed effects in a multivariable model using an intention to treat analysis. Covariates at trial randomization were: age, height, weight, race, known osteoporosis, tobacco use, prior bone fracture, prior hormone replacement therapy (HRT), bisphosphonate use and previous neo-/adjuvant chemotherapy (ChT). Results: A total of 247 out of 546 pts had between 1 and 5 DXA; a total of 576 DXA were collected. Arm A contained 67 pts, B 63 pts, C 55 pts and D 62 pts. Median follow-up was 5.8 years. Factors correlated with BMD in the multivariate analysis were weight (0.003/kg, p &lt; 0.0001), height (0.003/cm, p = 0.0083), osteoporosis (-0.130, p &lt; 0.0001), tobacco (current / previously vs. never: -0.057, p = 0.0011 / -0.042, p = 0.0798), previous HRT (0.030, p = 0.0244), ChT (0.032, p = 0.0174), time since endocrine therapy start (-0.009/year, p = 0.0164) and treatment arm (B / C / D vs. A: -0.068, p = 0.0002 / -0.091, p &lt; 0.0001 / -0.064, p = 0.003). Conclusions: Our statistical model describes the BMD evolution for pts treated with L and/or T. All treatment regimens affect BMD. Contrary to expectation, the switch schedule T followed by L does not seem to result in better bone protection compared to L monotherapy. [Table: see text]

Previous hormone-replacement therapy (HRT) and anastrozole treatment appear to be major risk factors for developing joint symptoms

Previous hormone-replacement therapy (HRT) and anastrozole treatment appear to be major risk factors for developing joint symptoms