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Purpose: The DIANA-5 randomized controlled trial assessed the effectiveness of a diet based on Mediterranean and macrobiotic traditions (macro-Mediterranean diet) in reducing breast cancer recurrence., Patients and Methods: The DIANA-5 study involved 1,542 patients with breast cancer at high risk of recurrence because of estrogen receptor-negative cancer, or metabolic syndrome, or high plasma levels of insulin or testosterone. Women were randomly assigned to an active dietary intervention (IG) or a control group (CG). Both groups received the 2007 American Institute for Cancer Research/World Cancer Research Fund recommendations for cancer prevention. The intervention consisted of meetings with kitchen classes, community meals, and dietary recommendations. Recommended foods included whole grain cereals, legumes, soy products, vegetables, fruit, nuts, olive oil, and fish. Foods to be avoided were refined products, potatoes, sugar and desserts, red and processed meat, dairy products, and alcoholic drinks. A compliance Dietary Index was defined by the difference between recommended and discouraged foods., Results: Over the 5 years of follow-up, 95 patients of the IG and 98 of the CG developed breast cancer recurrence [HR = 0.99; 95% confidence interval (CI): 0.69-1.40]. The analysis by compliance to the dietary recommendations (IG and CG together) showed that the women in the upper tertile of Dietary Index change had an HR of recurrence of 0.59 (95% CI: 0.36-0.92) compared with women in the lower tertile., Conclusions: The DIANA-5 dietary intervention trial failed to show a reduction in breast cancer recurrence, although self-reported diet at year 1 in IG and CG combined showed a protective association with the higher Dietary Index change. See related commentary by McTiernan, p. 931., (©2023 The Authors; Published by the American Association for Cancer Research.)

The Diet and Androgen-5 (DIANA-5) trial aimed at testing whether a dietary change based on the Mediterranean diet and on macrobiotic principles can reduce the incidence of breast cancer (BC)-related events. We analyzed the adherence to the DIANA-5 dietary recommendations by randomization group after 1 year of intervention. We evaluated the association between dietary adherence and changes in body weight and metabolic syndrome (MS) parameters. BC women aged 35-70 years were eligible. After the baseline examinations, women were randomized into an intervention group (IG) or a control group (CG). A total of 1344 BC women (689 IG and 655 CG) concluded the first year of dietary intervention. IG showed greater anthropometric and metabolic improvements compared to CG. These changes were significantly associated with increased adherence to the dietary recommendations. Women who increased recommended foods consumption or reduced discouraged foods consumption showed an Odds Ratio (OR) of 1.37 (0.70-2.67) and 2.02 (1.03-3.98) to improve three or more MS parameters. Moreover, women in the higher category of dietary change showed a four times higher OR of reducing body weight compared to the lower category ( p < 0.001). The DIANA-5 dietary intervention is effective in reducing body weight and MS parameters.

Introduction: DianaWeb is a community-based participatory project open to Italian breast cancer patients. The aim of the study was to assess the effectiveness of a lifestyle intervention in improving the prognosis after patients received diagnosis and surgery/chemotherapy. The DianaWeb study uses an interactive Web site (www.dianaweb.org) to monitor patients' lifestyles, and to obtain clinical and anthropometric data. Although detailed instructions for measuring height, body weight, waist circumference, and blood pressure (BP) are provided, individuals might tend to overestimate or underestimate those parameters. The aims of the present study were: (1) to compare self-recorded data with those from standardized ambulatory measurements; (2) to determine the trueness of a subject classification in the overweight/obesity or hypertensive subgroup on the basis of the patients' own measurements and estimates; and (3) to identify confounding variables., Patients and Methods: We compared self-reported with ambulatory measurements in a subgroup of 200 randomly selected women of approximately 1000 enrolled in the DianaWeb study (from September 2016 to March 2018)., Results: Bland-Altman analysis showed a close agreement for self-reported and ambulatory-measured height, weight, and body mass index (BMI). On the contrary, women overestimated waist circumference and underestimated BP. Cohen κ statistics showed fair agreement only for hypertension. Binary logistic regression analysis showed that BMI and diastolic BP self-measurements were biased according to age., Conclusion: The results suggest that self-reported height, weight, and BMI are satisfactorily accurate for patients in the DianaWeb study, such as accuracies of overweight/obese and central obesity classification, and that these data can be useful for our research., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Metformin (MET) is currently being used in several trials for cancer prevention or treatment in non-diabetics. However, long-term MET use in diabetics is associated with lower serum levels of total vitamin B 12 . In a pilot randomized controlled trial of the Mediterranean diet (MedDiet) and MET, whose participants were characterized by different components of metabolic syndrome, we tested the effect of MET on serum levels of B 12 , holo transcobalamin II (holo-TC-II), and methylmalonic acid (MMA). The study was conducted on 165 women receiving MET or placebo for three years. Results of the study indicate a significant overall reduction in both serum total B 12 and holo-TC-II levels according with MET-treatment. In particular, in the MET group 26 of 81 patients and 10 of the 84 placebo-treated subjects had B 12 below the normal threshold (<221 pmol/L) at the end of the study. Considering jointly all B 12 , Holo-TC-II, and MMA, 13 of the 165 subjects (10 MET and 3 placebo-treated) had at least two deficits in the biochemical parameters at the end of the study, without reporting clinical signs. Although our results do not affect whether women remain in the trial, B 12 monitoring for MET-treated individuals should be implemented.

Background: Despite the clear endocrine-metabolic relationship between androgenic activity and adiposity, the role of androgens in breast cancer prognosis according to patient's adiposity is scarcely explored. Here, we aimed at investigating the prognostic value of circulating testosterone in association with patient's body mass index (BMI)., Methods: Circulating testosterone and BMI were evaluated at breast cancer diagnosis in 460 estrogen receptor (ER)-positive postmenopausal patients. Local relapse, distant metastasi(e)s and contralateral breast cancer were considered recurrence events. The Kruskal-Wallis test was performed to evaluate if testosterone levels differed within subgroups of categorical tumour characteristics. The Cox proportional hazard regression model was fitted to estimate the impact of standard prognostic factors on relapse-specific hazard ratio (HR). After backward selection, a model including continuous testosterone level, BMI categories (< 25, normal-weight; =25-30, overweight; ≥30 kg/m 2 , obese), tumour size and lymph nodes number was fitted. Furthermore, Cox models provided the relapse-specific HRs for median, third quartile and 95th percentile compared to the first quartile of testosterone levels, stratified by BMI categories., Results: During a median follow up of 6.3 years, 45 patients relapsed. Testosterone levels significantly increased across BMI categories (p = 0.001). Both circulating testosterone and BMI were positively associated with disease free survival (p = 0.005 and p = 0.021, respectively). A significant interaction was found between testosterone and BMI (p = 0.006). For normal-weight women, testosterone concentration around median (0.403 ng/mL) or third quartile (0.532 ng/mL) showed a high significant HR of relapse (5.52; 95% CI:1.65-18.49 and 4.55; 95% CI:1.09-18.98, respectively). Overweight patients showed increased HR at increasing testosterone levels, reaching a significant high HR (4.68; 95% CI:1.39-15.70) for testosterone values of 0.782 ng/mL (95th percentile). For obese patients HR decreased (not significantly) at increased testosterone concentrations, explaining the interaction between testosterone levels and BMI categories., Conclusions: In ER-positive postmenopausal breast cancer patients, high testosterone levels are associated with worse prognosis in normal-weight and overweight women, whereas in obese seems to be associated with a better outcome. Although the results require further validation, they suggest that assessment of circulating testosterone and BMI could help to identify postmenopausal ER-positive patients at higher risk of relapse and potentially open new therapeutic strategies.

Insulin may affect breast cancer (BC) risk and prognosis. Exercise reduces insulin in obese BC survivors. We designed a randomised controlled trial to test the effect of an aerobic exercise intervention (AEI) on insulin parameters and body composition in non-obese BC women without insulin resistance. Thirty-eight BC women were randomised into an intervention group (IG = 18) or control group (CG = 20). IG participated in a structured AEI for 3 months, while CG received only the Word Cancer Research Fund/American Institute Cancer Research (WCRF/AICR) recommendation to be physically active. Fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) index, metabolic parameters and body composition were collected at baseline and after the AEI. IG reduced insulin and HOMA-IR index by 15% and 14%, while CG increased these parameters (+12% and +16%). Insulin changed differently over time in the two randomised groups (p interaction  = .04). The between-group differences in the change of insulin (IG = -1.2 μU/ml versus CG = +0.8 μU/ml) and HOMA-IR index (IG = -0.26 versus CG = +0.25) were respectively significant (p = .04) and non-significant (p = .06). IG significantly improved lower limb muscle mass in comparison with CG (p = .03). A structured AEI may improve insulin, HOMA-IR index and body composition in non-obese BC survivors without insulin resistance., (© 2016 John Wiley & Sons Ltd.)

MicroRNAs (miRNAs) might be considered both predictors and players of cancer development. The aim of the present report was to investigate whether many years before the diagnosis of breast cancer miRNA expression is already disregulated. In order to test this hypothesis, we compared miRNAs extracted from leukocytes in healthy women who later developed breast cancer and in women who remain healthy during the whole 15-year follow-up time. Accordantly, we used a case-control study design nested in the hOrmone and Diet in the ETiology of breast cancer (ORDET) prospective cohort study addressing the possibility that miRNAs can serve as both early biomarkers and components of the hormonal etiological pathways leading to breast cancer development in premenopausal women. We compared leukocyte miRNA profiles of 191 incident premenopausal breast cancer cases and profiles of 191 women who remained healthy over a follow-up period of 20 years. The analysis identified 20 differentially expressed miRNAs in women candidate to develop breast cancer versus control women. The upregulated miRNAs, miR-513-a-5p, miR-513b-5p and miR-513c-5p were among the most significantly deregulated miRNAs. In multivariate analysis, miR-513a-5p upregulation was directly and statistically significant associated with breast cancer risk (OR = 1.69; 95% CI 1.08-2.64; P = 0.0293). In addition, the upregulation of miR-513-a-5p displayed the strongest direct association with serum progesterone and testosterone levels. The experimental data corroborated the inhibitory function of miR-513a-5p on progesterone receptor expression confirming that progesterone receptor is a target of miR-513a-5p. The identification of upregulated miR-513a-5p with its oncogenic potential further validates the use of miRNAs as long-term biomarker of breast cancer risk., (© The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Hypotheses: Sleep disorders are associated with an increased risk of cancer, including breast cancer (BC). Physical activity (PA) can produce beneficial effects on sleep., Study Design: We designed a randomized controlled trial to test the effect of 3 months of physical activity on sleep and circadian rhythm activity level evaluated by actigraphy., Methods: 40 BC women, aged 35-70 years, were randomized into an intervention (IG) and a control group (CG). IG performed a 3 month of aerobic exercise. At baseline and after 3 months, the following parameters were evaluated both for IG and CG: anthropometric and body composition measurements, energy expenditure and motion level; sleep parameters (Actual Sleep Time-AST, Actual Wake Time-AWT, Sleep Efficiency-SE, Sleep Latency-SL, Mean Activity Score-MAS, Movement and Fragmentation Index-MFI and Immobility Time-IT) and activity level circadian rhythm using the Actigraph Actiwatch., Results: The CG showed a deterioration of sleep, whereas the IG showed a stable pattern. In the CG the SE, AST and IT decreased and the AWT, SL, MAS and MFI increased. In the IG, the SE, IT, AWT, SL, and MAS showed no changes and AST and MFI showed a less pronounced change in the IG than in the CG. The rhythmometric analysis revealed a significant circadian rhythm in two groups. After 3 months of PA, IG showed reduced fat mass %, while CG had improved weight and BMI., Conclusion: Physical activity may be beneficial against sleep disruption. Indeed, PA prevented sleep worsening in IG. PA can represent an integrative intervention therapy able to modify sleep behaviour.

Introduction: Breast cancer (BC) is the most frequent cancer in Europe and the International Agency for Research on Cancer (IARC) has estimated over 460 000 incident cases per year. Survival among patients with BC has increased in the past decades and EUROCARE-5 has estimated a 5-year relative survival rate of 82% for patients diagnosed in 2000-2007. There is growing evidence that lifestyle (such as a diet based on Mediterranean principles associated with moderate physical activity) may influence prognosis of BC; however, this information is not currently available to patients and is not considered in oncology protocols. Only a few epidemiological studies have investigated the role of diet in BC recurrence and metastasis., Methods and Analysis: DianaWeb is a community-based participatory research dedicated to patients with BC and represents a collaborative effort between participants and research institutions to determine if specified changes in lifestyle would result in improved outcomes in terms of quality of life or survival. The aim of the study is to recruit a large number of participants, to monitor their lifestyle and health status over time, to provide them tips to encourage sustainable lifestyle changes, to analyse clinical outcomes as a function of baseline risk factors and subsequent changes, and to share with patients methodologies and results. DianaWeb uses a specific interactive website (http://www.dianaweb.org/) and, with very few exceptions, all communications will be made through the web. In this paper we describe the pilot study, namely DianaWeb in Umbria., Ethics and Dissemination: DianaWeb does not interfere with prescribed oncological treatments; rather, it recommends that participants should follow the received prescriptions. The results will be used to plan guidelines for nutrition and physical activity for patients with BC. The pilot study was approved by the ethics committee of the University of Perugia (reference number 2015-002), and is supported by Fondazione Cassa di Risparmio di Perugia (2013.0185 021)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Obesity and metabolic syndrome are risk and prognostic factors for breast cancer (BC) and are associated with chronic inflammation. We investigated the association between distinct BC subtypes and markers of adiposity, dysmetabolisms, and inflammation. We analyzed 1779 patients with primary invasive BC treated at a single institution, for whom anthropometric and clinical-pathological data were archived. BC subtypes were classified by immunohistochemical staining of ER, PR, HER2, and Ki67, and their relations with the study markers were assessed by multinomial logistic regression. Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated taking luminal A as reference. All subtypes more aggressive than luminal A were significantly more frequent in younger (<45 years) than older women. Before menopause, luminal B HER2-negative tumors were positively associated with large waist (OR 2.55, 95 % CI 1.53-4.24) and insulin resistance (OR 1.90, 95 % CI 1.05-3.41); luminal B HER2-positive tumors with large waist (OR 2.11, 95 % CI 1.03-4.35) and triple-negative tumors with overweight (OR 3.04, 95 % CI 1.43-6.43) and high C-reactive protein (p trend = 0.026). In postmenopausal women aged <65, luminal B HER2-negative (OR 1.94, 95 % CI 1.16-3.24) and luminal B HER2-positive tumors (OR 2.48, 95 % CI 1.16-5.27) were positively related with metabolic syndrome. Dysmetabolisms and inflammation may be related to different BC subtypes. Before menopause, triple-negative cancers were related to obesity and chronic inflammation, and aggressive luminal subtypes to abdominal adiposity. After menopause, in women aged <65 these latter subtypes were related to metabolic syndrome. Control of adiposity and dysmetabolism can reduce the risk of aggressive BC subtypes, improving the prognosis.

Background: IGF1 is a key regulator of tissue growth and development and has been implicated in the initiation and progression of various cancers, including breast cancer. Through IGF1 mRNA splicing different precursor pro-peptides, i.e., the IGF1Ea, IGF1Eb and IGF1Ec pro-forms, are formed whose biological roles in the pathogenesis of breast cancer have not been established yet. The objective of this study was to assess the biological activity of the IGF1 pro-forms in human breast cancer-derived cells., Methods: The different IGF1 pro-forms were generated through transient transfection of HEK293 cells with the respective vector constructs. The resulting conditioned media were applied in vitro to MCF7, T47D and ZR751 breast cancer-derived cell cultures. The recombinant human IGF1 pro-forms were also tested for their binding affinity to an anti-IGF1 specific antibody by immunoprecipitation. To determine whether the IGF1 pro-forms induce cell proliferation, mature IGF1 was neutralised in HEK293-derived conditioned media., Results: We found that the IGF1 pro-forms were the only forms that were produced intra-cellularly, whereas both mature IGF1 and the IGF1 pro-forms were detected extra-cellularly. We also found that E peptides can impair the IGF1 pro-form binding affinity for the anti-IGF1 antibody and, thus, hamper an accurate measurement of the IGF1 pro-forms. Additionally, we found that the IGF1 antibody can completely inhibit IGF1-induced breast cancer cell proliferation and IGF1 receptor (IGF1R) phosphorylation, wheras the same antibody was found to only partially inhibit the biological activity of the pro-forms. Moreover, we found that the IGF1 pro-form activities can completely be inhibited by neutralising the IGF1R. Finally, we compared the bioactivity of the IGF1 pro-forms to that of mature IGF1, and found that the IGF1 pro-forms were less capable of phosphorylating the IGF1R in the breast cancer-derived cells tested., Conclusions: Our data indicate that IGF1 pro-forms can induce breast cancer cell proliferation via the IGF1R, independent from the mature IGF1 form. These results underline the importance of an accurate assessment of the presence of IGF1 pro-forms within the breast cancer microenvironment.

To investigate whether exercise training (ET) improves cardiopulmonary and endothelial function in women with breast cancer (BC). Fifty-one female patients (aged between 39 and 72 years) with a history of primary invasive BC within the previous 5 years and enrolled in the Mediterranean diet-based DIANA (diet and androgens)-5 Trial were subdivided into 2 groups: an ET group (n = 25) followed a formal ET program of moderate intensity (3 session/week on a bicycle at 60-70 % VO2peak for 3 months, followed by one session/week until 1-year follow-up), while a control group (n = 26) did not perform any formal ET. At baseline and at 1-year follow-up, all patients underwent cardiopulmonary exercise stress test (CPET) and measurements of vascular endothelial function by peripheral artery tonometry (Reactive Hyperemia Index, RHI). There were no significant differences between the groups in baseline anthropometrical, BC characteristics, and metabolic profile. No differences in baseline CPET and RHI parameters were found. Peak oxygen consumption (VO2peak) significantly increased in ET group (from 12.4 ± 2.9 to 14.3 ± 3.3 mL/kg/min, p < 0.001) compared to the control group (from 12.8 ± 2.5 to 12.6 ± 2.8 mL/kg/min, p = 0.55; p < 0.001 between groups). Compared to the control group (from 2.0 ± 0.4 to 1.9 ± 0.4, p = 0.62), the ET group showed a significant improvement of RHI after 1 year (from 2.1 ± 0.7 to 2.5 ± 0.8, p < 0.001). Changes in VO2peak were correlated with changes in RHI (ΔVO2peak vs. ΔRHI: r = 0.47, p = 0.017). In BC survivors, ET program improves cardiopulmonary functional capacity and vascular endothelial function after 12 months. Whether these changes may favorably modulate some of the pathophysiological mechanisms implied in cancer evolution should be investigated.

Metabolic syndrome (MetS), conventionally defined by the presence of at least three out of five dismetabolic traits (abdominal obesity, hypertension, low plasma HDL-cholesterol and high plasma glucose and triglycerides), has been associated with both breast cancer (BC) incidence and prognosis. We investigated the association between the prevalence of MetS and a score of adherence to the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) recommendations for the prevention of cancer in a cross-sectional study of BC patients. The DIet and ANdrogen-5 study (DIANA-5) for the prevention of BC recurrences recruited 2092 early stage BC survivors aged 35-70. At recruitment, all women completed a 24-hour food frequency and physical activity diary on their consumption and activity of the previous day. Using these diaries we created a score of adherence to five relevant WCRF/AICR recommendations. The prevalence ratios (PRs) and 95% confidence intervals (CIs) of MetS associated with the number of recommendations met were estimated using a binomial regression model. The adjusted PRs of MetS decreased with increasing number of recommendations met (p < 0.001). Meeting all the five recommendations versus meeting none or only one was significantly associated with a 57% lower MetS prevalence (95% CI 0.35-0.73). Our results suggest that adherence to WCRF/AICR recommendations is a major determinant of MetS and may have a clinical impact., (© 2015 UICC.)

Breast cancer is the most frequent cancer in women, and incidence rates have been rising in European Union (EU) countries over recent decades due in part to a sharp decline in breastfeeding practices. Evidence for a protective association between breastfeeding and the risk of breast cancer at all ages is convincing, and modest protective relationships between breastfeeding and the risk of endometrial and ovarian cancers have been suggested. The reduction in breast cancer risk is estimated at 2% for an increase of 5 months of lifetime breastfeeding. The longer women breastfeed, the more they are protected against breast cancer. In addition, breastfeeding is associated with several health benefits for both the mother and the breastfed child. Taking all this evidence into account, the 4th edition of the European Code against Cancer recommends: "Breastfeeding reduces the mother's cancer risk. If you can, breastfeed your baby"., (Copyright © 2015 International Agency for Research on Cancer. Published by Elsevier Ltd. All rights reserved.)

The aim was to investigate the association between pre-diagnostic intakes of polyphenol classes (flavonoids, lignans, phenolic acids, stilbenes, and other polyphenols) in relation to breast cancer survival (all-cause and breast cancer-specific mortality). We used data from the European Prospective Investigation into Cancer and Nutrition cohort. Pre-diagnostic usual diet was assessed using dietary questionnaires, and polyphenol intakes were estimated using the Phenol-Explorer database. We followed 11,782 breast cancer cases from time of diagnosis until death, end of follow-up or last day of contact. During a median of 6 years, 1482 women died (753 of breast cancer). We related polyphenol intake to all-cause and breast cancer-specific mortality using Cox proportional hazard models with time since diagnosis as underlying time and strata for age and country. Among postmenopausal women, an intake of lignans in the highest versus lowest quartile was related to a 28 % lower risk of dying from breast (adjusted model: HR, quartile 4 vs. quartile 1, 0.72, 95 % CI 0.53; 0.98). In contrast, in premenopausal women, a positive association between lignan intake and all-cause mortality was found (adjusted model: HR, quartile 4 vs. quartile 1, 1.63, 95 % CI 1.03; 2.57). We found no association for other polyphenol classes. Intake of lignans before breast cancer diagnosis may be related to improved survival among postmenopausal women, but may on the contrary worsen the survival for premenopausal women. This suggests that the role of phytoestrogens in breast cancer survival is complex and may be dependent of menopausal status.

In the field of cancer prevention, the public ask to be involved more actively in scientific research and in the production of knowledge. This is leading to an increase of participatory projects in the field of epidemiology. Community-based participatory research (CBPR) has received considerable attention in the past 15 years; it is becoming a recognized and important approach in addressing health disparities in cancer prevention. The increasing accessibility of new methods of comparison, discussion and information allows to link a large number of people. The project DianaWeb was born in 2015 at the Department of Predictive Medicine and Prevention of the National Cancer Institute, Milan. This CBPR involves women with diagnosis of breast cancer (BC). DianaWeb communications are based on an interactive online platform developed "ad hoc" (www.dianaweb.org). With very few exceptions, all communication between participants and research team will be on the web. The recruitment is done through Internet, hospitals, physicians, media and word of mouth. Women can join the project independently, under the control of researchers and the aim of the study is to assess whether healthy eating and regular physical activity can improve the quality of life and increase survival rates in women with diagnosis of BC. About 50,000 Italian women with a diagnosis of BC with or without metastasis, local recurrence or second cancers; with in situ or invasive cancer, whatever the disease stage at diagnosis, whatever histological diagnosis, whatever the time elapsed since diagnosis should be recruited in the DianaWeb project. The volunteers are asked to send clinical information about their condition from diagnosis onwards, on their weight and other anthropometric measures, lifestyles and nutrition through online questionnaires. Moreover, the women enrolled in the study, after login, can access evidence-based information and results obtained during the project (individual and whole community data). Volunteers can also contribute to the growth of knowledge about lifestyles to be adopted by sharing recipes, movement strategies, how to manage the change in daily practice, which will be judged by the researchers to verify the compliance with the recommendations provided before networking.

Background: miRNAs have been implicated in the regulation of key metabolic, inflammatory, and malignant pathways; hence, they might be considered both predictors and players of cancer development., Methods: Using a case-control study design nested in the ORDET prospective cohort study, we addressed the possibility that specific mRNAs can serve as early predictors of breast cancer incidence in postmenopausal women. We compared leukocyte miRNA profiles of 133 incident postmenopausal breast cancer cases and profiles of 133 women who remained healthy over a follow-up period of 20 years., Results: The analysis identified 20 differentially expressed miRNAs, 15 of which were downregulated. Of the 20 miRNAs, miR145-5p and miR145-3p, each derived from another arm of the respective pre-miRNA, were consistently and significantly downregulated in all the databases that we surveyed. For example, analysis of more than 1,500 patients (the UK Metabric cohort) indicated that high abundance of miR145-3p and miR145-5p was associated with longer, and for miR145-3p also statistically significant, survival. The experimental data attributed different roles to the identified miRNAs: Although the 5p isoform was associated with invasion and metastasis, the other isoform seems related to cell proliferation., Conclusions: These observations and the prospective design of our study lend support to the hypothesis that downregulation of specific miRNAs constitutes an early event in cancer development. This finding might be used for breast cancer prevention., Impact: The identification of the miRNAs as long-term biomarkers of breast cancer may have an impact on breast cancer prevention and early detection., (©2014 American Association for Cancer Research.)

Metabolic syndrome (MS), conventionally defined by the presence of at least three out of five dysmetabolic traits (abdominal obesity, hypertension, low plasma HDL-cholesterol, high plasma glucose and high triglycerides), has been associated with an increased risk of several age-related chronic diseases, including breast cancer (BC). This may have prognostic implications for BC survivors. 2,092 early stage BC survivors aged 35-70, recruited in eleven Italian centres 0-5 years after surgical treatment (1.74 years on average), were followed-up over 2.8 years on average for additional BC-related events, including BC-specific mortality, distant metastasis, local recurrences and contralateral BC. At recruitment, 20 % of the patients had MS. Logistic regression models were carried out to generate OR and 95 % confidence intervals (CI) for new BC events associated with MS, adjusting for baseline pathological prognostic factors. New BC events occurred in 164 patients, including 89 distant metastases. The adjusted ORs for women with MS versus women without any MS traits were 2.17 (CI 1.31-3.60) overall, and 2.45 (CI 1.24-4.82) for distant metastasis. The OR of new BC events for women with only one or two MS traits was 1.40 (CI 0.91-2.16). All MS traits were positively associated with new BC events, and significantly so for low HDL and high triglycerides. MS is an important prognostic factor in BC. As MS is reversible through lifestyle changes, interventions to decrease MS traits in BC patients should be implemented in BC clinics.

High serum levels of insulin-like growth factor I (IGF-I) are associated with an increased risk of sporadic breast cancer (BC). Furthermore, insulin and markers of insulin resistance, such as abdominal obesity, high blood glucose, high serum testosterone and metabolic syndrome, may affect both BC incidence and prognosis. We hypothesized that all these factors might be relevant also for hereditary BC, due to a deleterious mutation of BRCA genes. Epidemiological observation suggested that weight, energy intake (usually associated with higher bio-availability of growth factors) and physical activity may be relevant in BRCA mutation carriers. Mechanistic studies hypothesized a functional interaction between BRCA genes and the IGF-I system. We have provided some evidence that high serum levels of IGF-I are associated with a significantly increased penetrance. We are recruiting a larger cohort of BRCA mutation carriers in order to test potential modulators of penetrance and prognosis. Within this cohort, we have planned a randomized controlled trial to test whether moderate calorie and protein restriction, together with physical activity, decrease IGF-I. Eligible study subjects are women with or without BC, aged 18-70, with a proven deleterious BRCA mutation, and without metastases. All the women will receive recommendations for the dietary prevention of cancer. The women will be then randomized into an active life-style intervention group and into a control group that will receive only the baseline recommendations. We expect to significantly reduce IGF-I in the intervention group. This trial and the subsequent cohort follow-up might open up primary prevention options for genetic BC.

Purpose: To determine whether exercise training might exert anti-inflammatory effect by reducing HMGB1 levels in women with breast cancer (BC)., Methods: We analyzed monocentric data from the DIANA (DIET AND ANDROGENS)-5 PROJECT. Study population consisted of 94 patients randomized into two groups: 61 patients (53 +/- 8 yrs, training group) were assigned to a structured exercise training intervention (3 times/week for the first 3 months, and once /week for the following 9 months); whereas 33 patients (52 +/- 7 yrs, control group) followed only the general indications to adhere to the life-style intervention suggestions of the DIANA protocol. At study entry and after 12 months, all patients underwent cardiopulmonary exercise testing, biochemical as- sessment [HMGB1, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)]; and lipid and glycemic profile., Results: There were no significant differences between groups in baseline clinical and inflammatory profile. Among the training group, only 19/61 patients had high adherence to the exercise intervention. After stratifying the study population according to the level of adhesion to the exer- cise intervention, 1-year HMGB1 levels were lower among patients more adherent to exercise (p for trend = 0.001). Further adjusting for age, body mass index and baseline values, 1-year HMGB1 levels remained significantly and inversely associated to the level of adhesion to the exercise intervention (B = -0.97, SE = 0.43, p = 0.01)., Conclusions: Moderate intensity exercise training in BC survivors is associated with reduced HMGB1 levels that are proportional to the level of adhesion to the exercise intervention, independently from other classical inflammatory molecules, suggesting an exercise-induced anti-inflammatory effect mediated by HMGB1.

Recent cohort studies suggest that increased breast cancer risks were associated with longer smoking duration, higher pack-years and a dose-response relationship with increasing pack-years of smoking between menarche and first full-term pregnancy (FFTP). Studies with comprehensive quantitative life-time measures of passive smoking suggest an association between passive smoking dose and breast cancer risk. We conducted a study within the European Prospective Investigation into Cancer and Nutrition to examine the association between passive and active smoking and risk of invasive breast cancer and possible effect modification by known breast cancer risk factors. Among the 322,988 women eligible for the study, 9,822 developed breast cancer (183,608 women with passive smoking information including 6,264 cases). When compared to women who never smoked and were not being exposed to passive smoking at home or work at the time of study registration, current, former and currently exposed passive smokers were at increased risk of breast cancer (hazard ratios (HR) [95% confidence interval (CI)] 1.16 [1.05-1.28], 1.14 [1.04-1.25] and 1.10 [1.01-1.20], respectively). Analyses exploring associations in different periods of life showed the most important increase in risk with pack-years from menarche to FFTP (1.73 [1.29-2.32] for every increase of 20 pack-years) while pack-years smoked after menopause were associated with a significant decrease in breast cancer risk (HR = 0.53, 95% CI: 0.34-0.82 for every increase of 20 pack-years). Our results provide an important replication, in the largest cohort to date, that smoking (passively or actively) increases breast cancer risk and that smoking between menarche and FFTP is particularly deleterious., (© 2013 UICC.)

We prospectively evaluated fat intake as predictor of developing breast cancer (BC) subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptor (HER2), in a large (n = 337327) heterogeneous cohort of women, with 10062 BC case patients after 11.5 years, estimating BC hazard ratios (HRs) by Cox proportional hazard modeling. High total and saturated fat were associated with greater risk of ER(+)PR(+) disease (HR = 1.20, 95% confidence interval [CI] = 1.00 to 1.45; HR = 1.28, 95% CI = 1.09 to 1.52; highest vs lowest quintiles) but not ER(-)PR(-) disease. High saturated fat was statistically significantly associated with greater risk of HER2(-) disease. High saturated fat intake particularly increases risk of receptor-positive disease, suggesting saturated fat involvement in the etiology of this BC subtype., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: The association of reproductive factors with hormone receptor (HR)-negative breast tumors remains uncertain., Methods: Within the EPIC cohort, Cox proportional hazards models were used to describe the relationships of reproductive factors (menarcheal age, time between menarche and first pregnancy, parity, number of children, age at first and last pregnancies, time since last full-term childbirth, breastfeeding, age at menopause, ever having an abortion and use of oral contraceptives [OC]) with risk of ER-PR- (n = 998) and ER+PR+ (n = 3,567) breast tumors., Results: A later first full-term childbirth was associated with increased risk of ER+PR+ tumors but not with risk of ER-PR- tumors (≥35 vs. ≤19 years HR: 1.47 [95% CI 1.15-1.88] p(trend) < 0.001 for ER+PR+ tumors; ≥35 vs. ≤19 years HR: 0.93 [95% CI 0.53-1.65] p(trend) = 0.96 for ER-PR- tumors; P(het) = 0.03). The risk associations of menarcheal age, and time period between menarche and first full-term childbirth with ER-PR-tumors were in the similar direction with risk of ER+PR+ tumors (p(het) = 0.50), although weaker in magnitude and statistically only borderline significant. Other parity related factors such as ever a full-term birth, number of births, age- and time since last birth were associated only with ER+PR+ malignancies, however no statistical heterogeneity between breast cancer subtypes was observed. Breastfeeding and OC use were generally not associated with breast cancer subtype risk., Conclusion: Our study provides possible evidence that age at menarche, and time between menarche and first full-term childbirth may be associated with the etiology of both HR-negative and HR-positive malignancies, although the associations with HR-negative breast cancer were only borderline significant.

Purpose: We investigated the effect of fasting blood glucose and body mass index (BMI) at diagnosis on risk of breast cancer death for cases diagnosed in five Italian cancer registries in 2003-2005 and followed up to the end of 2008., Methods: For 1607 Italian women (≥15 years) with information on BMI or blood glucose or diabetes, we analysed the risk of breast cancer death in relation to glucose tertiles (≤84.0, 84.1-94.0, >94.0 mg/dl) plus diabetic and unspecified categories; BMI tertiles (≤23.4, 23.5-27.3, >27.3 kg/m(2), unspecified), stage (T1-3N0M0, T1-3N+M0 plus T4anyNM0, M1, unspecified), oestrogen (ER) and progesterone (PR) status (ER+PR+, ER-PR-, ER and PR unspecified, other), age, chemotherapy and endocrine therapy, using multiple regression models. Separate models for ER+PR+ and ER-PR- cases were also run., Results: Patients often had T1-3N0M0, ER+PR+ cancers and received chemotherapy or endocrine therapy; only 6% were M1 and 17% ER-PR-. Diabetic patients were older and had more often high BMI (>27 kg/m(2)), ER-PR-, M1 cancers than other patients. For ER+PR+ cases, with adjustment for other variables, breast cancer mortality was higher in women with high BMI than those with BMI 23.5-27.3 kg/m(2) (hazard ratio (HR)=2.9, 95% confidence interval (CI) 1.2-6.9). Breast cancer mortality was also higher in women with high (>94 mg/dl) blood glucose compared to those with glucose 84.1-94.0mg/dl (HR=2.6, 95% CI 1.2-5.7)., Conclusion: Our results provide evidence that in ER+PR+ patients, high blood glucose and high BMI are independently associated with increased risk of breast cancer death. Detection and correction of these factors in such patients may improve prognosis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Introduction: Diabetic patients treated with metformin have a lower risk of developing BC or a better BC prognosis. Metformin might reduce cancer growth through direct antiproliferative effects or through indirect mechanisms, particularly the reduction of insulin. In a randomized study on nondiabetic BC patients in natural menopause with high testosterone levels, we observed a significant decrease in insulin and in testosterone levels with metformin 1500 mg/d compared with 1000 mg/d. We present the results of a new analysis of our study on the effect of metformin on the bioavailability of sex hormones., Patients and Methods: One hundred twenty-four eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months continued the study using 1000 mg/d for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose to 1500 mg/d, and the other group continued with 1000 mg/d., Results: Ninety-six women completed the study, 43 receiving metformin 1500 mg/day, and 53 receiving 1000 mg/day. The women receiving 1500 mg/d showed a greater and significant reduction of free testosterone (-29%) and estradiol (-38%), a borderline significant reduction of estrone and insulin-like growth factor-1, and a nonsignificant reduction of androstenedione. They also showed a nonsignificant increase of dehydroepiandrosterone sulfate., Conclusion: Metformin does not interfere with the production of dehydroepiandrosterone sulfate. Besides, it decreases estradiol levels, basically through the reduction of testosterone. These hormonal changes might have clinical relevance., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies., Methods: Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided., Findings: We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06-1·35), calculated free oestradiol (1·17, 1·03-1·33), oestrone (1·27, 1·05-1·54), androstenedione (1·30, 1·10-1·55), dehydroepiandrosterone sulphate (1·17, 1·04-1·32), testosterone (1·18, 1·03-1·35), and calculated free testosterone (1·08, 0·97-1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92-1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors., Interpretation: Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women., (Copyright © 2013 Endogenous Hormones and Breast Cancer Collaborative Group. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: There are theoretical reasons for suspecting that a high glycemic index (GI) or glycemic load (GL) diet may increase breast cancer risk, perhaps via an effect on the insulin-like growth factor (IGF) axis. However observational studies have produced inconsistent findings and it is controversial whether breast cancer risk is influenced by the carbohydrate characteristics of the diet. We prospectively investigated the association between dietary GI and GL and breast cancer in the Italian section of the European Prospective Investigation into Cancer and Nutrition (EPIC)., Methods and Results: Women were recruited from 1993 to 1998 at five centers: Varese and Turin (north Italy), Florence (central Italy), and Ragusa and Naples (south Italy). Participants completed validated food frequency questionnaires from which GI and GL were estimated. Multivariable Cox proportional hazard regression models quantified the association between breast cancer risk and total carbohydrate intake, GI, and GL. During 11 years of follow-up, 879 breast cancer (797 invasive and 82 in situ) cases were indentified. High dietary GL was associated with increased breast cancer risk (RR 1.45, 95% CI = 1.06-1.99; highest vs. lowest quintile; p-trend 0.029), whereas dietary GI and total carbohydrate had no influence. The association was not modified by menopausal status or body mass index., Conclusion: Our data indicate that, in a Mediterranean population characterized by traditionally high and varied carbohydrate intake, a diet high in GL plays a role in the development of breast cancer., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: Previous studies showed that higher testosterone levels are associated with greater risk of breast cancer in premenopausal women, but the literature is scant and inconsistent., Methods: In a prospective nested case-control study of 104 premenopausal women with incident breast cancer and 225 matched controls, all characterized by regular menstrual cycles throughout their lifetime, we measured the concentration of estradiol, total and free testosterone (FT), progesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in blood samples collected on days 20 through 24 of their cycles., Results: In logistic regression models, the multivariate odds ratios (ORs) of invasive breast cancer for women in the highest tertile of circulating FT compared with the lowest was 2.43 (95% confidence interval (95% CI), 1.15 to 5.10; Ptrend = 0.03), whereas for total testosterone, the association had the same direction but was not statistically significant (OR, 1.27; 95% CI, 0.62 to 2.61; Ptrend = 0.51). Endogenous progesterone was not statistically associated with breast cancer (OR, 1.16; 95% CI, 0.60 to 2.27; Ptrend = 0.75), nor were the other considered hormones., Conclusions: Consistent with previous prospective studies in premenopausal women and our own earlier investigation, we observed that higher levels of FT are positively associated with breast cancer risk in women with regular menstrual cycles throughout their lifetimes. No evidence of risk was found associated with the other endogenous sex steroids.

Few studies have addressed longer-term survival for breast cancer in European women. We have made predictions of 10-year survival for European women diagnosed with breast cancer in 2000-2002. Data for 114,312 adult women (15-99 years) diagnosed with a first primary malignant cancer of the breast during 2000-2002 were collected in the EUROCARE-4 study from 24 population-based cancer registries in 14 European countries. We estimated relative survival at 1, 5, and 10 years after diagnosis for women who were alive at some point during 2000-2002, using the period approach. We also estimated 10-year survival conditional on survival to 1 and 5 years after diagnosis. Ten-year survival exceeded 70% in most regions, but was only 54% in Eastern Europe, with the highest value in Northern Europe (about 75%). Ten-year survival conditional on survival for 1 year was 2-6% higher than 10-year survival in all European regions, and geographic differences were smaller. Ten-year survival for women who survived at least 5 years was 88% overall, with the lowest figure in Eastern Europe (79%) and the highest in the UK (91%). Women aged 50-69 years had higher overall survival than older and younger women (79%). Six cancer registries had adequate information on stage at diagnosis; in these jurisdictions, 10-year survival was 89% for local, 62% for regional and 10% for metastatic disease. Data on stage are not collected routinely or consistently, yet these data are essential for meaningful comparison of population-based survival, which provides vital information for improving breast cancer control., (Copyright © 2012 UICC.)

Recent data can help to better define the long debated relationship between androgens and breast cancer (BC) after menopause. We reviewed the available literature data on: the origin of androgens after menopause, the association between circulating androgens and BC incidence and recurrence, the relationship between circulating and intratumoral hormones, the prognostic significance of the presence of androgen receptors (ARs) in the different BC subtypes, the androgen effect on BC cell lines, and the relationship between androgens and aromatase inhibitors. Epidemiological, clinical, and preclinical data on the role of androgens and of ARs on estrogen receptor (ER)-negative BC are somewhat controversial. However, most preclinical studies suggest that activated ARs, when present, have a proliferative effect, particularly in HER2 expressing cell lines, due to the cross-talk between AR and HER2 pathways. As regards ER-positive BC, epidemiological studies associate androgen levels with increased incidence and risk of recurrences, whilst clinical studies associate the AR positivity with a better prognosis. Preclinical studies suggest that the action of androgens is bidirectional: mainly proliferative, because circulating androgens are the precursors of estrogens, but also anti-proliferative, because AR activation restrains ER activity. The relative increase of androgenic action that follows the blocking of androgen aromatization into estrogens by aromatase inhibitors (AIs), could contribute to their therapeutic efficacy in AR-positive cases. Available data, although defining a complex picture, suggest that circulating androgen levels are clinically relevant, particularly when AIs are used.

High circulating glucose has been associated with increased risk of breast cancer (BC). There may also be a link between serum glucose and prognosis in women treated for BC. We assessed the effect of peridiagnostic fasting blood glucose and body mass index (BMI) on long-term BC prognosis. We retrospectively investigated 1,261 women diagnosed and treated for stage I-III BC at the National Cancer Institute, Milan, in 1996, 1999 and 2000. Data on blood tests and follow-up were obtained by linking electronic archives, with follow-up to end of 2009. Multivariate Cox modelling estimated hazard ratios (HR) with 95 % confidence intervals (CI) for distant metastasis, recurrence and death (all causes) in relation to categorized peridiagnostic fasting blood glucose and BMI. Mediation analysis investigated whether blood glucose mediated the BMI-breast cancer prognosis association. The risks of distant metastasis were significantly higher for all other quintiles compared to the lowest glucose quintile (reference <87 mg/dL) (respective HRs: 1.99 95 % CI 1.23-3.24, 1.85 95 % CI 1.14-3.0, 1.73 95 % CI 1.07-2.8, and 1.91 95 % CI 1.15-3.17). The risk of recurrence was significantly higher for all other glucose quintiles compared to the first. The risk of death was significantly higher than reference in the second, fourth and fifth quintiles. Women with BMI ≥ 25 kg/m(2) had significantly greater risks of recurrence and distant metastasis than those with BMI < 25 kg/m(2), irrespective of blood glucose. The increased risks remained invariant over a median follow-up of 9.5 years. Mediation analysis indicated that glucose and BMI had independent effects on BC prognosis. Peridiagnostic high fasting glucose and obesity predict worsened short- and long-term outcomes in BC patients. Maintaining healthy blood glucose levels and normal weight may improve prognosis.

Physical activity is associated with reduced risks of invasive breast cancer. However, whether this holds true for breast cancer subtypes defined by the estrogen receptor (ER) and the progesterone receptor (PR) status is controversial. The study included 257,805 women from the multinational EPIC-cohort study with detailed information on occupational, recreational and household physical activity and important cofactors assessed at baseline. During 11.6 years of median follow-up, 8,034 incident invasive breast cancer cases were identified. Data on ER, PR and combined ER/PR expression were available for 6,007 (67.6%), 4,814 (54.2%) and 4,798 (53.9%) cases, respectively. Adjusted hazard ratios (HR) were estimated by proportional hazards models. Breast cancer risk was inversely associated with moderate and high levels of total physical activity (HR = 0.92, 95% confidence interval (CI): 0.86-0.99, HR = 0.87, 95%-CI: 0.79-0.97, respectively; p-trend = 0.002), compared to the lowest quartile. Among women diagnosed with breast cancer after age 50, the largest risk reduction was found with highest activity (HR = 0.86, 95%-CI: 0.77-0.97), whereas for cancers diagnosed before age 50 strongest associations were found for moderate total physical activity (HR = 0.78, 95%-CI: 0.64-0.94). Analyses by hormone receptor status suggested differential associations for total physical activity (p-heterogeneity = 0.04), with a somewhat stronger inverse relationship for ER+/PR+ breast tumors, primarily driven by PR+ tumors (p-heterogeneity < 0.01). Household physical activity was inversely associated with ER-/PR- tumors. The results of this largest prospective study on the protective effects of physical activity indicate that moderate and high physical activity are associated with modest decreased breast cancer risk. Heterogeneities by receptor status indicate hormone-related mechanisms., (Copyright © 2012 UICC.)

Breast cancer survival is reportedly higher in the US than in Europe. The first worldwide study (CONCORD) found wide international differences in age-standardized survival. The aim of this study is to explain these survival differences. Population-based data on stage at diagnosis, diagnostic procedures, treatment and follow-up were collected for about 20,000 women diagnosed with breast cancer aged 15-99 years during 1996-98 in 7 US states and 12 European countries. Age-standardized net survival and the excess hazard of death up to 5 years after diagnosis were estimated by jurisdiction (registry, country, European region), age and stage with flexible parametric models. Breast cancers were generally less advanced in the US than in Europe. Stage also varied less between US states than between European jurisdictions. Early, node-negative tumors were more frequent in the US (39%) than in Europe (32%), while locally advanced tumors were twice as frequent in Europe (8%), and metastatic tumors of similar frequency (5-6%). Net survival in Northern, Western and Southern Europe (81-84%) was similar to that in the US (84%), but lower in Eastern Europe (69%). For the first 3 years after diagnosis the mean excess hazard was higher in Eastern Europe than elsewhere: the difference was most marked for women aged 70-99 years, and mainly confined to women with locally advanced or metastatic tumors. Differences in breast cancer survival between Europe and the US in the late 1990s were mainly explained by lower survival in Eastern Europe, where low healthcare expenditure may have constrained the quality of treatment., (Copyright © 2012 UICC.)

Background: Androgen receptors (AR) are frequently expressed in breast cancers, but their implication in cancer growth is still controversial. In the present study, we further investigated the role of the androgen/AR pathway in breast cancer development., Methods: AR expression was evaluated by immunochemistry in a cohort of 528 postmenopausal breast cancer patients previously examined for the association of serum testosterone levels with patient and tumor characteristics. AR expression was classified according to the percentage of stained cells: AR-absent (0%) and AR-poorly (1%-30%), AR-moderately (>30%-60%), and AR-highly (>60%) positive., Results: Statistical analysis was performed in 451 patients who experienced natural menopause. AR-high expression was significantly related with low histologic grade and estrogen receptor (ER)- and progesterone receptor (PR)-positive status (P trend<0.001). Mean testosterone levels were significantly higher in the AR-high category than in the other categories combined (P=0.022), although a trend across the AR expression categories was not present. When women defined by ER status were analyzed separately, regression analysis in the ER-positive group showed a significant association of high testosterone levels with AR-highly-positive expression (OR 1.86; 95% CI, 1.10-3.16), but the association was essentially due to patients greater than or equal to 65 years (OR 2.42; 95% CI, 1.22-4.82). In ER-positive group, elevated testosterone levels appeared also associated with AR-absent expression, although the small number of patients in this category limited the appearance of significant effects (OR 1.92; 95% CI, 0.73-5.02): the association was present in both age groups (<65 and ≥65 years). In the ER-negative group, elevated testosterone levels were found associated (borderline significance) with AR-absent expression (OR 2.82, 95% CI, 0.98-8.06). In this ER-negative/AR-absent subset of tumors, elevated testosterone levels cannot stimulate cancer growth either directly or after conversion into estrogens, but they probably induce increased synthesis of some other substance that is responsible for cancer growth through binding to its specific receptor., Conclusions: The findings in the present study confirm that testosterone levels are a marker of hormone-dependent breast cancer and suggest that the contemporary evaluation of ER status, AR expression, and circulating testosterone levels may identify different subsets of cancers whose growth may be influenced by androgens.

Adjuvant chemotherapy significantly decreases recurrences and improves survival in women with early breast cancer (BC). However, the side effects of chemotherapy include weight gain, which is associated with poorer prognosis. We have previously demonstrated that by means of a comprehensive dietary modification which aims at lowering insulin levels it is possible to reduce body weight and decrease the bioavailability of insulin, sex hormones and the growth factors linked to BC risk and prognosis. We are now going to present a randomized controlled study of adjuvant diet in BC patients undergoing chemotherapy. The diet was designed to prevent weight gain during chemotherapy treatment. Women of any age, operated for invasive BC, scheduled for adjuvant chemotherapy and without evidence of distant metastases, were randomized into a dietary intervention group and a control group. The intervention implied changing their usual diet for the whole duration of chemotherapy, following cooking classes and having lunch or dinner at the study centre at least twice per week. 96 BC patients were included in the study. The women in the intervention group showed a significant reduction in their body weight (2.9 kg on average), compared with the controls. They also significantly reduced body fat mass, waist and hip circumferences, biceps, underscapular and suprailiac skinfolds, compared with the women in the control group. Our results support the hypothesis that dietary intervention during adjuvant chemotherapy for BC is feasible and may prevent weight gain.

Unlabelled: This is a randomized controlled trial to test the effect of different doses of metformin in patients with breast cancer and without diabetes, with the aim of modifying the hormonal and metabolic parameters linked to breast cancer prognosis. Analysis of the results suggest that the dose of 1500 mg/d of metformin causes a significant reduction of insulin and testosterone serum levels., Background: Serum levels of insulin and testosterone may affect both breast cancer (BC) incidence and prognosis. Metformin reduces hyperglycemia and insulin levels in patients with diabetes. In women without diabetes and with polycystic ovary syndrome, metformin lowers both insulin and testosterone levels. Patients with diabetes who are treated with metformin showed a lower risk of cancer; a protective effect of metformin also was observed for BC. Recently, studies on metformin use for prevention or treatment of BC have been proposed in patients who are not diabetic. The aim of the present study was to test the effect of different doses of metformin on serum levels of insulin and testosterone in those postmenopausal patients with breast cancer and without diabetes who have basal testosterone levels ≥0.28 ng/mL (median value)., Patients and Methods: A total of 125 eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months were invited to continue the study with metformin 1000 mg/d (500 mg twice a day [b.i.d.]) for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose by taking metformin 1500 mg/d (500 mg 3 times a day [t.i.d.]), and the other group continued with metformin 1000 mg /d (500 [b.i.d.])., Results: A total of 96 women completed the study: 43 women received 1500 mg/d, and 53 women received 1000 mg/d. The women who took 1500 mg/d showed a significant reduction of insulin level, HOMA-IR index (homeostasis model assessment-insulin resistance index), testosterone level, and free androgen index compared with women treated with 1000 mg/d. After treatment with 1500 mg/d, the insulin level decreased by 25% and the testosterone level decreased by 23%., Conclusion: Both these changes might have a prognostic importance., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use., Methods: Within the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed., Results: For risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime., Conclusions: An elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.

The role of fruit and vegetables in breast cancer (BC) development has long been debated. A large variety of vegetables and fruit are consumed by Mediterranean populations, a favourable setting for evaluating the effects of these foods. The association between vegetables and fruit consumption, overall and by specific types, and BC risk was studied in the Italian section of the European Prospective Investigation into Cancer and Nutrition study. Over 31,000 women, aged 36-64 years, recruited in five Italian centers between 1993 and 1998, were available for analyses with dietary and lifestyle information and anthropometric measurements. After a median follow-up of 11.25 years, 1,072 invasive and in situ incident BC cases were identified. Cox proportional hazard models (adjusted for education, anthropometry, reproductive history, hormone replacement therapy, physical activity, alcohol consumption and smoking habits) showed an inverse association between consumption of all vegetables and BC risk (highest vs. lowest quintile HR 0.65; 95% CI 0.53-0.81, P for trend = 0.003). According to subtypes of vegetables, an inverse association emerged for increasing consumption of leafy vegetables (highest vs. lowest quintile HR 0.70; 95% CI 0.57-0.86, P for trend = 0.0001) and fruiting vegetables (highest vs. lowest quintile HR 0.75; 95% CI 0.60-0.94, P for trend = 0.01). An inverse association also emerged with increasing consumption of raw tomatoes (P for trend = 0.03). In contrast, no association of fruit, overall or by subtypes, with BC risk was found. In this Mediterranean population, a clear protective role of increasing vegetables consumption, mainly leafy and fruiting vegetables, on BC risk emerged.

High circulating glucose, insulin resistance and obesity appear to be associated with increased risk of breast cancer (BC). We sought further insight into the relation of these variables to BC. We assessed associations of BC risk with serum fasting glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) index and sex-binding hormone globulin (SHBG) in women recruited to the ORDET cohort who gave blood samples in 1987-1992. After a median 13.5 years of follow-up, 356 women developed BC. Four matched controls per case were selected by incidence density sampling, and rate ratios (RR) were estimated by conditional logistic regression. Women in the highest glucose quartile had a significantly greater risk of BC than those in the lowest glucose quartile (RR 1.63; 95% CI: 1.14-2.32; p for trend of 0.003). The association was significant in pre and post menopausal women separately and in women diagnosed after 55 years. Women in the highest HOMA-IR quartile had higher BC risk than the lowest quartile (RR 1.44; 95% CI: 1.03-2.02). Significantly increased BC risk in women diagnosed after 55 years was also present in the highest HOMA-IR quartile; in the same group decreased BC risk was significantly associated with high SHBG. The results of this study add to the existing epidemiological evidence that hyperglycemia and insulin resistance increase BC risk., (Copyright © 2011 UICC.)

Aims and Background: The DIANA (Diet and Androgens)-5 study is a multi-institutional randomized controlled trial of the effectiveness of a diet based on Mediterranean and macrobiotic recipes and principles, associated with moderate physical activity, in reducing additional breast cancer events in women with early stage invasive breast cancer at high risk of recurrence because of metabolic or endocrine milieu. The intervention is expected to reduce serum insulin and sex hormones, which were associated with breast prognosis in previous studies., Methods: Between 2008 and 2010, the study randomly assigned 1208 patients to an intensive diet and exercise intervention or to a comparison group, to be followed-up through 2015. General lifestyle recommendations for the prevention of cancer are given to both groups, and the intervention group is being offered a comprehensive lifestyle intervention, including cooking classes, conferences, common meals and exercise sessions. Adherence assessments occurred at baseline and at 12 months and are planned at 36 and 60 months. They include food frequency diaries, anthropometric measures, body fat distribution assessed with impedance scale, one week registration of physical activity with a multisensor arm-band monitor, metabolic and endocrine blood parameters. Outcome breast cancer events are assessed through self report at semi annual meetings or telephone interview and are validated through medical record verification., Results: The randomized groups were comparable for age (51.8 years), proportion of ER-negative tumors (22%), axillary node metastasis (42%), reproductive variables, tobacco smoking, blood pressure, anthropometric measurements and hormonal and metabolic parameters., Conclusions: DIANA-5 has the potential to establish whether a Mediterranean-macrobiotic lifestyle may reduce breast cancer recurrences. We will assess evidence of effectiveness, first by comparing the incidence of additional breast cancer events (local or distant recurrence, second ipsilateral or contralateral cancer) in the intervention and in the control group, by an intention-to-treat analysis, and second by analyzing the incidence of breast cancer events in the total study population by compliance assessment score.

Background: To further investigate the role of sex hormones in breast cancer, we assessed the relations of circulating estradiol and testosterone to tumor size and estrogen receptor (ER) status., Method: This was a cross-sectional study including 492 postmenopausal breast cancer patients. The relation of circulating hormones to patient and tumor characteristics was assessed using the Fisher or Cuzick tests. Multivariable logistic regression was used to estimate the odds ratios (ORs) of having tumors =2 cm (vs and <2 cm) and having ER-positive tumors (vs ER-negative) with increasing quartiles of estradiol and testosterone., Results: Mean estradiol and testosterone levels increased significantly with increasing tumor size. The ORs of tumors =2 cm increased significantly with increasing quartiles of estradiol (Ptrend and <0.001) and testosterone (Ptrend=0.005). When adjusted for estradiol, the association between testosterone and tumor size was no longer significant. Mean testosterone levels were higher in ER-positive than ER-negative patients (p and <0.001), while mean estradiol levels did not differ significantly between the two ER categories (p=0.192). The ORs of having an ER-positive tumor increased significantly with increasing quartiles of testosterone (Ptrend=0.002), whereas the increase with increasing estradiol quartiles was not significant (Ptrend=0.07)., Conclusion: The association of both hormones with tumor size implies that both are involved in tumor growth, testosterone mainly by conversion to estradiol. The strong association of testosterone with ER contrasts with the weak association of estradiol with ER and confirms testosterone as a marker of hormone-dependent tumors. These findings suggest that testosterone evaluation might be useful to better identify patients with hormone-dependent disease.

High serum levels of insulin-like growth factor I (IGF-I) are associated with an increased risk of sporadic breast cancer (BC). The aim of the present work is to evaluate the association between IGF-I and hereditary BC risk, using a case-control approach. The work represents an "ad interim" cross-sectional analysis of an ongoing study with a prospective design whose aim is to recruit a cohort of women belonging to high genetic risk families to test potential modulators of penetrance and prognosis. The odd of exposure to high serum IGF-I levels among women with a previous diagnosis of BC ("cases") was compared with the odd among unaffected "controls". The odds ratio (OR) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression, controlling for confounders. We analysed 308 women (209 cases and 99 controls) at high genetic risk of BC. The adjusted OR of BC for the upper tertile of serum IGF-I versus the lowest one was 3.5 (95%CI 1.4-8.8). Excluding from the analysis 64 women under current Tamoxifen or GnRH analogues treatment, the adjusted OR of BC became 3.7 (95%CI 1.4-9.9). The association became stronger restricting the analysis to the 161 women (97 cases and 64 controls) with a proven BRCA mutation. If confirmed by a prospective approach, the association between IGF-I and familial BC will open further options for reducing BC risk in susceptible women.

Background: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood., Methods: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies., Results: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer., Conclusion: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Aims and Background: Alcohol consumption increases the risk of developing breast cancer and may also be associated with late diagnosis, recurrence, distant metastases and death. Many studies have examined the role of alcohol as a risk factor for the development of breast cancer, but very few studies have addressed the role of alcohol as a prognostic factor for survival among women diagnosed with breast cancer. The aim of this study was to investigate the survival of women with breast cancer in relation to pre-diagnostic alcohol intake and other factors known to influence prognosis., Methods: We analyzed data for 264 women in the EUROCARE and ORDET studies who were diagnosed with breast cancer from 1987 up to 31 December 2001 and for whom information was available on follow-up, stage at diagnosis, HER-2 and hormone receptor status, and pre-diagnostic dietary alcohol intake, categorized as zero (0 g/day, non-drinkers), moderate (up to 13 g/day, about 1 serving) and high (>13 g/day). Ten-year relative survival was estimated using the maximum-likelihood approach. The excess risk of death within 10 years of diagnosis was modeled by level of alcohol intake, adjusting separately for age, stage, body mass index and tumor subtype., Results: Ten-year relative survival was lower in women who drank more than 13 g/day (65%; 95% CI, 47-78) than in non-drinkers (88%; 95% CI, 75-95). The excess risk of death within 10 years was significantly higher in women who drank more than 13 g/day than non-drinkers (relative excess risk, 4.13; 95% CI, 1.69-10.10) and was not altered by adjustment for other prognostic factors. The excess risk within 10 years was higher for women with a body mass index of 25 kg/m2 or higher (relative excess risk, 2.20; 95% CI, 1.01-4.70) and higher for those with more advanced disease., Conclusions: Women who drank more than 13 g alcohol per day had lower survival than non-drinkers. The excess risk of death within 10 years of diagnosis was unaffected by other known risk factors. High alcohol consumption may be an adverse prognostic factor for breast cancer.

Menopausal hormone therapy (MHT) is characterized by use of different constituents, regimens and routes of administration. We investigated the association between the use of different types of MHT and breast cancer risk in the EPIC cohort study. The analysis is based on data from 133,744 postmenopausal women. Approximately 133,744 postmenopausal women contributed to this analysis. Information on MHT was derived from country-specific self-administered questionnaires with a single baseline assessment. Incident breast cancers were identified through population cancer registries or by active follow-up (mean: 8.6 yr). Overall relative risks (RR) and 95% confidence interval (CI) were derived from country-specific Cox proportional hazard models estimates. A total of 4312 primary breast cancers were diagnosed during 1,153,747 person-years of follow-up. Compared with MHT never users, breast cancer risk was higher among current users of estrogen only (RR: 1.42, 95% CI 1.23-1.64) and higher still among current users of combined MHT (RR: 1.77, 95% CI 1.40-2.24; p = 0.02 for combined vs. estrogen-only). Continuous combined regimens conferred a 43% (95% CI: 19-72%) greater risk compared with sequential regimens. There was no significant difference between progesterone and testosterone derivatives in sequential regimens. There was no significant variation in risk linked to the estrogenic component of MHT, neither for oral vs. cutaneous administration nor for estradiol compounds vs. conjugated equine estrogens. Estrogen-only and combined MHT uses were associated with increased breast cancer risk. Continuous combined preparations were associated with the highest risk. Further studies are needed to disentangle the effects of the regimen and the progestin component., (Copyright © 2010 UICC.)

The authors investigated the role of known risk factors in educational differences in breast cancer incidence. Analyses were based on the European Prospective Investigation Into Cancer and Nutrition and included 242,095 women, 433 cases of in situ breast cancer, and 4,469 cases of invasive breast cancer. Reproductive history (age at first full-term pregnancy and parity), exposure to endogenous and exogenous hormones, height, and health behaviors were accounted for in the analyses. Relative indices of inequality (RII) for education were estimated using Cox regression models. A higher risk of invasive breast cancer was found among women with higher levels of education (RII = 1.22, 95% confidence interval (CI): 1.09, 1.37). This association was not observed among nulliparous women (RII = 1.13, 95% CI: 0.84, 1.52). Inequalities in breast cancer incidence decreased substantially after adjusting for reproductive history (RII = 1.11, 95% CI: 0.98, 1.25), with most of the association being explained by age at first full-term pregnancy. Each other risk factor explained a small additional part of the inequalities in breast cancer incidence. Height accounted for most of the remaining differences in incidence. After adjusting for all known risk factors, the authors found no association between education level and risk of invasive breast cancer. Inequalities in incidence were more pronounced for in situ breast cancer, and those inequalities remained after adjustment for all known risk factors (RII = 1.61, 95% CI: 1.07, 2.41), especially among nulliparous women.

Introduction: Breast cancer (BC) survivors are constantly increasing, and research investment for the identification of modifiable factors associated with BC recurrences is increasing too. The Western lifestyle, characterized by low levels of physical activity and a diet rich in refined carbohydrates, animal fats, and protein, is associated with high prevalence of metabolic syndrome, insulin resistance, and high serum levels of sex hormones and growth factors., Discussion: The present work summarizes the association between all these metabolic and hormonal factors with the risk of BC and BC recurrences. Since metabolic syndrome and endocrine imbalance may be favorably modified through comprehensive change in lifestyle, dietary changes should be recommended both for BC prevention and treatment.

Background: Lower urinary melatonin levels are associated with a higher risk of breast cancer in postmenopausal women. Literature for premenopausal women is scant and inconsistent., Methods: In a prospective case-control study, we measured the concentration of 6-sulphatoxymelatonin (aMT6s) in the 12-hour overnight urine of 180 premenopausal women with incident breast cancer and 683 matched controls., Results: In logistic regression models, the multivariate odds ratio (OR) of invasive breast cancer for women in the highest quartile of total overnight aMT6s output compared with the lowest was 1.43 [95% confidence interval (CI), 0.83-2.45; P(trend) = 0.03]. Among current nonsmokers, no association was existent (OR, 1.00; 95% CI, 0.52-1.94; P(trend) = 0.29). We observed an OR of 0.68 between overnight urinary aMT6s level and breast cancer risk in women with invasive breast cancer diagnosed >2 years after urine collection and a significant inverse association in women with a breast cancer diagnosis >8 years after urine collection (OR, 0.17; 95% CI, 0.04-0.71; P(trend) = 0.01). There were no important variations in ORs by tumor stage or hormone receptor status of breast tumors., Conclusion: Overall, we observed a positive association between aMT6s and risk of breast cancer. However, there was some evidence to suggest that this might be driven by the influence of subclinical disease on melatonin levels, with a possible inverse association among women diagnosed further from recruitment. Thus, the influence of lag time on the association between melatonin and breast cancer risk needs to be evaluated in further studies.