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Mechanistic Targets and Nutritionally Relevant Intervention Strategies to Break Obesity-Breast Cancer Links.
Bustamante-Marin, XM, Merlino, JL, Devericks, E, Carson, MS, Hursting, SD, Stewart, DA
Frontiers in endocrinology. 2021;:632284
Abstract
The worldwide prevalence of overweight and obesity has tripled since 1975. In the United States, the percentage of adults who are obese exceeds 42.5%. Individuals with obesity often display multiple metabolic perturbations, such as insulin resistance and persistent inflammation, which can suppress the immune system. These alterations in homeostatic mechanisms underlie the clinical parameters of metabolic syndrome, an established risk factor for many cancers, including breast cancer. Within the growth-promoting, proinflammatory milieu of the obese state, crosstalk between adipocytes, immune cells and breast epithelial cells occurs via obesity-associated hormones, angiogenic factors, cytokines, and other mediators that can enhance breast cancer risk and/or progression. This review synthesizes evidence on the biological mechanisms underlying obesity-breast cancer links, with emphasis on emerging mechanism-based interventions in the context of nutrition, using modifiable elements of diet alone or paired with physical activity, to reduce the burden of obesity on breast cancer.
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Adherence to Dietary Recommendations after One Year of Intervention in Breast Cancer Women: The DIANA-5 Trial.
Bruno, E, Krogh, V, Gargano, G, Grioni, S, Bellegotti, M, Venturelli, E, Panico, S, Santucci de Magistris, M, Bonanni, B, Zagallo, E, et al
Nutrients. 2021;(9)
Abstract
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.
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Low-fat dietary pattern and breast cancer mortality by metabolic syndrome components: a secondary analysis of the Women's Health Initiative (WHI) randomised trial.
Pan, K, Aragaki, AK, Neuhouser, ML, Simon, MS, Luo, J, Caan, B, Snetselaar, L, Mortimer, JE, Manson, JE, Kroenke, C, et al
British journal of cancer. 2021;(3):372-379
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Abstract
BACKGROUND In the Women's Health Initiative (WHI) dietary modification (DM) randomised trial, the low-fat dietary intervention reduced deaths from breast cancer (P = 0.02). Extending these findings, secondary analysis examined dietary intervention influence on breast cancer mortality by metabolic syndrome (MS) components. METHODS In total, 48,835 postmenopausal women with no prior breast cancer were randomised to a low-fat dietary intervention or comparison groups. Four MS components were determined at entry in 45,833 participants: (1) high waist circumference, (2) high blood pressure, (3) high cholesterol and (4) diabetes history. Forest plots of hazard ratios (HRs) were generated with P-values for interaction between randomisation groups and MS component score. Primary outcome was death from breast cancer by metabolic syndrome score. RESULTS HRs and 95% confidence intervals (CI) for dietary intervention influence on death from breast cancer were with no MS components (n = 10,639), HR 1.09, 95% CI 0.63-1.87; with 1-2 MS components (n = 30,948), HR 0.80, 95% CI 0.62-1.02; with 3-4 MS components (n = 4,246), HR 0.31, 95% CI 0.14-0.69 (interaction P = 0.01). CONCLUSIONS While postmenopausal women with 3-4 MS components were at higher risk of death from breast cancer, those randomised to a low-fat dietary intervention more likely had reduction in this risk. REGISTRY ClinicalTrials.gov (NCT00000611).
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Personalized Nutrition as a Key Contributor to Improving Radiation Response in Breast Cancer.
Shastri, AA, Lombardo, J, Okere, SC, Higgins, S, Smith, BC, DeAngelis, T, Palagani, A, Hines, K, Monti, DA, Volpe, S, et al
International journal of molecular sciences. 2021;(1)
Abstract
Understanding metabolic and immune regulation inherent to patient populations is key to improving the radiation response for our patients. To date, radiation therapy regimens are prescribed based on tumor type and stage. Patient populations who are noted to have a poor response to radiation such as those of African American descent, those who have obesity or metabolic syndrome, or senior adult oncology patients, should be considered for concurrent therapies with radiation that will improve response. Here, we explore these populations of breast cancer patients, who frequently display radiation resistance and increased mortality rates, and identify the molecular underpinnings that are, in part, responsible for the radiation response and that result in an immune-suppressive tumor microenvironment. The resulting immune phenotype is discussed to understand how antitumor immunity could be improved. Correcting nutrient deficiencies observed in these populations should be considered as a means to improve the therapeutic index of radiation therapy.
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Effects of a web-based expert support self-management program (WEST) for women with breast cancer: A randomized controlled trial.
Kim, HJ, Kim, HS
Journal of telemedicine and telecare. 2020;(7-8):433-442
Abstract
INTRODUCTION This study was a randomized controlled trial that examined the effects of a web-based expert support self-management program (WEST) on metabolic syndrome risk factors and self-efficacy among Korean women with breast cancer. METHODS Participants were 60 women with breast cancer (30 participants each in both the experimental and control groups) who also had metabolic risk factors. WEST is based on the self-efficacy theory and is a self-health management program consisting of a web-based program, DIETEX (which entails keeping a health diary, identifying a lifestyle type, inputting personal health information), and expert support. WEST was provided to the experimental group once a week for 24 weeks. Metabolic syndrome risk factors and self-efficacy of the experimental and control groups were examined pre-intervention and at 12 and 24 weeks after intervention. RESULTS The decreases in body fat, body fat percentage, and waist circumference were greater in the experimental group than in the control group at 24 weeks (p = 0.019, p = 0.025, and p = 0.038, respectively). DISCUSSION The present study can provide basic data for the development and application of interventions for women with breast cancer in the future. Additionally, we propose that WEST be included in the treatment process to complement the intervention of medical personnel for improving metabolic risk factors in women with breast cancer.
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Monitoring Vitamin B12 in Women Treated with Metformin for Primary Prevention of Breast Cancer and Age-Related Chronic Diseases.
Mastroianni, A, Ciniselli, CM, Panella, R, Macciotta, A, Cavalleri, A, Venturelli, E, Taverna, F, Mazzocchi, A, Bruno, E, Muti, P, et al
Nutrients. 2019;(5)
Abstract
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 B12. 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 B12, 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 B12 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 B12 below the normal threshold (<221 pmol/L) at the end of the study. Considering jointly all B12, 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, B12 monitoring for MET-treated individuals should be implemented.
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Metabolic syndrome and postmenopausal breast cancer: systematic review and meta-analysis.
Esposito, K, Chiodini, P, Capuano, A, Bellastella, G, Maiorino, MI, Rafaniello, C, Giugliano, D
Menopause (New York, N.Y.). 2013;(12):1301-9
Abstract
OBJECTIVE The role of metabolic syndrome (MS) and its individual components in postmenopausal breast cancer (PBC) risk is still unclear. We reviewed and summarized epidemiological studies assessing the association of MS with the risk of PBC. METHODS We conducted an electronic search, without restrictions, for articles published before October 31, 2012. Every included study was to report risk estimates with 95% CIs for the association between MS and PBC. Study-specific estimates were pooled using random-effects models. RESULTS Nine articles (with 6,417 cancer cases), all published in English, were included in the meta-analysis. MS was associated with a 52% increase in cancer risk (P < 0.001)-for the most part confined to noncohort studies (109% increased risk); the risk estimates changed little, depending on populations (United States and Europe) and definition of the syndrome (traditional vs nontraditional). The risk estimates for PBC were 1.12 (P = 0.068) for higher values of body mass index/waist circumference, 1.19 (P = 0.005) for hyperglycemia (higher fasting glucose or diabetes), 1.13 (P = 0.027) for higher blood pressure, 1.08 (P = 0.248) for higher triglycerides, and 1.39 (P = 0.008) for lower high-density lipoprotein cholesterol. All these estimates were lower than those associated with MS in the same studies. CONCLUSIONS MS is associated with a moderately increased risk of PBC. No single component explains the risk conveyed by the full syndrome.
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The effect of aerobic exercise on metabolic and inflammatory markers in breast cancer survivors--a pilot study.
Guinan, E, Hussey, J, Broderick, JM, Lithander, FE, O'Donnell, D, Kennedy, MJ, Connolly, EM
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2013;(7):1983-92
Abstract
PURPOSE Physical activity is associated with a reduced risk of breast cancer development and recurrence. There are several hypothesised mechanisms for this including positive effects on metabolic and inflammatory biomarkers and favourable changes in anthropometric variables. This pilot study examined the effect of an 8-week aerobic exercise intervention on several of these outcomes, including body composition, the metabolic syndrome, C-reactive protein (CRP) and physical activity, in breast cancer survivors 2-6 months post-chemotherapy. METHODS Assessments were completed at baseline, at 8-weeks and 3-months post-intervention. Measures taken following a 12-h fast included body composition (bioimpedance analysis), metabolic syndrome (waist circumference, blood pressure, high-density lipoprotein cholesterol, triglycerides and fasting glucose), insulin resistance (homeostatic model assessment), CRP and physical activity (accelerometry and questionnaire). Participants were randomized to either an 8-week moderate-intensity aerobic exercise group or a usual-care control group. Analysis was completed using repeated-measures analysis of variance (ANOVA) (p = 0.05). RESULTS Twenty-six breast cancer survivors participated (mean (standard deviation) age 48.1 (8.8) years, exercise group; n = 16, control group; n = 10). At baseline, 13 participants were overweight, 6 were obese and 19 centrally obese. Intention-to-treat analysis revealed no significant differences between the exercise and control groups in any of the outcomes measures; however, analysis of those who adhered to >90 % of the supervised exercise class showed a significant decrease in waist circumference (p = 0.05) and a significant increase in subjectively reported "total weekly" (p = 0.005) activity. CONCLUSION While this 8-week aerobic exercise pilot intervention did not elicit significant improvements in biomarkers of breast cancer risk, there was some suggestion of improvements in waist circumference and subjectively measured physical activity in participants with >90 % adherence to the programme. A trial of longer duration and greater subject numbers is warranted.
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Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer.
Vona-Davis, L, Howard-McNatt, M, Rose, DP
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2007;(5):395-408
Abstract
Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression.
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Risks and benefits of taxanes in breast and ovarian cancer.
Michaud, LB, Valero, V, Hortobagyi, G
Drug safety. 2000;(5):401-28
Abstract
The taxanes are a unique class of agents with a broad spectrum of clinical activity. They act by binding to tubulin, producing unnaturally stable microtubules and subsequent cell death. The distribution and elimination of paclitaxel depend on dose and administration rate. This nonlinearity is much less evident at lower infusion rates (24-hour infusions) and more evident at high plasma concentrations (3-hour infusions). The pharmacokinetics of docetaxel also suggest the presence of nonlinear pathways, but these appear to be clinically insignificant at the current doses utilised (60 to 100 mg/m2). Both agents undergo hepatic metabolism and biliary excretion and require dose adjustment in the setting of liver dysfunction. Drug interactions are quite common with these agents, some of which are sequence-dependent and clinically significant. The optimal dose of paclitaxel is not known at this time, and controversy over possible dose- or schedule-related differences in efficacy still remain. Docetaxel is somewhat more consistent in its dose and scheduling information, but controversy remains regarding a dose-benefit relationship as well as scheduling differences (weekly vs every 3 weeks). Toxicity profiles for these agents are somewhat different. Paclitaxel is more likely to be associated with peripheral neuropathy and myalgias/arthralgias than docetaxel. Docetaxel is more likely to be associated with a cumulative fluid retention syndrome that can be dose limiting. Paclitaxel and docetaxel are both highly active agents against breast cancer, including tumours that are resistant to anthracyclines. Docetaxel tends to have higher response rates overall, but direct comparisons at maximally tolerated doses have not been completed. Combination regimens with many different agents are attempting to improve on the responses seen with single-agent taxanes. The combination of paclitaxel and a platinum compound should be utilised as first-line therapy of advanced ovarian cancer. Controversy lies in the choice of the platinum compound and the dose and administration schedule of paclitaxel. Substitution of docetaxel for paclitaxel in these platinum-containing regimens is also being investigated. The taxanes also exhibit activity against ovarian cancer in patients previously exposed to platinum agents. These agents may also be administered intraperitoneally for local therapy of metastatic ovarian cancer. Although docetaxel and paclitaxel are often considered similar in activity and tolerability, this review emphasises the fact that these agents are indeed different. Clinicians need to be familiar with the benefits and adverse events related to each agent in order to make informed, appropriate clinical decisions.