Weight management and physical activity throughout the cancer care continuum.

Mounting evidence suggests that weight management and physical activity (PA) improve overall health and well being, and reduce the risk of morbidity and mortality among cancer survivors. Although many opportunities exist to include weight management and PA in routine cancer care, several barriers remain. This review summarizes key topics addressed in a recent National Academies of Science, Engineering, and Medicine workshop entitled, "Incorporating Weight Management and Physical Activity Throughout the Cancer Care Continuum." Discussions related to body weight and PA among cancer survivors included: 1) current knowledge and gaps related to health outcomes; 2) effective intervention approaches; 3) addressing the needs of diverse populations of cancer survivors; 4) opportunities and challenges of workforce, care coordination, and technologies for program implementation; 5) models of care; and 6) program coverage. While more discoveries are still needed for the provision of optimal weight-management and PA programs for cancer survivors, obesity and inactivity currently jeopardize their overall health and quality of life. Actionable future directions are presented for research; practice and policy changes required to assure the availability of effective, affordable, and feasible weight management; and PA services for all cancer survivors as a part of their routine cancer care. CA Cancer J Clin 2018;68:64-89. © 2017 American Cancer Society.

Metformin, placebo, and endocrine therapy discontinuation among participants in a randomized double-blind trial of metformin vs placebo in hormone receptor-positive early-stage breast cancer (CCTG MA32).

BACKGROUND: The MA32 study investigated whether 5 years of metformin (versus placebo) improves invasive disease-free survival in early-stage breast cancer (BC). Non-adherence to endocrine therapy (ET) and medications for chronic conditions is common and increases with drug toxicity and polypharmacy. This secondary analysis evaluates rates and predictors of early discontinuation of metformin, placebo, and ET among participants with HR-positive BC. METHODS: Patients with high-risk non-metastatic BC were randomized to 60 months of metformin (850 mg BID) or placebo BID. Patients were administered bottles of metformin/placebo every 180 days. Metformin/placebo adherence was defined as a bottle dispensed at month 48 or later. The ET adherence analysis included patients with HR-positive BC who received ET with start and stop date reported, with adherence defined as > 48 months of use. Associations of covariates with study drug and ET adherence were examined using multivariable models. RESULTS: Among the 2521 HR-positive BC patients, 32.9% were non-adherent to study drug. Non-adherence was higher among patients on metformin vs placebo (37.1% vs 28.7%, p < 0.001). Reassuringly, ET discontinuation rates were similar between treatment arms (28.4% vs 28.0%, p = 0.86). Patients who were non-adherent to ET were more likely to discontinue study therapy (38.8% vs 30.1%, p < 0.0001). In a multivariable analysis, study drug non-adherence was increased with metformin vs placebo (OR: 1.50, 95% CI 1.25-1.80; p < 0.0001); non-adherence to ET (OR: 1.47, 95% CI 1.20-1.79, p < 0.0001); grade 1 or greater GI toxicity during the first 2 years; lower age; and higher body mass index. CONCLUSION: While non-adherence was higher among patients on metformin, it was still considerable among patients on placebo. Reassuringly, treatment arm allocation did not impact ET adherence. Attention to global medication adherence is needed to improve BC and non-oncological outcomes in cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01.

Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial.

Importance: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. Objective: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. Design, Setting, and Participants: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Interventions: Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. Main Outcomes and Measures: The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Results: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Conclusions and Relevance: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01101438.

Prognostic associations of plasma hepcidin in women with early breast cancer.

PURPOSE: Iron is essential to energy metabolism, cell proliferation and DNA synthesis, and sufficient iron availability may be required for tumor growth. The hormone hepcidin is a systemic regulator of iron concentration in plasma. Intra-tumor RNA expression of hepcidin has been linked to shorter metastasis-free survival in women with early breast cancer, but the prognostic implications of this inflammatory marker and iron-regulating plasma peptide in the blood are unknown. METHODS: Using an ELISA assay, hepcidin was measured in the banked blood of 518 women who were recruited from 1989 to 1996 for a prospective cohort study of diet and lifestyle factors in breast cancer. Blood samples were obtained 4-12 weeks post-operatively, prior to treatment with chemotherapy or tamoxifen. RESULTS: Hepcidin was not associated with time to distant breast cancer recurrence (primary outcome) nor time to death from any cause. However, a pre-planned interaction test of body mass index (BMI) was statistically significant (p < 0.01). Among obese women (BMI > 30 kg/m2), higher hepcidin was associated with a shorter time to distant breast cancer recurrence in both uni- and multivariable analyses (adjusted HR 1.84; 95% CI 1.04-3.25). For overall survival, a similar pattern was seen in the univariable model but the effect was diminished in a multivariable analysis. Plasma hepcidin was not associated with high-sensitivity C-reactive protein, but it was significantly associated (r ≥ 0.32) with iron indices, including total iron (p < 0.01), transferrin (p < 0.01) and soluble transferrin receptor (p < 0.01). CONCLUSIONS: Hepcidin may be associated with poor breast cancer outcome in obese women, however, replication is required. The biologic basis for this prognostic association requires further research.

Sexual health in long-term breast cancer survivors.

PURPOSE: Sexual dysfunction is reported in women with breast cancer (BC). It is unclear whether symptoms persist over time as data comparing long-term survivors to controls are lacking. We compared sexual functioning in long-term breast cancer survivors (BCS) to controls and determined the impact of adjuvant therapy on sexual health. METHODS: A cohort of women with localized BC (1989-1996) was prospectively followed. BCS and controls (2005-2007) completed self-reported questionnaires. Sexual health was measured with the Sexual Activity Questionnaire (SAQ). Vasomotor, gynecological, and bladder symptoms were scored using the Menopausal Symptom Scale. Regression analysis was used to compare groups, with adjustment for age and secondly menopausal status. RESULTS: BCS (n = 248, 87%) and controls (n = 159, 95%) completed the SAQ at a median time from diagnosis of 12.5 years. BCS were older (62 vs 59 years, p = 0.0004) and more likely to be menopausal (94 vs 86%, p = 0.0025). Sexual activity did not differ significantly between BCS and controls, but when adjusted for menopausal status, pre/peri-menopausal BCS were less likely to be sexually active than pre/peri-controls (odds ratio OR 0.12, p = 0.012). In those sexually active, no significant differences were noted on the SAQ Pleasure, Discomfort, and Habit scales. BCS reported worse gynecological symptoms and pre/peri-menopausal patients had more bladder complaints (standardized effect size 0.36 p = 0.002 and 1.11, p = 0.011). Adjuvant treatments were not significantly associated with sexual function, but BCS treated with chemotherapy reported worse gynecological symptoms. CONCLUSION: Sexual health and uro-genital symptom counseling should be provided to BCS, particularly pre/peri-menopausal patients, even at long-term follow-up.

Impact of the obesity epidemic on cancer.

There is growing appreciation that the current obesity epidemic is associated with increases in cancer incidence at a population level and may lead to poor cancer outcomes; concurrent decreases in cancer mortality at a population level may represent a paradox, i.e., they may also reflect improvements in the diagnosis and treatment of cancer that mask obesity effects. An association of obesity with cancer is biologically plausible because adipose tissue is biologically active, secreting estrogens, adipokines, and cytokines. In obesity, adipose tissue reprogramming may lead to insulin resistance, with or without diabetes, and it may contribute to cancer growth and progression locally or through systemic effects. Obesity-associated changes impact cancer in a complex fashion, potentially acting directly on cells through pathways, such as the phosphoinositide 3-kinase (PI3K) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways, or indirectly via changes in the tumor microenvironment. Approaches to obesity management are discussed, and the potential for pharmacologic interventions that target the obesity-cancer link is addressed.

Metabolic factors, anthropometric measures, diet, and physical activity in long-term breast cancer survivors: change from diagnosis and comparison to non-breast cancer controls.

PURPOSE: We studied metabolic factors, diabetes, and anthropometric measurements at diagnosis and long-term follow-up (LTFU), mean 12.5 years post-diagnosis, in breast cancer (BC) survivors, and compared their status at LTFU to that of age-matched women without BC. Diet and physical activity were also assessed. METHOD: 535 non-diabetic BC patients treated at three University of Toronto hospitals were followed prospectively; 285 surviving patients, without distant recurrence, participated in a LTFU study. A control group of 167 age-matched women without BC was recruited from a mammogram screening program at one of the hospitals. Change over time was analyzed using paired t tests, and comparisons between BC survivors and controls used age and education (AE)-adjusted regression models. RESULTS: Median weight gain in BC survivors was 2.00 kg (p < 0.0001); BMI, glucose, insulin, homeostasis model assessment (HOMA), and total cholesterol increased modestly but significantly. Waist circumference, glucose, and triglycerides were higher in LTFU BC survivors versus controls. BC survivors had significantly greater prevalence of diabetes/pre-diabetes versus controls (33 vs. 20.4%, AE-adjusted odds ratio (OR) 1.59, p = 0.050). This effect was restricted to those with lower levels of physical activity (<56 metabolic equivalent (MET)-hours/week: OR 2.70 versus 0.94 for those with higher physical activity, interaction p = 0.034). At LTFU, BC survivors were more physically active than at diagnosis (median increase 28 MET-hours/week interquartile range -14.8 to 82), and compared to controls (median 68.2 vs. 44 MET-hours/week, p < 0.0001). CONCLUSION: The prevalence of the metabolic syndrome and diabetes/pre-diabetes was significantly higher in BC survivors than in controls group, notably in those with lower levels of physical activity. Enhanced diabetes/metabolic syndrome screening and promotion of physical activity may be warranted in BC survivors.

Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study.

INTRODUCTION: The antidiabetic drug metformin exhibits potential anticancer properties that are believed to involve both direct (insulin-independent) and indirect (insulin-dependent) actions. Direct effects are linked to activation of AMP-activated protein kinase (AMPK) and an inhibition of mammalian target of rapamycin mTOR signaling, and indirect effects are mediated by reductions in circulating insulin, leading to reduced insulin receptor (IR)-mediated signaling. However, the in vivo impact of metformin on cancer cell signaling and the factors governing sensitivity in patients remain unknown. METHODS: We conducted a neoadjuvant, single-arm, "window of opportunity" trial to examine the clinical and biological effects of metformin on patients with breast cancer. Women with untreated breast cancer who did not have diabetes were given 500 mg of metformin three times daily for ≥2 weeks after diagnostic biopsy until surgery. Fasting blood and tumor samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, and immunohistochemical analysis of tumors was used to characterize cellular markers before and after treatment. RESULTS: Levels of IR expression decreased significantly in tumors (P = 0.04), as did the phosphorylation status of protein kinase B (PKB)/Akt (S473), extracellular signal-regulated kinase 1/2 (ERK1/2, T202/Y204), AMPK (T172) and acetyl coenzyme A carboxylase (S79) (P = 0.0001, P < 0.0001, P < 0.005 and P = 0.02, respectively). All tumors expressed organic cation transporter 1, with 90% (35 of 39) exhibiting an Allred score of 5 or higher. CONCLUSIONS: Reduced PKB/Akt and ERK1/2 phosphorylation, coupled with decreased insulin and IR levels, suggest insulin-dependent effects are important in the clinical setting. These results are consistent with beneficial anticancer effects of metformin and highlight key factors involved in sensitivity, which could be used to identify patients with breast cancer who may be responsive to metformin-based therapies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00897884. Registered 8 May 2009.

Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial.

Metformin has therapeutic potential against breast cancer, but the mechanisms of action in vivo remain uncertain. This study examined biomarker effects of metformin in primary breast cancer in a preoperative window of opportunity trial. Non-diabetic women with operable invasive breast cancer were randomized to receive open label pre-operative metformin (500 mg daily for 1 week then 1 g twice daily for a further week) or as controls, not receiving metformin. Patients in both arms had a core biopsy pre-randomisation and again at the time of surgery. Immunohistochemistry for phospho-AMPK (pAMPK), phospho-Akt (pAkt), insulin receptor, cleaved caspase-3, and Ki67 was performed on formalin-fixed paraffin-embedded cores, scored blinded to treatment and analysed by paired t test. In metformin-treated patients, significant up-regulation of pAMPK (paired t test, p = 0.04) and down-regulation of pAkt (paired t test, p = 0.043) were demonstrated compared to the control group. Insulin receptor and serum insulin remained similar following metformin treatment compared with a rise in insulin receptor and insulin in controls. Significant falls in Ki67 and cleaved caspase-3 (paired t test, p = 0.044) were seen in the metformin-treated patients but not in the control group. Changes were independent of body mass index. These biomarker data suggest mechanisms for metformin action in vivo in breast cancer patients via up-regulation of tumor pAMPK, down-regulation of pAkt, and suppression of insulin responses reflecting cytostatic rather than cytotoxic mechanisms.

Breast Cancer Survivorship: Where Are We Today?

Breast cancer is the most common cancer in women, and survivors with this diagnosis account for almost one fourth of the over 14 million cancer survivors in the US. After several decades of basic and clinical trials research, we have learned much about the heterogeneity of breast cancer and have evolved a complex and multidisciplinary treatment approach to the disease. Increasingly, we are paying attention to the long term and late effects of breast cancer treatment, and this is largely the subject of this volume. In this chapter, the authors introduce the topic of breast cancer survivorship and highlight the organization and content of this volume, briefly describing the contents of the subsequent chapters.

Host Factors and Risk of Breast Cancer Recurrence: Genetic, Epigenetic and Biologic Factors and Breast Cancer Outcomes.

Among women with breast cancer, there is wide variability in outcomes, both in treatment-related toxicities and disease-free survival (DFS). Primary predictors of DFS are those related to the extent of the disease and tumor characteristics, associated not only with tumor aggressiveness, but also responsiveness to targeted therapies. Inherited germline variation may also play a role in cancer treatment outcomes, and there have been studies targeting drug metabolism and other candidate pathways as well as genome-wide association studies (GWAS), which take a more agnostic approach and interrogate hundreds of thousands single nucleotide polymorphisms (SNPs) to determine those that modify response to breast cancer treatment. While this field of pharmacogenetics and pharmacogenomics has held exciting promise for personalized medicine, the results have not been as consistent, or the effects as profound, as first hoped. An emerging field in studies of cancer prognosis is epigenetics, which regulates DNA expression and can be influenced by numerous biologic processes as well as environmental exposures. Although young, this field of research likely holds promise for understanding of epigenetic mechanisms driving cancer and cancer outcomes, with a potential to modify these factors through drugs or other approaches. Finally, circulating markers in blood that reflect some lifestyle factors have also been studies in relation to cancer outcomes, particularly Vitamin D. In this chapter, we highlight advances in the areas noted above, and comment on factors that can impact interpretation of results from observational studies. We also discuss future directions, and avenues necessary to move the field forward.

Comorbidities and Their Management: Potential Impact on Breast Cancer Outcomes.

Pre-existing comorbidities negatively impacts overall breast cancer prognosis, increasing both breast cancer specific deaths as well as death from competing causes. Improvements in breast cancer survival in recent decades, however, have primarily been experienced among cancer patients without comorbidities, and less so among those with moderate or severe comorbidities. As guidelines for the treatment of breast cancer are mostly based on studies excluding patients with moderate and severe comorbidities with under-representation of older women with comorbid conditions, information regarding treatment effectiveness in breast cancer patients with comorbidities is currently lacking. This chapter describes the impact of comorbidities on breast cancer treatment and outcomes, previous research approaches taken, and specific populations that may be most susceptible to the effects of comorbidities on breast cancer outcomes. Future research directions are suggested that may help to improve understanding of comorbidity-related factors that underlie disparities in breast cancer outcomes, and to examine the potential role of effective management of comorbidities among breast cancer patients as a strategy to help close gaps in disease prognosis.

Modifiable Lifestyle Factors and Breast Cancer Outcomes: Current Controversies and Research Recommendations.

Lifestyle factors, particularly obesity, have been associated with poor breast cancer outcomes in a large number of observational studies. Despite a growing body of research, controversy exists regarding obesity associations across breast cancer subtypes and the importance of obesity versus physical activity and dietary composition in determining breast cancer outcome. These controversies are reviewed and the complex biologic nature of the association of obesity with breast cancer addressed. Potential mediators, including insulin, estrogens, adipokines and inflammation markers are identified. Relevant prognostic findings of previous research involving dietary, physical activity and weight loss interventions are summarized. A broad-based program of research is outlined, highlighting the need for a randomized trial of weight loss that is adequately powered to examine survival effects, as well as correlative and preclinical research to investigate mediators and mechanisms of obesity effects on breast cancer outcomes. Finally, potential contributions of alcohol intake and tobacco use in breast cancer survivors are discussed.

Post-surgical highly sensitive C-reactive protein and prognosis in early-stage breast cancer.

Obesity, associated with inflammation, has been linked to poor prognosis in breast cancer. Research investigating the potential role of C-reactive protein (CRP), an obesity-associated systemic marker of inflammation, as a mediator of adverse prognostic effects of obesity has yielded inconsistent results. We examined the association of highly sensitive CRP (hsCRP) with obesity-related factors and breast cancer outcome. A cohort of 535 non-diabetic women diagnosed with T1-3, N0-1, M0 breast cancer, was assembled between 1989 and 1996 and followed prospectively. Circulating levels of hsCRP were analyzed on blood obtained postoperatively, prior to systemic therapy, in 501 women. Correlations and prognostic associations were analyzed using one-way analysis of variance, Spearman's rank correlation coefficients (r) and Cox models. hsCRP was significantly correlated with body mass index (r = 0.60), insulin (r = 0.44), leptin (r = 0.54), and lipids, but not T or N stage, grade or estrogen receptor/progesterone receptor. At a median follow-up of 12 years, hsCRP was not associated with distant disease-free survival or overall survival in univariable [Q4 vs. Q1 hazard ratio (HR) 1.03, 95 % confidence interval (CI) 0.69-1.52, P = 0.9 and HR 1.27, 95 % CI 0.86-1.86, P = 0.24, respectively] or multivariable [Q4 vs Q1 HR 1.02, 95 % CI 0.66-1.59, P = 0.93 and HR 1.17, 95 % CI 0.76-1.81, P = 0.48 respectively] analyses. hsCRP was associated with age, comorbidities, and the insulin resistance syndrome but not with breast cancer outcome.

Blood levels of vitamin D and early stage breast cancer prognosis: a systematic review and meta-analysis.

Vitamin D regulates expression of genes important in development and progression of breast cancer. The association of vitamin D with breast cancer outcomes among breast cancer patients is controversial. We conducted a systematic review and meta-analysis of this association in early stage breast cancer outcome. We searched MEDLINE (1982-May 1, 2013), the American Society of Clinical Oncology (2009-2012), and the San Antonio Breast Cancer Symposium (2010-2012) for abstracts, using the following keywords: "breast cancer" and "prognosis" or "survival", and "vitamin D" or" calcitriol" to identify studies reporting the associations of blood vitamin D levels (drawn close to diagnosis) with breast cancer outcomes. Meta-analyses were performed using an inverse-variance weighted fixed-effects model with Stata Version 12. Eight studies including 5,691 patients were identified. Vitamin D deficiency was variably categorized across studies; a median of 36.8 % of patients were classified as deficient. Low vitamin D levels were associated with a pooled hazard ratio of 2.13 (95 % CI 1.64-2.78) and 1.76 (95 % CIs 1.35-2.30) for recurrence (six studies) and death (four studies), respectively, with no evidence of significant heterogeneity across studies. There was potential evidence of a publication bias in studies examining associations with death (but not in those examining associations with recurrence). These findings support an association of low levels of vitamin D with increased risk of recurrence and death in early stage breast cancer patients. Given the observational nature of the included studies, it cannot be concluded that this association is causal. Further research is warranted to investigate the potential beneficial effects of vitamin D in breast cancer.

Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin (v placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; P = .13. These included 48 contralateral invasive breast cancers (27 metformin v 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; P = .40 and 136 new nonbreast primary cancers (75 metformin v 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; P = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.

Body size and breast cancer prognosis in relation to hormone receptor and menopausal status: a meta-analysis.

Obesity is associated with poor survival after breast cancer diagnosis in individual studies and meta-analyses. Evidence regarding associations of obesity with breast cancer-specific survival (BCSS) and overall survival (OS) in relation to hormone receptor status, or BCSS in relation to menopausal status has not been evaluated in a previous meta-analysis. In this study, we conducted a meta-analysis of the association of obesity with OS and BCSS in relation to hormone receptor status and menopausal status. MEDLINE, EMBASE, and COCHRANE databases from the first record to December 2011 and presentations made at major international meetings in the last 5 years were searched. We included observational or interventional studies reporting hazard ratios (HRs) of obesity with OS and/or BCSS in relation to hormone receptor and/or menopausal status. Twenty-one studies qualified, meeting the above criteria. The pooled HR for OS in heavier versus lighter women was 1.31 (95 % CI 1.17-1.46) for estrogen receptor/progesterone receptor (ER/PgR) positive cancers; 1.18 (95 % CI 1.06-1.31) for ER/PgR negative cancers; and the difference between the two groups was not significant (p = 0.31). The pooled HR for OS in heavier versus lighter women was 1.23 (95 % CI 1.07-1.42) for premenopausal women and 1.15 (95 % CI 1.06-1.26) for post-menopausal women, and the difference between the two groups was not significant (p = 0.57). Comparable pooled HRs for BCSS were 1.36 (95 % CI 1.20-1.54) for ER/PgR positive cancers and 1.46 (95 % CI 0.98-2.19) for ER/PgR negative cancers; and 1.18 (95 % CI 0.82-1.70) for pre-menopausal women and 1.38 (95 % CI 1.11-1.71) for post-menopausal women, also without significant group differences. Results were similar after adjustment for BMI measurement technique, years of follow-up, or study design. These findings led us to conclude that there is no evidence showing that the association of obesity with breast cancer outcome differs by hormone receptor or menopausal status. This has implications for studies of weight loss interventions in the adjuvant BC setting.

Feasibility of a randomized controlled trial of vitamin D vs. placebo in women with recently diagnosed breast cancer.

Low serum vitamin D levels have been associated with poor outcomes in women diagnosed with early breast cancer. However, no randomized controlled trials (RCTs) have been performed to determine whether vitamin D supplementation might be an effective intervention in this population. We prospectively evaluated vitamin D adequacy and supplementation rates in a contemporary cross-sectional sample of breast cancer patients from 2 large urban centers and examined the feasibility of an RCT of vitamin D supplementation. Women with recently diagnosed early breast cancer were prospectively identified and recruited in Toronto and Los Angeles between March 2009 and January 2010. Anthropometric measurements, dietary, lifestyle, and medication histories were obtained by means of structured questionnaires and interviews. Tumor and treatment characteristics were abstracted from clinical records and blood samples were collected for analysis of 25-OH vitamin D. 173 eligible patients (median age 57) were enrolled. Clinical and treatment characteristics were similar between centres. 84.4 % of women reported use of vitamin D-containing supplements with median daily doses of 1,400 IU. Median 25-OH vitamin D levels were 85.5 and 98.5 nmol/L (P = 0.1), and levels of deficiency (<50 nmol/L), insufficiency (50-72 nmol/L), and adequacy (>72 nmol/L) were 3.8, 23.8, 72.5 % (Toronto) and 4.3, 20.7, 75 % (Los Angeles). 25-OH vitamin D levels were strongly correlated with vitamin D supplement use (r = 0.41, P < 0.0001). 68 % of women expressed willingness to participate in a vitamin D supplementation RCT; however, only 12.7 % of the study population met the pre-specified feasibility criteria (25-OH vitamin D <72 nmol/L, willing to participate, and taking ≤1,000 IU vitamin D supplement/day). Both vitamin D levels and supplementation rates are higher than in previous reports. While the majority of women would be willing to participate in an RCT of vitamin D supplementation, low levels of deficiency/insufficiency and high rates of supplement use would limit the feasibility of such a study.

25-Hydroxy vitamin-D, obesity, and associated variables as predictors of breast cancer risk and tamoxifen benefit in NSABP-P1.

Observational studies suggest that host factors are associated with breast cancer risk. The influence of obesity, vitamin-D status, insulin resistance, inflammation, and elevated adipocytokines in women at high risk of breast cancer is unknown. The NSABP-P1 trial population was used for a nested case-control study. Cases were drawn from those who developed invasive breast cancer and controls selected from unaffected participants (≤4 per case) matched for age, race, 5 year Gail score, and geographic location of clinical center as a surrogate for latitude. Fasting serum banked at trial enrolment was assayed for 25-hydroxy vitamin-D (25OHD), insulin, leptin (adipocytokine), and C-reactive protein (CRP, marker of inflammation). Logistic regression was used to test for associations between study variables and the risk of invasive breast cancer. Two hundred and thirty-one cases were matched with 856 controls. Mean age was 54, and 49% were premenopausal. There were negative correlations for 25OHD with body mass index (BMI), insulin, CRP, and leptin. BMI ≥ 25 kg/m(2) was associated with higher breast cancer risk (odds ratio [OR] 1.45, p = 0.02) and tamoxifen treatment was associated with lower risk (OR = 0.44, p < 0.001). Suboptimal 25OHD (<72 nmol/l) did not influence breast cancer risk (OR = 1.06, p = 0.76). When evaluated as continuous variables, 25OHD, insulin, CRP, and leptin levels were not associated with breast cancer risk (all p > 0.34). In this high risk population, higher BMI was associated with a greater breast cancer risk. Serum levels of 25OHD, insulin, CRP, and leptin were not independent predictors of either breast cancer risk or tamoxifen benefit.