Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study.

Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant "window of opportunity" study of metformin in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood [fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin] attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13-40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (-0.5 kg/m(2), p < 0.0001), weight (-1.2 kg, p < 0.0001), and HOMA (-0.21, p = 0.047) decreased significantly while non-significant decreases were seen in insulin (-4.7 pmol/L, p = 0.07), leptin (-1.3 ng/mL, p = 0.15) and CRP (-0.2 mg/L, p = 0.35). Ki67 staining in invasive tumor tissue decreased (from 36.5 to 33.5 %, p = 0.016) and TUNEL staining increased (from 0.56 to 1.05, p = 0.004). Short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed.

High insulin levels in newly diagnosed breast cancer patients reflect underlying insulin resistance and are associated with components of the insulin resistance syndrome.

BACKGROUND: High insulin levels have been associated with poor outcomes in breast cancer. Our goal was to investigate whether hyperinsulinemia was associated with insulin resistance in a cohort of newly diagnosed locoregional breast cancer patients and to examine associations of hyperinsulinemia with the broader insulin resistance syndrome (IRS). METHODS: Five hundred and four women with T1-3, N0-1, M0 breast cancer provided fasting blood that was analyzed for glucose, insulin and lipids. They underwent anthropomorphic measurements and provided information on diet, exercise and sleep. Relationships of insulin with three validated indices of insulin resistance and with attributes of the IRS were examined. RESULTS: High insulin levels were strongly correlated with insulin resistance calculated using the three indices of insulin resistance/sensitivity (Spearman r=0.83-0.98). Hyperinsulinemia was also associated with other components of the IRS (obesity, high waist-hip ratio, lipid profile). CONCLUSIONS: High insulin levels in women with locoregional breast cancer reflect the presence of insulin resistance and are associated with other components of the IRS. These observations have implications for the development of therapies that target hyperinsulinemia in early stage breast cancer and for the long-term management of breast cancer survivors.

Is leptin a mediator of adverse prognostic effects of obesity in breast cancer?

PURPOSE: Leptin, an adipocyte-derived cytokine that is elevated in obesity, has been associated with carcinogenesis, tumor migration and invasion, enhancement of angiogenesis, and increased aromatase activity. It has been suggested that leptin may mediate adverse prognostic effects of obesity in breast cancer. PATIENTS AND METHODS: Four hundred seventy-one women with surgically resected T1-3, N0-1, M0 breast cancer were studied. Leptin was assayed in stored fasting blood specimens obtained before adjuvant therapy. Women were followed prospectively for distant disease-free survival (DDFS) and overall survival (OS). RESULTS: Patients ranged from 26 to 74 years of age, and staging was as follows: T1 = 262, T2 = 151, T3 = 23, TX = 35, N0 = 323, and N1 = 148. Estrogen receptor was positive in 286 patients, and progesterone receptor was positive in 259 patients. One hundred forty-five patients received adjuvant chemotherapy, 146 received adjuvant tamoxifen, 46 received both, and 134 received neither. Mean leptin was 15.2 +/- 10.1 ng/mL. Univariately, leptin was associated with OS (overall P = .049; P = .014 postmenopausal). Leptin was not associated with DDFS overall or in any menopausal subgroup (P > or = .19). In multivariate Cox modeling, leptin was not significantly associated with DDFS or OS (P = .11 and 0.075, respectively). Adjustment for insulin or body mass index further reduced the association of leptin with outcome. CONCLUSION: Although leptin is strongly correlated with obesity and insulin, we could not show that it is independently associated with prognosis in early-stage breast cancer. Because we cannot rule out modest prognostic effects, we recommend additional research to explore this potential association, particularly in postmenopausal women.

Diet and breast cancer: evidence that extremes in diet are associated with poor survival.

PURPOSE: Diet has been postulated to influence breast cancer prognosis; however, existing evidence is weak and inconsistent. Previous studies have sought evidence of a linear relationship between diet and breast cancer outcomes. Because of a U-shaped association of body mass index (BMI) with survival in breast cancer, we hypothesized that a nonlinear association also existed for dietary variables. PATIENTS AND METHODS: Four hundred seventy-seven women with surgically resected T1 to T3, N0/1, M0 breast cancer completed the Block Food Frequency Questionnaire 9.3 +/- 4.6 weeks (mean +/- standard deviation) after diagnosis, reporting intake over the preceding 12 months. Data on tumor-related factors, treatment, and outcomes were obtained prospectively from medical records. A series of Cox models was performed, modeling the association of dietary factors with breast cancer survival linearly and quadratically, adjusting for total energy intake, tumor- and treatment-related variables, and BMI. RESULTS: Significant nonlinear survival associations were found for protein, oleic acid, cholesterol, polyunsaturated-saturated fat ratio, and for percentage of calories from fat and percentage of calories from carbohydrates in multivariate models. The shape of the survival associations varied across nutrients. Hazard ratios for highest risk quintiles ranged from 2.1 to 6.5. For total fat, adjustment for BMI reduced the multivariate P value obtained from nonlinear Cox models from.05 to.10. No significant linear associations were identified. CONCLUSION: The association of key dietary variables with breast cancer survival may be U-shaped rather than linear. Our data suggest that midrange intake of most major energy sources is associated with the most favorable outcomes, and extremes are associated with less favorable outcomes.

Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study.

PURPOSE: Insulin, a member of a family of growth factors that includes insulin-like growth factor (IGF)-I and IGF-II, exerts mitogenic effects on normal and malignant breast epithelial cells, acting via insulin and IGF-I receptors. Because of this and because of its recognized association with obesity, an adverse prognostic factor in breast cancer, we examined the prognostic associations of insulin in early-stage breast cancer. PATIENTS AND METHODS: A cohort of 512 women without known diabetes, who had early-stage (T1 to T3, N0 to N1, and M0) breast cancer, was assembled and observed prospectively. Information on traditional prognostic factors and body size was collected, and fasting blood was obtained. RESULTS: Fasting insulin was associated with distant recurrence and death; the hazard ratios and 95% confidence intervals (CI) for those in the highest (> 51.9 pmol/L) versus the lowest (< 27.0 pmol/L) insulin quartile were 2.0 (95% CI, 1.2 to 3.3) and 3.1 (95% CI, 1.7 to 5.7), respectively. There was some evidence to suggest that the association of insulin with breast cancer outcomes may be nonlinear. Insulin was correlated with body mass index (Spearman r = 0.59, P <.001), which, in turn, was associated with distant recurrence and death (P <.001). In multivariate analyses that included fasting insulin and available tumor- and treatment-related variables, adjusted hazard ratios for the upper versus lower insulin quartile were 2.1 (95% CI, 1.2 to 3.6) and 3.3 (95% CI, 1.5 to 7.0) for distant recurrence and death, respectively. CONCLUSION: Fasting insulin level is associated with outcome in women with early breast cancer. High levels of fasting insulin identify women with poor outcomes in whom more effective treatment strategies should be explored.

Health-related quality of life and psychosocial status in breast cancer prognosis: analysis of multiple variables.

PURPOSE: Evidence that psychosocial status and health-related quality of life (HRQOL) are associated with breast cancer (BC) outcomes is weak and inconsistent. We examined prognostic effects of these factors in a prospective cohort study. PATIENTS AND METHODS: Three hundred ninety-seven women with surgically resected T1 to T3, N0/N1, M0 BC completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (Core 30 items), Profile of Mood States, Psychosocial Adjustment to Illness Scale, Impact of Events Scale, Mental Adjustment to Cancer Scale, and the Courtauld Emotional Control Scale 2 months after diagnosis and 1 year later. Data on tumor-related factors, treatment, and outcomes were obtained prospectively from medical records, and Cox survival analyses were performed. RESULTS: Mean age was 52.0 +/- 9.9 years. Two hundred twenty-five women had T1, 136 women had T2, 16 women had T3, and 20 women had TX tumors; 127 were N1. One hundred thirteen women received adjuvant chemotherapy, 130 received hormone therapy, 45 received both, and 109 received neither. We investigated 140 prognostic associations; four were found to be statistically significant at a P value of

Quality of life in long-term breast cancer survivors.

PURPOSE: There is considerable interest in the quality of life (QOL) of long-term breast cancer (BC) survivors. We studied changes in QOL from time of BC diagnosis to long-term survivorship and compared QOL in long-term survivors to that of age-matched women with no history of BC. PATIENTS AND METHODS: In all, 535 women with localized BC (T1-3N0-1M0) were recruited from 1989 to 1996 and followed prospectively, completing QOL questionnaires at diagnosis and 1 year postdiagnosis. Between 2005 and 2007, those alive without distant recurrence were recontacted to participate in a long-term follow-up (LTFU) study. A control group was recruited from women presenting for screening mammograms, and both groups completed LTFU QOL questionnaires. Longitudinal change in BC survivors and differences between BC survivors and controls were assessed in eight broad categories with clinically significant differences set at 5% and 10% of the breadth of each QOL scale. RESULTS: A total of 285 patients with BC were included in the study, on average 12.5 years postdiagnosis. Longitudinally, clinically significant improvements were observed in overall QOL by 1 year postdiagnosis with further improvements by LTFU. Some clinically significant improvements over time were seen in all categories. A total of 167 controls were recruited. Deficits were observed in self-reported cognitive functioning (5.3% difference) and financial impact (6.3% difference) in BC survivors at LTFU compared with controls. CONCLUSION: Long-term BC survivors show improvement in many domains of QOL over time, and they appear to have similar QOL in most respects to age-matched noncancer controls, although small deficits in cognition and finances were identified.

Insulin- and obesity-related variables in early-stage breast cancer: correlations and time course of prognostic associations.

PURPOSE: To investigate patterns of prognostic associations over time of insulin- and obesity-related variables measured at diagnosis of early breast cancer (BC), focusing on whether the prognostic associations with distant recurrence and death changed over time. PATIENTS AND METHODS: Five hundred thirty-five nondiabetic women with T1-3, N0-1, M0 invasive BC diagnosed from 1989 to 1996 were included in the study. Insulin-related variables included fasting insulin, Homeostasis Model Assessment, C-peptide, and glucose. Obesity-related variables included weight, body mass index (BMI), waist and hip circumference, and leptin. Correlations were examined using the Pearson correlation coefficient and prognostic associations using the Cox model. RESULTS: There was evidence that associations of baseline insulin-related variables with distant recurrence and death were not constant over time; univariable adverse prognostic associations were significant only during the first 5 years (eg, insulin quartile 4 v 1: hazard ratio [HR], 2.32; 95% CI, 1.39 to 3.86; P < .001 for distant disease-free survival [DDFS]; and HR, 2.85; 95% CI, 1.48 to 5.50; P = .002 for overall survival [OS], with little attenuation of this pattern in multivariable analyses). In contrast, obesity-related variables (BMI, weight, leptin) exerted significant adverse univariable associations that were constant over time (eg, BMI quartile 4 v 2: HR, 1.40; 95% CI, 1.07 to 1.82 for DDFS; P = .014; and HR, 1.50; 95% CI, 1.16 to 1.93; P < .001 for OS); prognostic associations of leptin remained significant in multivariable analyses. CONCLUSION: Baseline insulin- and obesity-related variables exert different patterns of prognostic associations over time in early BC.

Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer.

PURPOSE: Vitamin D has been linked to breast cancer risk, but prognostic effects are unknown. Such effects are biologically plausible given the presence of vitamin D receptors in breast cancer cells, which act as nuclear transcription factors to regulate gene activity. PATIENTS AND METHODS: The study was conducted in a prospective inception cohort of 512 women with early breast cancer diagnosed 1989 to 1996. Vitamin D levels were measured in stored blood. Clinical, pathologic, and dietary data were accessed to examine prognostic effects of vitamin D. RESULTS: Mean age was 50.4 years, mean vitamin D was 58.1 +/- 23.4 nmol/L. Vitamin D levels were deficient (< 50 nmol/L) in 37.5% of patients, insufficient (50 to 72 nmol/L) in 38.5% of patients, and sufficient (> 72 nmol/L) in 24.0% of patients. There was little variation in mean vitamin D levels between summer and winter months. Mean follow-up was 11.6 years; 116 women had distant recurrences, and 106 women died. Women with deficient vitamin D levels had an increased risk of distant recurrence (hazard ratio [HR] = 1.94; 95% CI, 1.16 to 3.25) and death (HR = 1.73; 95% CI, 1.05 to 2.86) compared with those with sufficient levels. The association remained after individual adjustment for key tumor and treatment related factors but was attenuated in multivariate analyses (HR = 1.71; 95% CI, 1.02 to 2.86 for distant recurrence; HR = 1.60; 95% CI, 0.96 to 2.64 for death). CONCLUSION: Vitamin D deficiency may be associated with poor outcomes in breast cancer.

Influence of young age at diagnosis and family history of breast or ovarian cancer on breast cancer outcomes in a population-based cohort study.

PURPOSE: The objective of this study was to examine the association of: (i) diagnosis at age

Insulin-like growth factor binding proteins 1 and 3 and breast cancer outcomes.

The IGF family of growth factors is believed to play a role in the development and progression of breast cancer. We recently identified an adverse prognostic effect of insulin in breast cancer; we now report prognostic effects of circulating IGFBP's 1 and 3. 512 women with T1-3, N0-1, M0 breast cancer provided fasting blood which was analysed for IGFBP's I and 3. Information on body size, diet and traditional prognostic factors and treatment was obtained; women were followed for recurrence and death. IGFBP-1 levels correlated inversely with insulin levels (Spearman r = -0.60, p < 0.0001), reflecting known inhibition of IGFBP-1 gene expression by insulin. Insulin explained 36% of the variance in IGFBP-1 levels. IGFBP-1 levels were also correlated with obesity and diet. Levels of IGFBP-1 significantly predicted distant recurrence and death, hazard ratio (95% CI) for lower versus upper quartile 2.08 (1.20-3.61) and 3.0 (1.45-6.21), respectively. These effects persisted after adjustment for tumor-related variables and treatment but were not independent of insulin levels. High levels of IGFBP-3 predicted distant recurrence (hazard ratio upper v.s. lower quartile 1.8, 95% CI 1.1-3.0) but not death (hazard ratio 1.0, 95% CI 0.5-1.9). The effect on distant recurrence was restricted to postmenopausal women (hazard ratio 3.8, 95% CI 1.6-9.0) and to those with estrogen receptor positive tumors (p = 0.002). Prognostic effects of IGFBP-1 appear related to the known effect of insulin on IGFBP-1 gene expression. The adverse effect of IGFBP-3 on distant recurrence in postmenopausal women with estrogen receptor positive breast cancer should be further investigated.