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1.  Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study 
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.
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.
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.
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 identifier: NCT00897884. Registered 8 May 2009.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0540-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4381495  PMID: 25849721
2.  Association Between Metformin Therapy and Mortality After Breast Cancer 
Diabetes Care  2013;36(10):3018-3026.
Metformin has been associated with a reduction in breast cancer risk and may improve survival after cancer through direct and indirect tumor-suppressing mechanisms. The purpose of this study was to evaluate the effect of metformin therapy on survival in women with breast cancer using methods that accounted for the duration of treatment with glucose-lowering therapies.
This population-based study, using Ontario health care databases, recruited women aged 66 years or older diagnosed with diabetes and breast cancer between 1 April 1997 and 31 March 2008. Using Cox regression analyses, we explored the association between cumulative duration of past metformin use and all-cause and breast cancer–specific mortality. We modeled cumulative duration of past metformin use as a time-varying exposure.
Of 2,361 breast cancer patients identified, mean (± SD) age at cancer diagnosis was 77.4 ± 6.3 years, and mean follow-up was 4.5 ± 3.0 years. There were 1,101 deaths(46.6%), among which 386 (16.3%) were breast cancer–specific deaths. No significant association was found between cumulative duration of past metformin use and all-cause mortality (adjusted hazard ratio 0.97 [95% CI 0.92–1.02]) or breast cancer–specific mortality (0.91 [0.81–1.03]) per additional year of cumulative use.
Our findings failed to show an association between improved survival and increased cumulative metformin duration in older breast cancer patients who had recent-onset diabetes. Further research is needed to clarify this association, accounting for effects of cancer stage and BMI in younger populations or those with differing stages of diabetes as well as in nondiabetic populations.
PMCID: PMC3781496  PMID: 23633525
3.  The Role of Obesity in Cancer Survival and Recurrence 
Obesity and components of energy imbalance, i.e., excessive energy intake and suboptimal levels of physical activity, are established risk factors for cancer incidence. Accumulating evidence suggests that these factors also may be important after the diagnosis of cancer and influence the course of disease, as well as overall health, well-being, and survival. Lifestyle and medical interventions that effectively modify these factors could potentially be harnessed as a means of cancer control. However, for such interventions to be maximally effective and sustainable, broad sweeping scientific discoveries ranging from molecular and cellular advances, to developments in delivering interventions on both individual and societal levels are needed. This review summarizes key discussion topics that were addressed in a recent Institute of Medicine Workshop entitled, “The Role of Obesity in Cancer Survival and Recurrence”; discussions included: 1) mechanisms associated with obesity and energy balance that influence cancer progression; 2) complexities of studying and interpreting energy balance in relation to cancer recurrence and survival; 3) associations between obesity and cancer risk, recurrence, and mortality; 4) interventions that promote weight loss, increased physical activity, and negative energy balance as a means of cancer control; and 5) future directions.
PMCID: PMC3415558  PMID: 22695735
neoplasms; obesity; diet; physical activity; survival; recurrence
4.  25-Hydroxy vitamin-D, obesity, and associated variables as predictors of breast cancer risk and tamoxifen benefit in NSABP-P1 
Breast Cancer Research and Treatment  2012;133(3):1077-1088.
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/m2 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.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-012-2012-x) contains supplementary material, which is available to authorized users.
PMCID: PMC3396331  PMID: 22415479
Breast cancer; Vitamin-D; Obesity; Cancer prevention; Tamoxifen
5.  Past recreational physical activity, body size, and all-cause mortality following breast cancer diagnosis: results from the Breast Cancer Family Registry 
Few studies have considered the joint association of body mass index (BMI) and physical activity, two modifiable factors, with all-cause mortality after breast cancer diagnosis. Women diagnosed with invasive breast cancer (n=4,153) between 1991 and 2000 were enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. During a median follow-up of 7.8 years, 725 deaths occurred. Baseline questionnaires assessed moderate and vigorous recreational physical activity and BMI prior to diagnosis. Associations with all-cause mortality were assessed using Cox proportional hazards regression, adjusting for established prognostic factors. Compared with no physical activity, any recreational activity during the three years prior to diagnosis was associated with a 34% lower risk of death (hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.51-0.85) for women with estrogen receptor (ER)-positive tumors, but not those with ER-negative tumors; this association did not appear to differ by race/ethnicity or BMI. Lifetime physical activity was not associated with all-cause mortality. BMI was positively associated with all-cause mortality for women diagnosed at age ≥50 years with ER-positive tumors (compared with normal-weight women, HR for overweight = 1.39, 95% CI: 0.90-2.15; HR for obese = 1.77, 95% CI: 1.11-2.82). BMI associations did not appear to differ by race/ethnicity. Our findings suggest that physical activity and BMI exert independent effects on overall mortality after breast cancer.
PMCID: PMC2920352  PMID: 20140702
breast cancer; physical activity; body mass index; obesity; mortality
6.  Understanding the benefit of metformin use in cancer treatment 
BMC Medicine  2011;9:33.
Biguanides have been developed for the treatment of hyperglycemia and type 2 diabetes. Recently, metformin, the most widely prescribed biguanide, has emerged as a potential anticancer agent. Epidemiological, preclinical and clinical evidence supports the use of metformin as a cancer therapeutic. The ability of metformin to lower circulating insulin may be particularly important for the treatment of cancers known to be associated with hyperinsulinemia, such as those of the breast and colon. Moreover, metformin may exhibit direct inhibitory effects on cancer cells by inhibiting mammalian target of rapamycin (mTOR) signaling and protein synthesis. The evidence supporting a role for metformin in cancer therapy and its potential molecular mechanisms of action are discussed.
PMCID: PMC3224599  PMID: 21470407
7.  Family history of breast cancer and all-cause mortality after breast cancer diagnosis in the Breast Cancer Family Registry 
Although having a family history of breast cancer is a well established breast cancer risk factor, it is not known whether it influences mortality after breast cancer diagnosis.
Subjects were 4,153 women with first primary incident invasive breast cancer diagnosed between 1991 and 2000, and enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. Cases were oversampled for younger age at diagnosis and/or family history of breast cancer. Carriers of germline mutations in BRCA1 or BRCA2 were excluded. Cases and their relatives completed structured questionnaires assessing breast cancer risk factors and family history of cancer. Cases were followed for a median of 6.5 years, during which 725 deaths occurred. Cox proportional hazards regression was used to evaluate associations between family history of breast cancer at the time of diagnosis and risk of all-cause mortality after breast cancer diagnosis, adjusting for established prognostic factors.
The hazard ratios for all-cause mortality were 0.98 (95% confidence interval [CI]=0.84-1.15) for having at least one first- or second-degree relative with breast cancer, and 0.85 (95% CI=0.70-1.02) for having at least one first-degree relative with breast cancer, compared with having no such family history. Estimates did not vary appreciably when stratified by case or tumor characteristics.
Family history of breast cancer is not associated with all-cause mortality after breast cancer diagnosis for women without a known germline mutation in BRCA1 or BRCA2. Therefore, clinical management should not depend on family history of breast cancer.
PMCID: PMC2728159  PMID: 19034644
breast cancer; survival; mortality; family history
8.  Pre-diagnosis reproductive factors and all-cause mortality for women with breast cancer in the Breast Cancer Family Registry 
Studies have examined the prognostic relevance of reproductive factors prior to breast cancer (BC) diagnosis, but most have been small and overall their findings inconclusive. Associations between reproductive risk factors and all-cause mortality after BC diagnosis were assessed using a population-based cohort of 3,107 women of white European ancestry with invasive BC (1,130 from Melbourne and Sydney, Australia; 1,441 from Ontario, Canada; and 536 from Northern California, USA). During follow-up with a median of 8.5 years, 567 deaths occurred. At recruitment, questionnaire data were collected on oral contraceptive use, number of full-term pregnancies, age at first full-term pregnancy, time from last full-term pregnancy to BC diagnosis, breastfeeding, age at menarche and menopause and menopausal status at BC diagnosis. Hazard ratios (HR) for all-cause mortality were estimated using Cox proportional hazards models with and without adjustment for age at diagnosis, study center, education and body mass index. Compared with nulliparous women, those who had a child up to 2 years, or between 2 to 5 years, prior to their BC diagnosis were more likely to die. The unadjusted HR estimates were 2.75 (95%CI=1.98–3.83, p<0.001) and 2.20 (95%CI=1.65–2.94, p<0.001), respectively, and the adjusted estimates were 2.25 (95%CI=1.59–3.18, p<0.001) and 1.82 (95%CI=1.35–2.46, p<0.001), respectively). When evaluating the prognosis of women recently diagnosed with BC, the time since last full-term pregnancy should be routinely considered along with other established host and tumor prognostic factors, but consideration of other reproductive factors may not be warranted.
PMCID: PMC2746957  PMID: 19505912
Breast cancer; survival; reproductive; outcome; pregnancy
9.  Physical Activity, Weight Control, and Breast Cancer Risk and Survival: Clinical Trial Rationale and Design Considerations 
Substantial observational epidemiological evidence exists that physical activity and weight control are associated with decreased risk of postmenopausal breast cancer. Uncertainty remains regarding several aspects of these associations, including the effect of possible confounding factors on these associations. We present the rationale and design for two randomized controlled trials that can help resolve this uncertainty. In a 5-year prevention trial conducted among women at high risk of breast cancer, the primary endpoint would be breast cancer incidence. For a comparable survivorship trial, the primary endpoint would be the disease-free interval and secondary endpoints would be breast cancer recurrence–free interval, second primary breast cancer, and total invasive plus in situ breast cancer. A set of inclusion and exclusion criteria is proposed for both trials. Intervention goals are the same for both trials. Goals for the weight control intervention would be, for women whose body mass index (BMI) is greater than 25 kg/m2, to lose 10% of body weight and, for women whose BMI is less than or equal to 25 kg/m2, to avoid weight gain. The goal for the physical activity intervention would be to achieve and maintain regular participation in a moderate-intensity physical activity program for a total of 150–225 minutes over at least 5 days per week. Sample size calculations are based on alternative assumptions about hazard ratio, adherence, follow-up duration, and power and are presented for the primary prevention and survivorship trials. Although both studies could enhance our understanding of breast cancer etiology and benefit public health, practical considerations, including smaller sample size, ease of recruitment, and reduced likelihood of early termination, favor the survivorship trial at this time.
PMCID: PMC2677576  PMID: 19401543
10.  Polymorphisms cMyc-N11S and p27-V109G and breast cancer risk and prognosis 
BMC Cancer  2007;7:99.
cMyc and p27 are key genes implicated in carcinogenesis. Whether polymorphisms in these genes affect breast cancer risk or prognosis is still unclear. In this study, we focus on a rare non-synonymous polymorphism in cMyc (N11S) and a common polymorphism in p27 (V109G) and determine their role in risk and prognosis using data collected from the Ontario Breast Cancer Family Registry.
Risk factor data was collected at baseline on a large group of women (cases = 1,115 and population-based controls = 710) and clinical data (including treatment and follow-up) were collected prospectively by periodic review of medical records for a subset of cases (N = 967) for nearly a decade. A centralized pathology review was conducted. Unconditional logistic regression was used to determine the association of polymorphisms with breast cancer risk and the Cox proportional hazards model was used to determine their association with survival.
Our results suggest that while cMyc-N11S can be considered a putatively functional polymorphism located in the N-terminal domain, it is not associated with risk, tumor characteristics or survival. The p27-G109 allele was associated with a modest protective effect in adjusted analyses and higher T stage. We found no evidence to suggest that p27-V109G alone or in combination with cMyc-N11S was associated with survival. Age at onset and first-degree family history of breast or ovarian cancer did not significantly modify the association of these polymorphisms with breast cancer risk.
Further work is recommended to understand the potential functional role of these specific non-synonymous amino acid changes and a larger, more comprehensive investigation of genetic variation in these genes (e.g., using a tagSNP approach) in combination with other relevant genes is needed as well as consideration for treatment effects when assessing their potential role in prognosis.
PMCID: PMC1906827  PMID: 17567920
11.  Breast self-examination: Resistance to change 
Canadian Family Physician  2005;51(5):699.
To investigate whether Canadian family practitioners routinely teach breast self-examination (BSE) after publication of the 2001 Canadian Preventive Health Task Force guideline advising them to exclude teaching BSE from periodic health examinations.
Self-administered cross-sectional mailed survey.
A random sample of English-speaking general practitioners and physicians certified by the College of Family Physicians of Canada.
Current and past BSE practices and opinions on the value of BSE.
Response rate was 47.4%. Most respondents (88%) were aware of the new recommendations, yet only 16% had changed their usual practice of routinely teaching BSE. Most physicians agreed that before the recommendation they almost always taught BSE (74.3%). Only 9.5% agreed that physicians should follow the recommendation and not routinely teach BSE. A few also agreed that they now spend less time discussing BSE (25.7%) and that the recommendation has influenced them to stop teaching (12.4%) and encouraging (12.9%) women to practise BSE. Physicians who had changed their BSE practices were less likely to agree that BSE increases early detection of breast cancer and more likely to agree that BSE increases benign breast biopsies. They were also more likely to agree that screening mammography in women older than 50 decreases mortality from breast cancer.
This survey, which assessed routine teaching of BSE, revealed poor adherence by Canadian family physicians to a well publicized evidence-based guideline update. Resistance to change could in part be attributed to a lack of knowledge of the supporting evidence, a lack of confidence in the evidence to date, and personal experiences with patients within their practices.
PMCID: PMC1472923  PMID: 16926925

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