Clinically Defined Type 2 Diabetes Mellitus and Prognosis in Early-Stage Breast Cancer

Erickson, Kirsten; Patterson, Ruth E.; Flatt, Shirley W.; Natarajan, Loki; Parker, Barbara A.; Heath, Dennis D.; Laughlin, Gail A.; Saquib, Nazmus; Rock, Cheryl L.; Pierce, John P.

doi:10.1200/jco.2010.29.3183

Cited by 156 publications

(151 citation statements)

References 34 publications

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“…In the setting of established cancer, higher levels of insulin or C-peptide have been independently associated with poor outcomes (increased risk of recurrence and death) in breast and prostate cancers (Goodwin et al 2002, Pasanisi et al 2006, Ma et al 2008, Emaus et al 2010, Erickson et al 2011, Pritchard et al 2011. Our group has demonstrated a more than doubled risk of distant recurrence and tripled risk of death in women with locoregional breast cancer whose insulin levels were in the highest quartile, even though those levels were within the normal range (Goodwin et al 2002).…”

Section: Metabolicmentioning

confidence: 67%

Metformin in cancer: translational challenges

Dowling

Niraula²,

Stambolic³

et al. 2012

Journal of Molecular Endocrinology

323

232

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The anti-diabetic drug metformin is rapidly emerging as a potential anti-cancer agent. Metformin, effective in treating type 2 diabetes and the insulin resistance syndromes, improves insulin resistance by reducing hepatic gluconeogenesis and by enhancing glucose uptake by skeletal muscle. Epidemiological studies have consistently associated metformin use with decreased cancer incidence and cancer-related mortality. Furthermore, numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to an explosion of interest in evaluating this agent in human cancer. The effects of metformin on circulating insulin levels indicate a potential efficacy towards cancers associated with hyperinsulinaemia; however, metformin may also directly inhibit tumour growth. In this review, we describe the mechanism of action of metformin and summarise the epidemiological, clinical and preclinical evidence supporting a role for metformin in the treatment of cancer. In addition, the challenges associated with translating preclinical results into therapeutic benefit in the clinical setting will be discussed.

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Section: Metabolicmentioning

confidence: 67%

Metformin in cancer: translational challenges

Dowling

Niraula²,

Stambolic³

et al. 2012

Journal of Molecular Endocrinology

323

232

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“…Furthermore, diabetes seems to worsen cancer-specific and overall survival in several cancers (10)(11)(12)(13). Among patients with diabetes, metformin has been associated with a decreased overall risk for developing certain cancers (14,15).…”

Section: At a Glance Commentarymentioning

confidence: 99%

Survival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin

Lin

Gallagher

Sigel

et al. 2015

Am J Respir Crit Care Med

121

106

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Rationale: Prior studies have shown an anticancer effect of metformin in patients with breast and colorectal cancer. It is unclear, however, whether metformin has a mortality benefit in lung cancer.Objectives: To compare overall survival of patients with diabetes with stage IV non-small cell lung cancer (NSCLC) taking metformin versus those not on metformin.Methods: Using data from the Surveillance, Epidemiology, and End Results registry linked to Medicare claims, we identified 750 patients with diabetes 65-80 years of age diagnosed with stage IV NSCLC between 2007 and 2009. We used propensity score methods to assess the association of metformin use with overall survival while controlling for potential confounders.Measurements and Main Results: Overall, 61% of patients were on metformin at the time of lung cancer diagnosis. Median survival in the metformin group was 5 months, compared with 3 months in patients not treated with metformin (P , 0.001). Propensity score analyses showed that metformin use was associated with a statistically significant improvement in survival (hazard ratio, 0.80; 95% confidence interval, 0.71-0.89), after controlling for sociodemographics, diabetes severity, other diabetes medications, cancer characteristics, and treatment.Conclusions: Metformin is associated with improved survival among patients with diabetes with stage IV NSCLC, suggesting a potential anticancer effect. Further research should evaluate plausible biologic mechanisms and test the effect of metformin in prospective clinical trials.

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“…34 The metabolic syndrome comprises a number of clinical disorders, such as obesity, insulin resistance, and dyslipidemia, and is associated with worse outcomes for patients with breast cancer. [61][62][63][64][65] Breast WAT inflammation may constitute a local mechanism contributing to the association between the metabolic syndrome systemically and adverse breast cancer outcomes. Elevated levels of insulin and www.jco.org glucose are found in individuals with WAT inflammation.…”

Section: Extended Impact Of the Inflamed Microenvironmentmentioning

confidence: 99%

Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation

Iyengar

Gucalp

Dannenberg

et al. 2016

JCO

703

522

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There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. MethodsWe review recent findings regarding obesity-associated alterations in the microenvironment and the local and systemic mechanisms through which these changes support tumor growth. ResultsLocally, hyperadiposity is associated with altered adipose tissue function, adipocyte death, and chronic low-grade inflammation. Most individuals who are obese harbor inflamed adipose tissue, which resembles chronically injured tissue, with immune cell infiltration and remodeling. Within this distinctly altered local environment, several pathophysiologic changes are found that may promote breast and other cancers. Consistently, adipose tissue inflammation is associated with a worse prognosis in patients with breast and tongue cancers. Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth. Importantly, adipose inflammation and its protumor consequences can be found in some individuals who are not considered to be obese or overweight by body mass index. ConclusionThe tumor-promoting effects of obesity occur at the local level via adipose inflammation and associated alterations in the microenvironment, as well as systemically via circulating metabolic and inflammatory mediators associated with adipose inflammation. Accurately characterizing the obese state and identifying patients at increased risk for cancer development and progression will likely require more precise assessments than body mass index alone. Biomarkers of adipose tissue inflammation would help to identify high-risk populations. Moreover, adipose inflammation is a reversible process and represents a novel therapeutic target that warrants further study to break the obesity-cancer link.

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Clinically Defined Type 2 Diabetes Mellitus and Prognosis in Early-Stage Breast Cancer

Cited by 156 publications

References 34 publications

Metformin in cancer: translational challenges

Metformin in cancer: translational challenges

Survival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin

Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation

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