· The earliest link between diabetes and cancer was alluded to in the 1930s. However, convincing epidemiological evidence has emerged only recently proving an association between diabetes and cancer.
· Multiple studies suggest a correlative relationship between diabetes and poor prognosis or increased risk of breast cancer; however, a cause-and-effect relationship is not clear.
· 16% to 20% of women with breast cancer have diabetes
· Several factors may contribute to the increased risk of death in diabetic breast cancer patients. These include: delayed cancer diagnosis, suboptimal cancer treatments, direct tumor promoting effects of hyperinsulinemia, and adverse effects of diabetes-related comorbidities or certain antidiabetic medications.
· Metformin, a widely used antidiabetic medication, was shown to improve the breast cancer treatment response rate in type 2 diabetic patients.
Both diabetes and cancer have long preoccupied public health concerns, strained national budgets, and are associated with complications that may affect quality of life. They also share some of the same risk factors, such as age, smoking, weight gain, and a diet poor in fruits and vegetables. The earliest link between diabetes and cancer was alluded to in the 1930s.1,2 However, convincing epidemiological evidence has emerged only recently proving an association between diabetes and cancer.3
The segment of the population affected by diabetes or breast cancer is large. Type 2 diabetes, which includes 90% of all diabetes diagnoses, effect 7% of the adult population, and 15% of people over 60 years of age.4 Breast cancer will affect 1 in 9 women in their lifetime,4 and 16% to 20% of women with breast cancer have diabetes.5 The percent of breast cancer patients with previously undiagnosed or delayed diagnosed diabetes may be as large as 30%.5
A recent meta-analysis of published studies evaluating the effect of preexisting diabetes on breast cancer outcomes found a 49% increase in the risk of death (all cause mortality) in diabetic women with breast cancer compared to nondiabetic counterparts (pooled hazard ratio [HR], 1.49; 95% CI=1.35, 1.65).6 The analysis also found a positive association between preexisting diabetes and late or advanced stage breast cancer disease in women; an increased risk of late stage disease in women with diabetes (diabetes vs nondiabetes, OR 1.17; 95% CI=1.08, 1.27) and more often with stage III or stage IV than their nondiabetic counterparts (19% vs 12% stage III or IV).6
Several factors may contribute to the increased risk of death in diabetic breast cancer patients. These include delayed cancer diagnosis, suboptimal cancer treatments, direct tumor promoting effects of hyperinsulinemia, and adverse effects of diabetes-related comorbidities or certain antidiabetic medications.7 Visceral obesity, a shared risk factor for diabetes and breast cancer, may hamper timely breast cancer diagnosis as early signs of breast cancer may be missed. Metabolic alterations with aberrant signaling pathways associated with diabetes may contribute to the aggressiveness of breast cancer as well. 8
Type 2 diabetes is characterized by insulin resistance—poor glucose utilization by peripheral tissues such as skeletal muscle—and compensatory increase in circulating insulin levels (hyperinsulinemia) and hyperglycemia. Hyperinsulinemia increases insulin-like growth factor (IGF) which is correlated with an increased risk of breast cancer. Hyperinsulinemia also decreases the plasma levels of insulin-like growth factor-binding protein 1 (IGF-BP1) and thus increases the levels of bioactive IGF-1.3
Three biological pathways have been proposed to explain the pathophysiological basis of increased breast cancer risk in diabetic patients: activation of the insulin pathway, activation of the IGF signaling transduction pathways, and dysregulated sex hormone signaling pathways.4 Insulin and IGF-1 (or IGF-2) bind to their respective receptors and activate common signaling mediators, such as RAS-RAF-MEK-ERK MAP kinase pathway, and PI3K-AKT kinase pathway. MAP kinase and AKT kinase pathways are key signal transduction pathways promoting cell proliferation and preventing apoptosis. (Figure 1) Breast cancer cells express high levels of insulin receptor (IR), insulin-like growth factor receptor (IGFR), and IGFR/IR hybrid receptor. Breast cancer patients with diabetes also have high plasma levels of estrogens and androgens, low sex hormone binding globulin levels,4 and high levels of inflammatory mediators which promote tumor growth and metastasis. 9 Patients with preexisting diabetes may also preclude aggressive or even optimal cancer treatment due to increased incidence of treatment-related complications.5 In addition, these patients have higher risk of hospitalizations due to chemotherapy-associated toxicities, such as neutropenia, anemia, or any cause (OR, 1.38; 95% CI=1.23, 1.56).6
It is estimated that 30% of the patients with chronic hyperglycemia and symptomless diabetes remain undiagnosed at the time of breast cancer diagnosis. These breast cancer patients may end up with poor prognosis which otherwise could have been prevented. Hemoglobin A1C (A1C) levels provide precise estimation of blood glycemic levels, and is a preferred test for diagnosis of diabetes. A1C levels above 7% are associated with increased cardiovascular risk. In a study of 3003 early breast cancer survivors, Erickson et al5 found that less than half of the 3% of patients with A1C ≥7.0% reported that they had diabetes on the self-report questionnaire, and only 10% of the 3% with A1C levels between 6.5% and 6.9% reported that they had diabetes.
Undiagnosed or underreported diabetes has serious implications for breast cancer prognosis. The risk of death in early breast cancer patients increases significantly with hyperglycemia: patients with A1C levels of 6.5% to 6.9% and ≥7.0% were 60% (HR, 1.6; 95% CI=1.00-2.57) and three times (HR, 3.01; 95% CI=2.05-4.43), more likely to die within the follow-up period compared to those with A1C levels of less than 6.5%.5 These authors, however, also raised important caveats—it was not clear if there is a threshold A1C level for elevated risk of poor prognosis, and if increased risk of death was due to cancer recurrence or cardiovascular and other diabetic complications.5