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 this is a preferred test for diagnosis of diabetes. A1C levels above 7% are associated with increased cardiovascular risk. In a study of 3,003 early breast cancer survivors, Erickson et al.5 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
Similar to hyperglycemia, higher fasting serum insulin or C-peptide (a marker of insulin production) levels are also associated with poor prognosis in breast cancer patients. A 1ng/mL increase in serum C-peptide level (>2.5ng/mL vs. <1.7ng/mL; normal levels=0.5–2.0ng/mL) was associated with 35% increase in death due to breast cancer, and 31% increase in overall risk of death. This risk was skewed towards patients with type 2 diabetes, estrogen receptor positive cancers and higher-stage disease.11 These observations suggest that lowering glycemia and C-peptide levels may significantly improve prognosis, and managing diabetes in breast cancer patients must be part of oncology care.
Metformin, a widely used antidiabetic medication, was shown to improve the breast cancer treatment response rate in type 2 diabetic patients. A study of 2,529 early breast cancer patients receiving neoadjuvant chemotherapy showed that diabetic patients on a metformin regimen achieved a 24% pathological complete response (pCR) while the rate of pCR was 8% in the nonmetformin group and 16% in nondiabetic cancer patients.12 Interestingly, other classes of antidiabetic drugs do not appear to confer survival advantage, and in fact, may increase the risk of cancer and worsen cancer prognosis.13 Metformin’s antiproliferative effect on breast cancer cells in vitro can be explained by the following mechanisms: It directly inhibits mTOR cell proliferative pathway indirectly acts by decreasing insulin levels and activating adenosine monophosphate-activated protein kinase cell signaling; and also targets breast cancer stem cells.14,15