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 1 ng/mL increase in serum C-peptide level (>2.5 ng/mL vs <1.7 ng/mL; normal levels=0.5-2.0 ng/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 2529 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
In summary, 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. Nevertheless, available data and clinical experiences provide strong rationale for bringing internists and oncologists into the same room and including diabetes management as part of the breast cancer treatment program.
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