UNC Durham Division of Gynecologic Oncology, Durham, NC
Dario R. Roque , A. Mitch Dizon , Brooke S. Rambally , Siobhan O'Connor , Paola A. Gehrig , Sheri Denslow , Victoria Lin Bae-Jump
Background: Metformin, has been found to decrease proliferation and inhibit downstream targets of the mTOR pathway in a phase 0 trial in endometrial cancer (EC) patients. Given this, we aimed to determine molecular differences between ECs from patients with Type II diabetes (T2DM) taking metformin versus those not on metformin. Methods: Patients with T2DM who underwent surgical staging for EC were divided into two cohorts based on whether or not they were on metformin. The use of insulin and other anti-diabetic agents was recorded. Tissue microarrays (triplicate cores) were constructed from formalin-fixed, paraffin-embedded hysterectomy specimens. Expression of the estrogen receptor (ER), progesterone receptor (PR), PTEN, LKB1, phosphorylated (p)-AKT, p-4EBP-1, p-S6, p-insulin growth factor-1 receptor (pIGF1R), p-insulin receptor substrate-1 (P-IRS1), PMAT, MATE1 and MATE2 was measured by immunohistochemistry. Results: Of 162 EC patients with T2DM, 102 (63%) were taking metformin and 60 (37%) were not on metformin. There was no significant difference in tumor stage, grade or histology between the two groups. Expression of transporters, hormone receptors, and mTOR pathway targets was similar between the two groups. However, when adjusting for age, BMI, race, tumor grade and stage, there was a trend towards decreased p-AKT expression in metformin users (0.7, 95% CI 0.4-1.1). In addition, BMI > 30 was associated with increased expression of p-S6 (2.8, 95% CI 1.2-6.7) and a trend towards higher p-4EBP-1 expression (2.0, 95% CI 1.0-4.1). Conclusions: We did not find a strong relationship between metformin use and transporters, hormone receptors or mTOR pathway targets in EC patients with T2DM. However, metformin use trended towards decreased p-AKT expression, which is consistent with its ability to inhibit the mTOR pathway. Obesity is known to activate the mTOR pathway, and was associated with increased expression of p-S6 and p-4EBP-1 in ECs. Further studies should focus on identifying molecular biomarkers in patients with T2DM that may predict response to metformin as an anti-tumorigenic agent.
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