The levonorgestrel-releasing intrauterine system (LNG-IUS) is a conservative management option for atypical hyperplasia (AH) and low grade early stage endometrial cancer (EEC), but around 1 in 3 patients fail to respond to treatment. The aim of this study was to investigate if serum and/or tissue HE4 expression could predict response to LNG-IUS therapy. Patients with AH or presumed Stage I EEC had serum and endometrial samples taken at baseline and at 3-month intervals over 12 months post-insertion of LNG-IUS. 74 patients were recruited and baseline demographics recorded. Of 57 patients for whom response was histologically determinable, 39 (68%) were responders and 18 (32%) non-responders. Mean baseline serum HE4 was significantly lower in responders (62.1 ± 1.1 pM, 95% confidence interval (CI) 52.7–73.2), compared to non-responders (125.6 ± 1.3 pM, 95% CI 74.5–211.7, p = 0.014), including when considering age, BMI, menopausal status, smoking status, and histological grade as covariables (p = 0.005). Baseline tissue HE4 expression was not significantly different in responders compared to non-responders (p = 0.999). Responders showed a significant mean reduction (−9.8 ± 3.4%, 95% CI −16.7 to −2.8%, p = 0.008) in serum HE4 between baseline and 3 months (p = 0.008), whereas non-responders showed no significant change (p = 0.676). Neither responders nor non-responders showed a significant percentage change in serum HE4 from baseline beyond 3 months (p > 0.05). Change in serum HE4 between baseline and 3 and 6 months and tissue HE4 tissue expression between baseline and 3, 6, and 12 months was not significantly different in responders compared to non-responders (p > 0.05). This study suggests that baseline serum HE4, but not baseline tissue HE4 expression, is independently predictive of response to the LNG-IUS and could be used to guide management decisions.

Purpose Endometrioid endometrial cancer is strongly associated with obesity and insulin resistance. Metformin,an insulin sensitizer, reduces endometrial tumor growth in vitro. Presurgical window studies allow rapid in vivo assessment of antitumor activity. Previous window studies found metformin reduced endometrial cancer proliferation but these lacked methodological rigor. PREMIUM measured the anti-proliferative effect of metformin in vivo using a robust window study design. Patients and Methods A multicenter, double-blind, placebo-controlled trial randomized women with atypical hyperplasia or endometrioid endometrial cancer to receive metformin (850 mg daily for 3 days, and twice daily thereafter) or placebo for 1 to 5 weeks until surgery. The primary outcome was posttreatment IHC expression of Ki-67. Secondary outcomes investigated the effect of metformin on markers of the PI3K–Akt–mTOR and insulin signaling pathways and obesity. Results Eighty-eight women received metformin (n = 45) or placebo (n = 43) and completed treatment. There was no overall difference in posttreatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference −0.57%; 95% CI, −7.57%–6.42%; P = 0.87). Metformin did not affect expression of markers of the PI3K–Akt–mTOR or insulin signaling pathways, and did not result in weight loss. Conclusions Short-term treatment with standard diabetic doses of metformin does not reduce tumor proliferation in women with endometrioid endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings.

<p>Immunohistochemistry staining protocols</p>