Metformin Associates With Aggressive Features of Endometrial Cancer in Women With Type 2 Diabetes

Background/Aim: Preclinical studies on metformin use and endometrial cancer have been promising but epidemiological studies have reported variable results. This study aimed to assess if metformin use is associated with endometrial cancer aggressiveness and survival in women with type 2 diabetes (T2D). Patients and Methods: This retrospective hospital-based cohort consisted of women with T2D who were treated for endometrial cancer at the Oulu University Hospital, Finland, between 2007 and 2014. Results: The sample size was 121 patients: 58 metformin users and 63 metformin non-users. Intriguingly,type 2 histology, deep myometrial invasion and the presence of lymphovascular invasion were more common in the metformin user group. However, metformin use showed no association with overall survival and progression-free survival. Conclusion: Metformin use was associated with poorer prognostic factors in endometrial cancer patients with T2D.Peer reviewe

No Association Between Statin Use and the Prognosis of Endometrial Cancer in Women With Type 2 Diabetes

Preclinical studies have suggested statins have antiproliferative and anti-metastatic effects on endometrial cancer cells. Similarly, most previous epidemiological studies have reported a better prognosis of endometrial cancer in patients who used statins. In this study, we explored the role of statins in the prognosis of endometrial cancer in women with type 2 diabetes in a hospital-based cohort. This retrospective cohort consisted of 119 women with type 2 diabetes who were diagnosed and treated for endometrial cancer at Oulu University Hospital, Finland, between 2007 and 2014. The patients were classified as statin users (n = 58) and nonusers (n = 61) based on the type of medication they were using at the time of endometrial cancer diagnosis. Statin use showed no association with progression-free survival or overall survival in the whole cohort nor the subgroups with type I or type II histology, in lower or higher body mass index groups, or at an early or advanced stage. The results remained similar in the multivariate analysis after adjusting for the patient's age, cancer stage, and histology. Furthermore, statin use seemed not to have any association with most of the prognostic factors at the time of endometrial cancer diagnosis.Peer reviewe

Oxidative Stress-regulating Enzymes and Endometrial Cancer Survival in Relation to Metformin Intake in Diabetic Patients

Background/Aim: Metformin inhibits tumorigenesis in endometrial carcinoma and interferes with the expression of oxidative stress-regulating proteins, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1). Although manganese superoxide dismutase (MnSOD) is vital for withstanding mitochondrial oxidative stress, it has also been linked with chemoresistance and poorer outcomes in several cancer types. However, data on endometrial cancers are limited. This study aimed to highlight the relationship between mitochondrial redox regulation and endometrial cancer survival in relation to metformin consumption in women with type 2 diabetes mellitus (T2DM). Patients and Methods: Our retrospective hospital-based cohort study included 121 patients diagnosed with endometrial carcinoma and T2DM between 2007 and 2014. Fifty-eight patients were using metformin at the time of diagnosis. Nrf2 and Keap1 expression levels in the tumor samples were assessed immunohistochemically, and MnSOD levels were measured both immunohistochemically and from the serum samples. Results: High MnSOD tissue expression was associated with better overall survival among metformin users in the univariate analysis (p=0.03). When adjusted for histology and stage, high serum MnSOD was associated with better overall survival (HR=0.22, 95%CI=0.07-0.71, p=0.01). No association was found between MnSOD, Nrf2, or Keap1 and overall survival among metformin non-users. Conclusion: Higher expression of MnSOD in patients with endometrial cancer and T2DM is associated with better overall survival if the patient is consuming metformin.Peer reviewe

The Association of Metformin, Other Antidiabetic Medications, and Statins With the Prognosis of Colon Cancer in Patients With Type 2 Diabetes : A Retrospective Cohort Study

BackgroundUse of metformin and statins have been associated with improved prognosis of colon cancer (CC) in patients with type 2 diabetes (T2D). We examined the survival from CC in relation to the use of metformin, other oral antidiabetic medications (ADM), insulin, and statins in T2D patients.Materials and MethodsA cohort (n = 2252) of persons with pre-existing T2D diagnosed with incident CC between 1998 and 2011 was identified from several Finnish registers. Cox models were fitted for cause-specific mortality rates to obtain adjusted estimates of the hazard ratios (HR) with 95% confidence intervals (CI) in relation to use of ADM and statins before the CC diagnosis. Cox models were also fitted for mortality in relation to post-diagnostic use of the medications treating these as time-dependent exposures, and starting follow-up 1 year after the CC diagnosisResultsPre- and post-diagnostic metformin use was weakly associated with the risk of CC-related death (HR .75; 95% CI .58-.99, and HR .78; 95% CI .54-1.14, respectively) compared to the use of other oral ADMs. Pre- and post-diagnostic statin use predicted a reduced risk of CC-related death (HR .83; 95% CI .71- .98, and HR .69; 95% CI .54-.89, respectively).ConclusionAdditional evidence was found for use of statins being associated with an improved survival from CC in patients with pre-existing T2D, but for metformin use the evidence was weaker.Peer reviewe

The Association of Metformin, Other Antidiabetic Medications and Statins on the Prognosis of Rectal Cancer in Patients with Type 2 Diabetes: A Retrospective Cohort Study

Metformin and statin use have been associated with an improved prognosis for colorectal cancer in persons with type 2 diabetes (T2D). Data regarding rectal cancer (RC) have been inconclusive; therefore, we investigated the issue with high-quality data and a robust study design. We identified 1271 eligible patients with T2D and incident RC between 1998 and 2011 from the Diabetes in Finland (FinDM) database. Cox models were fitted for cause-specific mortality rates to obtain adjusted estimates of the hazard ratios (HR) with 95% confidence intervals (CI) in relation to use of antidiabetic medication (ADM) and statins before the RC diagnosis and for post-diagnostic use in a time-dependent exposure manner. No sufficient evidence was found for either pre- or post-diagnostic metformin use and RC mortality (HR 0.96, 95% CI 0.67–1.38, and 0.70, 95% CI 0.45–1.10, respectively) when compared to other oral ADMs. Both pre- and post-diagnostic statin use appeared to be inversely associated with mortality from RC (HR 0.77 95% CI 0.63–0.94, and 0.57, 95% CI 0.42–0.78, respectively). Our study was inconclusive as to the association of metformin use with the prognosis of RC, but statin use was found to predict reduced mortality, both from RC and from other causes of death in persons with T2D

Association of antidiabetic medication and statins with survival from ductal and lobular breast carcinoma in women with type 2 diabetes

We investigated the survival of female patients with pre-existing type 2 diabetes (T2D) diagnosed with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of breast, in relation to the use of metformin, other antidiabetic medication (ADM) and statins. The study cohort consisted of 3,165 women (2,604 with IDC and 561 with ILC). The cumulative mortality from breast cancer (BC) and from other causes was calculated using the Aalen-Johansen estimator. The cause-specific mortality rates were analysed by Cox models, and adjusted hazard ratios (HRs) were estimated for the use of different medications. No evidence of an association of metformin use with BC mortality was observed in either IDC (HR 0.92, 95% confidence interval [CI] 0.64-1.31) or ILC (HR 0.68, 95% CI 0.32-1.46) patients, when compared to other oral ADMs. The mortality from other causes was found to be lower amongst the IDC patients using metformin (HR 0.64, 95% CI 0.45-0.89), but amongst ILC patients the evidence was inconclusive (HR 1.22, 95% CI 0.64-2.32). Statin use was consistently associated with reduced mortality from BC in IDC patients (HR 0.77, 95% CI 0.62-0.96) and ILC patients (HR 0.59, 95% CI 0.37-0.96), and also mortality from other causes in IDC patients (HR 0.81, 95% CI 0.67-0.96) and in ILC patients (HR 0.66, 95% CI 0.43-1.01). We found no sufficient evidence for the possible effects of metformin and statins on the prognosis of BC being different in the two histological subtypes.Peer reviewe

Prognosis of ovarian cancer in women with type 2 diabetes using metformin and other forms of antidiabetic medication or statins : a retrospective cohort study

Abstract Background Ovarian cancer is one of the most lethal cancers and women with type 2 diabetes (T2D) have even poorer survival from it. We assessed the prognosis of ovarian cancer in women with type 2 diabetes treated with metformin, other forms of antidiabetic medication, or statins. Methods Study cohort consisted of women with T2D diagnosed with ovarian cancer in Finland 1998–2011. They were identified from a nationwide diabetes database (FinDM), being linked to several national registers. Patients were grouped according to their medication in the three years preceding ovarian cancer diagnosis. The Aalen–Johansen estimator was used to describe cumulative mortality from ovarian cancer and from other causes in different medication groups. Mortality rates were analysed by Cox models, and adjusted hazard ratios (HR) with 95% confidence intervals (95% CIs) were estimated in relation to the use of different forms of medication. Main outcome measures were death from ovarian cancer and death from other causes. Results During the accrual period 421 newly diagnosed ovarian cancers were identified in the FinDM database. No evidence was found for any differences in mortality from ovarian cancer or other causes between different antidiabetic medication groups. Pre-diagnostic use of statins was observed to be associated with decreased mortality from ovarian cancer compared with no such use (HR 0.72, 95% CI 0.56–0.93). Conclusions Our findings are inconclusive as regards the association between metformin and ovarian cancer survival. However, some evidence was found for improved prognosis of ovarian cancer with pre-diagnostic statin use, requiring cautious interpretation, though

The Association of Metformin, Other Antidiabetic Medications and Statins on the Prognosis of Rectal Cancer in Patients with Type 2 Diabetes : A Retrospective Cohort Study

Metformin and statin use have been associated with an improved prognosis for colorectal cancer in persons with type 2 diabetes (T2D). Data regarding rectal cancer (RC) have been inconclusive; therefore, we investigated the issue with high-quality data and a robust study design. We identified 1271 eligible patients with T2D and incident RC between 1998 and 2011 from the Diabetes in Finland (FinDM) database. Cox models were fitted for cause-specific mortality rates to obtain adjusted estimates of the hazard ratios (HR) with 95% confidence intervals (CI) in relation to use of antidiabetic medication (ADM) and statins before the RC diagnosis and for post-diagnostic use in a time-dependent exposure manner. No sufficient evidence was found for either pre- or post-diagnostic metformin use and RC mortality (HR 0.96, 95% CI 0.67–1.38, and 0.70, 95% CI 0.45–1.10, respectively) when compared to other oral ADMs. Both pre- and post-diagnostic statin use appeared to be inversely associated with mortality from RC (HR 0.77 95% CI 0.63–0.94, and 0.57, 95% CI 0.42–0.78, respectively). Our study was inconclusive as to the association of metformin use with the prognosis of RC, but statin use was found to predict reduced mortality, both from RC and from other causes of death in persons with T2D.publishedVersionPeer reviewe

Low Expression of Stanniocalcin 1 (STC-1) Protein Is Associated With Poor Clinicopathologic Features of Endometrial Cancer

Stanniocalcin-1 (STC-1) is a glycoprotein hormone involved in diverse biological processes, including regulation of calcium phosphate homeostasis, cell proliferation, apoptosis, inflammation, oxidative stress responses, and cancer development. The role of STC-1 in endometrial cancer (EC) is yet to be elucidated. In this study, we investigated the protein expression pattern of STC-1 in a tissue microarray (TMA) cohort of hysterectomy specimens from 832 patients with EC. We then evaluated the prognostic value of STC-1 expression regarding the clinicopathologic features and patients survival over a period of 140 months. Our results revealed that in EC tissue samples, STC-1 is mainly localized in the endometrial epithelium, although some expression was also observed in the stroma. Decreased STC-1 expression was associated with factors relating to a worse prognosis, such as grade 3 endometrioid tumors (p = 0.030), deep myometrial invasion (p = 0.003), lymphovascular space invasion (p = 0.050), and large tumor size (p = 0.001). Moreover, STC-1 expression was decreased in tumors obtained from obese women (p = 0.014) and in women with diabetes mellitus type 2 (DMT2; p = 0.001). Interestingly, the data also showed an association between DNA mismatch repair (MMR) deficiency and weak STC-1 expression, specifically in the endometrial epithelium (p = 0.048). No association was observed between STC-1 expression and disease-specific survival. As STC-1 expression was particularly low in cases with obesity and DMT2 in the TMA cohort, we also evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n = 111). The analysis showed no difference in STC-1 expression in either the epithelium or the stroma in women undergoing metformin therapy compared to metformin non-users. Overall, our data may suggest a favorable role for STC-1 in EC behavior; however, further studies are required to elucidate the detailed mechanism and possible applications to cancer treatment.</p