The role of metformin and statins in ovarian and breast cancer in women with type 2 diabetes

Abstract Patients with type 2 diabetes (T2D) are at a greater risk of some cancer types, possible together with worse prognosis. Various types of antidiabetic medication have been reported to have different relationships to cancer prognosis. Metformin seems to reduce mortality in some forms of cancer and it has effects on cell cycle arrest and apoptosis in vitro. T2D is a risk factor of coronary heart disease, which is widely treated with statins. Statins are associated with both reduced incidence and better prognosis in some cancers. Epidemiological studies on the associations between metformin and statin use and breast and ovarian cancer have reported inconclusive results. The aim of the present epidemiological study was to find out whether metformin and statin use are associated with reduced incidence and mortality in ovarian and/or breast cancer. The source population for the study was drawn from the Finnish nationwide diabetes database (FinDM; n = 244,322), supplemented with other Finnish registry data. The data from FinDM was combined with data from the Finnish Cancer Registry. The use of metformin and/or statins was found not to be associated with the incidence of either ovarian (n=303) or breast cancer (n=2,300) in women with type 2 diabetes. The use of insulin seemed to be associated with a higher incidence of breast cancer. Metformin use was not observed to be associated with mortality from ovarian or breast cancer but mortality from other causes seemed to be lower in breast cancer patients among metformin users compared with the users of other types of oral antidiabetic medication. Prediagnostic statin use seemed to be associated with decreased mortality from breast cancer and other causes in breast cancer patients, but in ovarian cancer, an association with reduced mortality was seen only in connection with ovarian cancer itself. On the basis of our study results, it would not be reasonable to initiate metformin or statin treatment solely in order to avoid ovarian or breast cancer development in a woman with T2D. However, the results suggest that tailoring of glycaemic and hypercholesterolaemia treatment might have far-reaching consequences to both cancer development and survival.Tiivistelmä Tyypin 2 diabetesta sairastavilla potilailla on yleensä suurentunut riski sairastua maksa-, haima- ja suolistosyöpiin, ja tämä heikentää ainakin näiden syöpien ennustetta. Diabeteslääkkeillä on todettu olevan toisistaan poikkeava vaikutus syöpäennusteeseen. Metformiini vaikuttaa alentavan kuolleisuutta, ja solutöissä sillä on todettu olevan vaikutuksia solusyklin pysähtymiseen ja ohjelmoituun solukuolemaan. Tyypin 2 diabetes on riskitekijä sydän- ja verisuonisairauksiin, ja sen vuoksi diabetespotilaiden hoitoon kuuluu usein kolesterolia alentavat statiinit. Statiinien käyttö on yhdistetty joidenkin syöpäsairauksien vähenemiseen ja niiden parempaan ennusteeseen. Epidemiologiset tutkimukset metformiinin ja statiinien käytön välisestä yhteydestä munasarja- ja rintasyöpiin ovat kuitenkin epäyhtenäisiä. Tutkimuksen tarkoituksena oli selvittää, onko metformiinin ja statiinien käytöllä yhteyttä munasarja- ja rintasyöpätapausten vähenemiseen ja niiden paranemisennusteeseen. Lähdeaineistona on käytetty erilaisia suomalaisia rekistereitä yhdistävää kansallista diabetes-tietokantaa (FinDM; n = 244 322), jonka tiedot on yhdistetty Suomen Syöpärekisteriin. Metformiinin ja statiinien käytöllä ei todettu olevan yhteyttä munasarjasyövän (n = 303) tai rintasyövän (n = 2 300) ilmaantuvuuteen tyypin 2 diabetesta sairastavilla naisilla. Insuliinin käytöllä oli sen sijaan yhteys korkeampaan rintasyövän ilmaantuvuuteen. Metformiinin käytöllä ei todettu olevan yhteyttä munasarja- tai rintasyöpäkuolleisuuteen. Rintasyöpää sairastavilla naisilla muista syistä johtuva kuolleisuus oli metformiinin käyttäjillä kuitenkin matalampaa verrattaessa muihin suun kautta otettavien diabeteslääkkeiden käyttäjiin. Ennen syöpädiagnoosia aloitettu statiinien käyttö vaikutti vähentävän kuolleisuutta sekä rintasyöpään että muihin syihin rintasyöpäpotilailla. Munasarjasyövän suhteen yhteys todettiin ainoastaan munasarjasyöpäkuolleisuudessa. Tutkimuksemme mukaan ei ole perusteltua aloittaa metformiinia tai statiineja tyypin 2 diabetesta sairastavalle naiselle pelkästään ehkäisemään munasarja- tai rintasyöpää. Kuitenkin tutkimuksemme osoittaa, että niin diabetes- kuin kolesterolilääkitykselläkin voi olla yhteyttä sekä syövän kehittymiseen että paranemisennusteeseen

Metformin diminishes the unfavourable impact of Nrf2 in breast cancer patients with type 2 diabetes

Abstract Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a major regulator of the oxidative stress response and it is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1). The Keap1–Nrf2 axis has a fundamental role in carcinogenesis. In previous studies, the widely used diabetes drug metformin has appeared to have a critical role in the regulation of Nrf2 function. In this study, we assessed the expression of Nrf2 and Keap1 immunohistochemically in 157 patients with type 2 diabetes who underwent breast cancer surgery with curative intent. In total, 78 (49.7%) of these patients were taking metformin alone or combined with other oral anti-diabetic medication at the time of breast cancer diagnosis. We found that high-level cytoplasmic Nrf2 expression predicted dismal overall survival and breast cancer–specific survival, but only in the patients who were not taking metformin at the time of diagnosis. Similarly, low-level nuclear Keap1 expression had an adverse prognostic value in terms of overall survival and breast cancer–specific survival in patients without metformin. On the other hand, high-level nuclear Keap1 expression was associated with prolonged overall survival and breast cancer–specific survival. The results may be explained in terms of non-functioning or displaced Keap1, although more mechanistic pre-clinical and prospective clinical studies are warranted

Immunological markers of Chlamydia trachomatis infection in epithelial ovarian cancer

Abstract Background/Aim: Pelvic inflammatory disease (PID) is a risk factor for epithelial ovarian cancer (EOC). Chlamydia trachomatis infection, a major cause of PID, may persist in some women. Serum IgG antibodies to chlamydial TroA and HtrA are more common in ascending or repeat chlamydial infection than in uncomplicated infection. The aim of this study was to explore the role of C. trachomatis infection in EOC by analyzing chlamydial TroA, HtrA and major outer membrane protein (MOMP) IgG serum antibody responses. Patients and Methods: The study is based on the review of Oulu University Hospital medical records of 162 women diagnosed with EOC between March 2008 and May 2018. Serum IgG antibody responses to recombinant C. trachomatis TroA, HtrA and MOMP were analyzed using enzyme-linked immunoassay. Complete response to the first line therapy and the three-year survival were the study endpoints. Results: Altogether, 16.7%, 11.1% and 12.3% women were C. trachomatis TroA, HtrA and MOMP IgG positive, respectively. Women with these antibodies were more likely to have a complete response to the first-line treatment, compared to women without these antibodies (63.0% vs. 34.1% for TroA IgG, 50.0% vs. 37.5% for HtrA IgG and 50% vs. 37.3% for MOMP IgG, respectively). The presence of these antibodies predicted better three-year survival. Conclusion: Women with EOC and positive markers of persistent C. trachomatis infection have better response to the first-line treatment and seem to have better three-year survival

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

Abstract 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 metformin, other antidiabetic medications, and statins with incidence of colon cancer in patients with type 2 diabetes

Abstract Background: Metformin and statins may have anticancer effects, with plausible cellular mechanisms. However, the association of these agents with the risk of colorectal cancer is unclear. Patients and Methods: This was a retrospective cohort study on a large population (N = 316,317) of patients with type 2 diabetes. Data were obtained from the Diabetes in Finland database (FinDM). In a full cohort analysis, hazard ratios (HRs) with their 95% confidence intervals (CIs) for ever use versus never use were estimated using a multiple Poisson regression model. A nested case–control design within the cohort was used to examine the association of colon cancer (CC) with the defined daily dose of medication. The data were analyzed by conditional logistic regression. The analyses were adjusted for the patient’s age, sex, and duration of diabetes. Results: In total, 1351 CC cases were diagnosed during 1996–2011. The results revealed insufficient evidence for an association between metformin (HR, 1.01; 95% CI, 0.90–1.14), other oral antidiabetic medications (HR, 1.05; 95% CI, 0.93–1.19), insulin (HR, 1.02; 95% CI, 0.86–1.22), or statins (HR, 0.94; 95% CI, 0.84–1.05) and the incidence of CC in the full cohort analysis. The results from the case–control study were similar, with no consistent trend in the incidence of CC according to the cumulative dose of metformin or the other studied medications. Conclusion: This study found insufficient evidence for an association between metformin, insulin, other oral type 2 diabetes medications, or statins and the incidence of CC

Association of antidiabetic medication and statins with breast cancer incidence in women with type 2 diabetes

Abstract Purpose: To address the possible association between the use of metformin, other forms of antidiabetic medication (ADM) and statins with the incidence of breast cancer in women with type 2 diabetes (T2D). Methods: Data were collected from a Finnish nationwide diabetes database (FinDM). The study cohort consisted of women diagnosed with T2D in 1996–2011 in Finland. In full-cohort analysis, Poisson regression was used to estimate hazard ratios (HRs) in relation to use of metformin, insulin, other forms of oral ADM and statins. In nested case–control analysis, up to 20 controls were matched for age and duration of diabetes to each case of breast cancer. Conditional logistic regression was used to estimate HRs in relation to medication use and cumulative use of different forms of ADM, and statins. Results: 2300 women were diagnosed with breast cancer during follow-up. No difference in breast cancer incidence was observed between metformin users [HR 1.02, 95% confidence interval (CI) 0.93–1.11] or statin users (HR 0.97, 95% CI 0.89–1.05) compared with non-users. In nested case–control analysis the results were similar. Use of insulin (HR 1.18, 95% CI 1.03–1.36) was associated with a slightly increased incidence of breast cancer. Conclusions: No evidence of an association between the use of metformin or statins and the incidence of breast cancer in women with T2D was found. Among insulin users, a slightly higher incidence of breast cancer was observed

Survival after breast cancer in women with type 2 diabetes using antidiabetic medication and statins:a retrospective cohort study

Abstract Background/Objectives: We assessed survival of breast cancer in women with type 2 diabetes (T2D) treated with metformin, other types of antidiabetic medication (ADM) and statins. Materials and methods: The study cohort consisted of women with T2D and diagnosed with breast cancer in Finland in 1998─2011. Mortality rates from breast cancer and other causes were analysed by Cox models, and adjusted hazard ratios (HRs) with 95% confidence intervals (Cls) were estimated in relation to the use of different types of medication. Results: The final cohort consisted of 3,533 women. No clear evidence was found for breast cancer mortality being different in metformin users (HR 0.86, 95% Cl 0.63–1.17), but their other-cause mortality appeared to be lower (HR 0.73, 95% Cl 0.55–0.97) in comparison with women using other types of oral ADM. Other-cause mortality was higher among insulin users (HR 1.45, 95% Cl 1.16–1.80) compared with users of other oral ADMs, other than metformin. Prediagnostic statin use was observed to be associated with decreased mortality from both breast cancer (HR 0.76, 95% Cl 0.63–0.92) and other causes (HR 0.75, 95% Cl 0.64–0.87). Conclusions: We did not find any association between ADM use and disease-specific mortality among women with T2D diagnosed with breast cancer. However, interestingly, prediagnostic statin use was observed to predict reduced mortality from breast cancer and other causes. We hypothesise that treating treatment practices of T2D or hypercholesterolaemia of breast cancer patients might affect overall prognosis of women diagnosed with breast cancer and T2D

The role of metformin and statins in the incidence of epithelial ovarian cancer in type 2 diabetes:a cohort and nested case–control study

Abstract Objective: To obtain evidence of the effects of metformin and statins on the incidence of ovarian cancer in women with type 2 diabetes (T2D). Design: A retrospective cohort study and nested case–control study. Setting: The data were obtained from a diabetes database (FinDM) combining information from several nationwide registers. Population: A cohort of 137 643 women over 40 years old and diagnosed with T2D during 1996–2011 in Finland. Methods: In full cohort analysis Poisson regression was used to estimate the hazard ratios (HR) in relation to ever use of metformin, insulin other oral anti‐diabetic medication or statins. In the nested case–control analysis 20 controls were matched to each case of ovarian cancer. Conditional logistic regression was used to estimate HRs in relation to medication use and cumulative use of different medications. The estimates were adjusted for age and duration of T2D. Main outcome measure: Incidence of ovarian cancer. Results: In all, 303 women were diagnosed with ovarian cancer during the follow up. Compared with other forms of oral anti‐diabetic medication, metformin (HR 1.02, 95% CI: 0.72–1.45) was not found to be associated with the incidence of ovarian cancer. Neither was there evidence for statins to affect the incidence (HR 0.99, 95% CI: 0.78–1.25). In nested case–control analysis the results were essentially similar. Conclusions: No evidence of an association between the use of metformin or statins and the incidence of ovarian cancer in women with T2D was found. Tweetable abstract: No evidence found for metformin or statins reducing the incidence of ovarian cancer

Antidiabetic medication, statins and the risk and prognosis of non-endometrioid endometrial cancer in women with type 2 diabetes

Abstract Aim: To determine the incidence and prognosis of non-endometrioid endometrial cancer (EC) in relation to the use of metformin, other antidiabetic medication (ADM) and statins in patients with type 2 diabetes (T2D). Materials and Methods: In order to analyze the incidence and prognosis of non-endometrioid EC, two cohorts were obtained from a nationwide diabetes database (FinDM); 57 non-endometrioid ECs were observed in a cohort of 92,366 women with newly-diagnosed T2D during the follow-up (1996 to 2011) to assess the incidence, and a retrospective cohort of 105 women with T2D diagnosed with non-endometrioid EC (1998 to 2011) was used to estimate cumulative mortality from EC and other causes of death. Hazard ratios (HRs) with 95% confidence intervals (CIs) for EC incidence were estimated in the full-cohort analysis and in the nested case–control analysis, matched for age and duration of T2D. Cumulative mortality was estimated by using the Aalen–Johansen estimator. Cause-specific mortality rates were analyzed by using Cox models regarding the pre-diagnostic use of different forms of ADM and statins. Results: In the nested case–control analysis, the use of metformin was not associated with the risk of non-endometrioid EC (HR=1.09, 95% CI=0.59–2.00), whereas statin use was associated with a lower risk (HR=0.47, 95% CI=0.26–0.84). The results from the full-cohort analysis supported these findings. Mortality from non-endometrioid EC was not different between users of metformin and other types of oral ADM (HR=1.56, 95% CI=0.40–6.07) but was observed to be lower in statin users (HR=0.41, 95% CI=0.20–0.82). Conclusions: Our findings were inconclusive regarding the association of metformin with the risk and prognosis of non-endometrioid EC. However, statin use was associated with a lower incidence and mortality from this disease