Skip to main content
Top
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

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

Authors: Elina Urpilainen, Mikko Marttila, Ari Hautakoski, Martti Arffman, Reijo Sund, Pirjo Ilanne-Parikka, Reetta Arima, Jenni Kangaskokko, Ulla Puistola, Marianne Hinkula, Esa Läärä

Published in: BMC Cancer | Issue 1/2018

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
go back to reference Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–291.CrossRefPubMed Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–291.CrossRefPubMed
2.
go back to reference Hunn J, Rodriguez GC. Ovarian cancer: etiology, risk factors, and epidemiology. Clin Obstet Gynecol. 2012;55(1):3–23.CrossRefPubMed Hunn J, Rodriguez GC. Ovarian cancer: etiology, risk factors, and epidemiology. Clin Obstet Gynecol. 2012;55(1):3–23.CrossRefPubMed
3.
4.
go back to reference Shah MM, Erickson BK, Matin T, McGwin G Jr, Martin JY, Daily LB, Pasko D, Haygood CW, Fauci JM, Leath CA 3rd. Diabetes mellitus and ovarian cancer: more complex than just increasing risk. Gynecol Oncol. 2014;135(2):273–7.CrossRefPubMedPubMedCentral Shah MM, Erickson BK, Matin T, McGwin G Jr, Martin JY, Daily LB, Pasko D, Haygood CW, Fauci JM, Leath CA 3rd. Diabetes mellitus and ovarian cancer: more complex than just increasing risk. Gynecol Oncol. 2014;135(2):273–7.CrossRefPubMedPubMedCentral
5.
go back to reference Inzucchi SE, Majumdar SK. Current therapies for the medical Management of Diabetes. Obstet Gynecol. 2016;127(4):780–94.CrossRefPubMed Inzucchi SE, Majumdar SK. Current therapies for the medical Management of Diabetes. Obstet Gynecol. 2016;127(4):780–94.CrossRefPubMed
6.
go back to reference Kumar S, Meuter A, Thapa P, Langstraat C, Giri S, Chien J, Rattan R, Cliby W, Shridhar V. Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer. 2013;119(3):555–62.CrossRefPubMed Kumar S, Meuter A, Thapa P, Langstraat C, Giri S, Chien J, Rattan R, Cliby W, Shridhar V. Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer. 2013;119(3):555–62.CrossRefPubMed
7.
go back to reference Bar D, Lavie O, Stein N, Feferkorn I, Shai A. The effect of metabolic comorbidities and commonly used drugs on the prognosis of patients with ovarian cancer. Eur J Obstet Gynecol Reprod Biol. 2016;207:227–31.CrossRefPubMed Bar D, Lavie O, Stein N, Feferkorn I, Shai A. The effect of metabolic comorbidities and commonly used drugs on the prognosis of patients with ovarian cancer. Eur J Obstet Gynecol Reprod Biol. 2016;207:227–31.CrossRefPubMed
8.
go back to reference Romero IL, McCormick A, McEwen KA, Park S, Karrison T, Yamada SD, Pannain S, Lengyel E. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol. 2012;119(1):61–7.CrossRefPubMedPubMedCentral Romero IL, McCormick A, McEwen KA, Park S, Karrison T, Yamada SD, Pannain S, Lengyel E. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol. 2012;119(1):61–7.CrossRefPubMedPubMedCentral
9.
go back to reference Gadducci A, Biglia N, Tana R, Cosio S, Gallo M. Metformin use and gynecological cancers: a novel treatment option emerging from drug repositioning. Crit Rev Oncol Hematol. 2016;105:73–83.CrossRefPubMed Gadducci A, Biglia N, Tana R, Cosio S, Gallo M. Metformin use and gynecological cancers: a novel treatment option emerging from drug repositioning. Crit Rev Oncol Hematol. 2016;105:73–83.CrossRefPubMed
10.
go back to reference Rattan R, Giri S, Hartmann LC, Shridhar V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med. 2011;15(1):166–78.CrossRefPubMed Rattan R, Giri S, Hartmann LC, Shridhar V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med. 2011;15(1):166–78.CrossRefPubMed
11.
go back to reference Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 2011;13(5):483–91.CrossRefPubMedPubMedCentral Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 2011;13(5):483–91.CrossRefPubMedPubMedCentral
12.
go back to reference Shank JJ, Yang K, Ghannam J, Cabrera L, Johnston CJ, Reynolds RK, Buckanovich RJ. Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol Oncol. 2012;127(2):390–7.CrossRefPubMedPubMedCentral Shank JJ, Yang K, Ghannam J, Cabrera L, Johnston CJ, Reynolds RK, Buckanovich RJ. Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol Oncol. 2012;127(2):390–7.CrossRefPubMedPubMedCentral
13.
go back to reference Vehko T, Sund R, Arffman M, Manderbacka K, Ilanne-Parikka P, Keskimäki I. Monitoring the use of lipid-lowering medication among persons with newly diagnosed diabetes: a nationwide register-based study. BMJ Open. 2013;3(11):e003414.CrossRefPubMedPubMedCentral Vehko T, Sund R, Arffman M, Manderbacka K, Ilanne-Parikka P, Keskimäki I. Monitoring the use of lipid-lowering medication among persons with newly diagnosed diabetes: a nationwide register-based study. BMJ Open. 2013;3(11):e003414.CrossRefPubMedPubMedCentral
14.
go back to reference Solomon KR, Freeman MR. Do the cholesterol-lowering properties of statins affect cancer risk? Trends Endocrinol Metab. 2008;19(4):113–21.CrossRefPubMed Solomon KR, Freeman MR. Do the cholesterol-lowering properties of statins affect cancer risk? Trends Endocrinol Metab. 2008;19(4):113–21.CrossRefPubMed
15.
go back to reference Chan KK, Oza AM, Siu LL. The statins as anticancer agents. Clin Cancer Res. 2003;9(1):10–9.PubMed Chan KK, Oza AM, Siu LL. The statins as anticancer agents. Clin Cancer Res. 2003;9(1):10–9.PubMed
16.
go back to reference Lavie O, Pinchev M, Rennert HS, Segev Y, Rennert G. The effect of statins on risk and survival of gynecological malignancies. Gynecol Oncol. 2013;130(3):615–9.CrossRefPubMed Lavie O, Pinchev M, Rennert HS, Segev Y, Rennert G. The effect of statins on risk and survival of gynecological malignancies. Gynecol Oncol. 2013;130(3):615–9.CrossRefPubMed
17.
go back to reference Elmore RG, Ioffe Y, Scoles DR, Karlan BY, Li AJ. Impact of statin therapy on survival in epithelial ovarian cancer. Gynecol Oncol. 2008;111(1):102–5.CrossRefPubMed Elmore RG, Ioffe Y, Scoles DR, Karlan BY, Li AJ. Impact of statin therapy on survival in epithelial ovarian cancer. Gynecol Oncol. 2008;111(1):102–5.CrossRefPubMed
18.
go back to reference Vogel TJ, Goodman MT, Jeon CY. Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer. Gynecol Oncol. 2017;146(2):340–5.CrossRefPubMed Vogel TJ, Goodman MT, Jeon CY. Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer. Gynecol Oncol. 2017;146(2):340–5.CrossRefPubMed
19.
go back to reference Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012;367(19):1792–802.CrossRefPubMed Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012;367(19):1792–802.CrossRefPubMed
20.
go back to reference Habis M, Wroblewski K, Bradaric M, Ismail N, Yamada SD, Litchfield L, Lengyel E, Romero IL. Statin therapy is associated with improved survival in patients with non-serous-papillary epithelial ovarian cancer: a retrospective cohort analysis. PLoS One. 2014;9(8):e104521.CrossRefPubMedPubMedCentral Habis M, Wroblewski K, Bradaric M, Ismail N, Yamada SD, Litchfield L, Lengyel E, Romero IL. Statin therapy is associated with improved survival in patients with non-serous-papillary epithelial ovarian cancer: a retrospective cohort analysis. PLoS One. 2014;9(8):e104521.CrossRefPubMedPubMedCentral
21.
go back to reference von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–9.CrossRefPubMed von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–9.CrossRefPubMed
22.
go back to reference Sund R, Koski S. FinDM II: On the register-based measurement of the prevalence and incidence of diabetes and its long-term complications - A technical report. 2009. Sund R, Koski S. FinDM II: On the register-based measurement of the prevalence and incidence of diabetes and its long-term complications - A technical report. 2009.
23.
go back to reference Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15(7):539–53.CrossRefPubMed Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15(7):539–53.CrossRefPubMed
24.
go back to reference Sund R, Harno K, Ranta S, Tolppanen E. Evaluation of case inclusion in two population-based diabetes registers. Fin J eHealth eWelfare. 2010;2(3):136-46 Sund R, Harno K, Ranta S, Tolppanen E. Evaluation of case inclusion in two population-based diabetes registers. Fin J eHealth eWelfare. 2010;2(3):136-46
25.
go back to reference Pukkala E, Engholm G, Hojsgaard Schmidt LK, Storm H, Khan S, Lambe M, Pettersson D, Olafsdottir E, Tryggvadottir L, Hakanen T, Malila N, Virtanen A, Johannesen TB, Laronningen S, Ursin G. Nordic Cancer registries - an overview of their procedures and data comparability. Acta Oncol. 2018;57(4):440–55.CrossRefPubMed Pukkala E, Engholm G, Hojsgaard Schmidt LK, Storm H, Khan S, Lambe M, Pettersson D, Olafsdottir E, Tryggvadottir L, Hakanen T, Malila N, Virtanen A, Johannesen TB, Laronningen S, Ursin G. Nordic Cancer registries - an overview of their procedures and data comparability. Acta Oncol. 2018;57(4):440–55.CrossRefPubMed
26.
go back to reference Pukkala E, Söderman B, Okeanov A. Finland – cancer registration. Cancer Atlas of Northern Europe. Helsinki: Cancer Society of Finland Publication; 2001. Pukkala E, Söderman B, Okeanov A. Finland – cancer registration. Cancer Atlas of Northern Europe. Helsinki: Cancer Society of Finland Publication; 2001.
27.
go back to reference Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and multi-state models. Stat Med. 2007;26(11):2389–430.CrossRefPubMed Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and multi-state models. Stat Med. 2007;26(11):2389–430.CrossRefPubMed
28.
go back to reference de Glas NA, Kiderlen M, Vandenbroucke JP, de Craen AJ, Portielje JE, van de Velde CJH, Liefers G, Bastiaannet E, Le Cessie S. Performing survival analyses in the presence of competing risks: a clinical example in older breast cancer patients. J Natl Cancer Inst. 2016;108(5):1.CrossRef de Glas NA, Kiderlen M, Vandenbroucke JP, de Craen AJ, Portielje JE, van de Velde CJH, Liefers G, Bastiaannet E, Le Cessie S. Performing survival analyses in the presence of competing risks: a clinical example in older breast cancer patients. J Natl Cancer Inst. 2016;108(5):1.CrossRef
29.
go back to reference Heinzl H, Kaider A. Gaining more flexibility in cox proportional hazards regression models with cubic spline functions. Comput Methods Prog Biomed. 1997;54(3):201–8.CrossRef Heinzl H, Kaider A. Gaining more flexibility in cox proportional hazards regression models with cubic spline functions. Comput Methods Prog Biomed. 1997;54(3):201–8.CrossRef
30.
go back to reference Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81(3):515–26.CrossRef Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81(3):515–26.CrossRef
32.
go back to reference R Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2017. R Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2017.
33.
go back to reference Taylor-Harding B, Orsulic S, Karlan BY, Li AJ. Fluvastatin and cisplatin demonstrate synergistic cytotoxicity in epithelial ovarian cancer cells. Gynecol Oncol. 2010;119(3):549–56.CrossRefPubMed Taylor-Harding B, Orsulic S, Karlan BY, Li AJ. Fluvastatin and cisplatin demonstrate synergistic cytotoxicity in epithelial ovarian cancer cells. Gynecol Oncol. 2010;119(3):549–56.CrossRefPubMed
34.
go back to reference Robinson E, Nandi M, Wilkinson LL, Arrowsmith DM, Curtis AD, Richardson A. Preclinical evaluation of statins as a treatment for ovarian cancer. Gynecol Oncol. 2013;129(2):417–24.CrossRefPubMed Robinson E, Nandi M, Wilkinson LL, Arrowsmith DM, Curtis AD, Richardson A. Preclinical evaluation of statins as a treatment for ovarian cancer. Gynecol Oncol. 2013;129(2):417–24.CrossRefPubMed
35.
go back to reference Chen HY, Wang Q, Xu QH, Yan L, Gao XF, Lu YH, Wang L. Statin as a combined therapy for advanced-stage ovarian Cancer: a propensity score matched analysis. Biomed Res Int. 2016;2016:9125238.PubMedPubMedCentral Chen HY, Wang Q, Xu QH, Yan L, Gao XF, Lu YH, Wang L. Statin as a combined therapy for advanced-stage ovarian Cancer: a propensity score matched analysis. Biomed Res Int. 2016;2016:9125238.PubMedPubMedCentral
36.
go back to reference Verdoodt F, Kjaer Hansen M, Kjaer SK, Pottegard A, Friis S, Dehlendorff C. Statin use and mortality among ovarian cancer patients: a population-based cohort study. Int J Cancer. 2017;14(2):279–86.CrossRef Verdoodt F, Kjaer Hansen M, Kjaer SK, Pottegard A, Friis S, Dehlendorff C. Statin use and mortality among ovarian cancer patients: a population-based cohort study. Int J Cancer. 2017;14(2):279–86.CrossRef
37.
go back to reference Wang SB, Lei KJ, Liu JP, Jia YM. Continuous use of metformin can improve survival in type 2 diabetic patients with ovarian cancer: a retrospective study. Medicine (Baltimore). 2017;96(29):e7605.CrossRef Wang SB, Lei KJ, Liu JP, Jia YM. Continuous use of metformin can improve survival in type 2 diabetic patients with ovarian cancer: a retrospective study. Medicine (Baltimore). 2017;96(29):e7605.CrossRef
38.
go back to reference Garcia C, Yao A, Camacho F, Balkrishnan R, Cantrell LA. A SEER-Medicare analysis of the impact of metformin on overall survival in ovarian cancer. Gynecol Oncol. 2017;146(2):346–50.CrossRefPubMed Garcia C, Yao A, Camacho F, Balkrishnan R, Cantrell LA. A SEER-Medicare analysis of the impact of metformin on overall survival in ovarian cancer. Gynecol Oncol. 2017;146(2):346–50.CrossRefPubMed
39.
go back to reference Sund R. Quality of the Finnish hospital discharge register: a systematic review. Scand J Public Health. 2012;40(6):505–15.CrossRefPubMed Sund R. Quality of the Finnish hospital discharge register: a systematic review. Scand J Public Health. 2012;40(6):505–15.CrossRefPubMed
40.
go back to reference Nagle CM, Dixon SC, Jensen A, Kjaer SK, Modugno F, de Fazio A, et al. Ovarian cancer association consortium: obesity and survival among women with ovarian cancer: results from the ovarian Cancer association consortium. Br J Cancer. 2015;113(5):817–26.CrossRefPubMedPubMedCentral Nagle CM, Dixon SC, Jensen A, Kjaer SK, Modugno F, de Fazio A, et al. Ovarian cancer association consortium: obesity and survival among women with ovarian cancer: results from the ovarian Cancer association consortium. Br J Cancer. 2015;113(5):817–26.CrossRefPubMedPubMedCentral
41.
go back to reference Leminen A, Bützow R, Grénman S, Kuoppala T, Mervaala E, Mäenpää J, et al. Munasarjasyöpä. Duodecim; lääketieteellinen aikakauskirja. 2007;123(19):2339.PubMed Leminen A, Bützow R, Grénman S, Kuoppala T, Mervaala E, Mäenpää J, et al. Munasarjasyöpä. Duodecim; lääketieteellinen aikakauskirja. 2007;123(19):2339.PubMed
42.
go back to reference Haukka J, Suvisaari J, Tuulio-Henriksson A, Lonnqvist J. High concordance between self-reported medication and official prescription database information. Eur J Clin Pharmacol. 2007;63(11):1069–74.CrossRefPubMed Haukka J, Suvisaari J, Tuulio-Henriksson A, Lonnqvist J. High concordance between self-reported medication and official prescription database information. Eur J Clin Pharmacol. 2007;63(11):1069–74.CrossRefPubMed
Metadata
Title
Prognosis of ovarian cancer in women with type 2 diabetes using metformin and other forms of antidiabetic medication or statins: a retrospective cohort study
Authors
Elina Urpilainen
Mikko Marttila
Ari Hautakoski
Martti Arffman
Reijo Sund
Pirjo Ilanne-Parikka
Reetta Arima
Jenni Kangaskokko
Ulla Puistola
Marianne Hinkula
Esa Läärä
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4676-z

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine