Skip to main content

Chemoprevention for Endometrial Cancers

  • Chapter
  • First Online:
Preventive Oncology for the Gynecologist
  • 478 Accesses

Abstract

In recent years, the development of new antineoplastic agents that can halt the process of carcinogenesis prior to development of disease and/or symptoms for various cancers with minimal systemic morbidity is an area of interest. Such agents have been proven to be useful for breast and ovarian cancers. An endometrial cancer (EC) is also a hormone-dependent cancer, like breast cancer, and has a well-proven risk factor profile to provide a defined population for identification. A variety of hormonal and non-hormonal agents have been studied for chemoprevention of endometrial cancers. Among hormonal agents, OCPs and depoMPA are most commonly used agents with equal efficacy; however, local route of hormonal administration (vaginal or endometrial) is preferred for minimal systemic effects. Among non-hormonal agents, metformin for obese women, COX-2 inhibitors, and statins are among certain drugs with different mechanisms, efficacy, and side effects. Recently, a new agent from peroxisome proliferator-activated receptor gamma (PPAR-y) agonist group, rosiglitazone, has been found to inhibit proliferation and induce apoptosis in both PTEN-wild and PTEN-null type endometrial cancer cell lines. However, most of the studies are observational studies with small sample size. Thus, these agents really need to be studied on a much larger population to establish their efficacy as chemopreventive drugs for endometrial cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. MayoClinic.com. Endometrial cancer. http://www.mayoclinic.com/health/endometrial-cancer/DS00306. Updated 7 Dec 2004.

  2. The American Cancer Society. Cancer facts and figures, 1998. Atlanta: The American Cancer Society; 1998.

    Google Scholar 

  3. Goss PE, Ingle JN, Alés-Martinez JE, Cheung AM, Chlebowski RT, Wactawski-Wende J, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364:2381–91.

    Article  CAS  Google Scholar 

  4. Narod SA, Risch H, Moslehi R, Dorum A, Neuhausen S, Olsson H, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med. 1998;339:424–8.

    Article  CAS  Google Scholar 

  5. Pike MC, Spicer DV. Oral contraceptives and cancer. In: Shoupe D, Haseltine F, editors. Contraception. New York: Springer; 1993. p. 67–84.

    Chapter  Google Scholar 

  6. Mueck AO, Seeger H, Rabe T. Hormonal contraception and risk of endometrial cancer: a systematic review. Endocr Relat Cancer. 2010;17:R263–71.

    Article  CAS  Google Scholar 

  7. Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner’s oral contraception study. BMJ. 2007;335:651.

    Article  Google Scholar 

  8. Maxwell GL, Schildkraut JM, Calingaert B, Risinger JI, Dainty L, Marchbanks PA, et al. Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk. Gynecol Oncol. 2006;103:535–40.

    Article  CAS  Google Scholar 

  9. Key TJ, Pike MC. The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer. 1988;57:205–12.

    Article  CAS  Google Scholar 

  10. Lu KH, Loose DS, Yates MS, Nogueras-Gonzalez GM, Munsell MF, Chen LM, et al. Prospective Multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with lynch syndrome. Cancer Prev Res. 2013;6:774–81.

    Article  Google Scholar 

  11. Rodriguez GC, Rimel BJ, Watkin W, Turbov JM, Barry C, Du H, et al. Progestin treatment induces apoptosis and modulates transforming growth factor-beta in the uterine endometrium. Cancer Epidemiol Biomark Prev. 2008;17:578–84.

    Article  CAS  Google Scholar 

  12. Chan M-F, Dowsett M, Folkerd E, Wareham N, Luben R, Welch A, et al. Past oral contraceptive and hormone therapy use and endogenous hormone concentrations in postmenopausal women. Menopause. 2007;15:332–9.

    Google Scholar 

  13. Gold EB, Crawford SL, Avis NE, Crandall CJ, Matthews KA, Waetjen LE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol. 2013;178:70–83.

    Article  Google Scholar 

  14. Zhou X, Dowdy S, Podratz K, Jiang S. Epigenetic considerations for endometrial cancer prevention, diagnosis and treatment. Gynecol Oncol. 2007;107:143–53.

    Article  Google Scholar 

  15. Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril. 1994;62:485–90.

    Article  CAS  Google Scholar 

  16. Hampel H, de la Chapelle A. The search for unaffected individuals with Lynch syndrome: do the ends justify the means? Cancer Prev Res. 2011;4:1–5.

    Article  Google Scholar 

  17. Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304–10.

    Article  CAS  Google Scholar 

  18. Stoffel E, Mukherjee B, Raymond VM, Tayob N, Kastrinos F, Sparr J, et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 2009;137:1621–7.

    Article  Google Scholar 

  19. Lu KH, Loose DS, Yates MS, Nogueras-Gonzalez GM, Munsell MF, Chen LM, et al. Prospective, multi-center randomized intermediate biomarker study of oral contraceptive vs. Depo-Provera for prevention of endometrial cancer in women with Lynch syndrome. Cancer Prev Res. 2013;6:774–81.

    Article  Google Scholar 

  20. Haslam DW, James WP. Obesity. Lancet. 2005;366:1197–209.

    Article  Google Scholar 

  21. Yach D, Stuckler D, Brownell KD. Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nat Med. 2006;12:62–6.

    Article  CAS  Google Scholar 

  22. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–91.

    Article  CAS  Google Scholar 

  23. Zhang Q, Shen Q, Celestino J, et al. Enhanced estrogen-induced proliferation in obese rat endometrium. Am J Obstet Gynecol. 2009;200:186 e1–8.

    Article  Google Scholar 

  24. Del Barco S, Vazquez-Martin A, Cufi S, et al. Metformin: multi-faceted protection against cancer. Oncotarget. 2011;2:896–917.

    PubMed  PubMed Central  Google Scholar 

  25. Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 2011;9:33.

    Article  CAS  Google Scholar 

  26. Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy. Gynecol Oncol. 2010;116:92–8.

    Article  CAS  Google Scholar 

  27. Zhang Q, Celestino J, Schmandt R, et al. Chemopreventive effects of metformin on obesity-associated endometrial proliferation. Am J Obstet Gynecol. 2013;209(1):24.e1–24.e12.

    Article  CAS  Google Scholar 

  28. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006;66:10269–73.

    Article  CAS  Google Scholar 

  29. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251–62.

    Article  CAS  Google Scholar 

  30. Bodey B. Genetically engineered antibodies for direct antineoplastic treatment and systematic delivery of various therapeutic agents to cancer cells. Expert Opin Biol Ther. 2001;1:603–17.

    Article  CAS  Google Scholar 

  31. Hawk ET, Viner JL, Dannenberg A, DuBois RN. COX-2 in cancer–a player that’s defining the rules. J Natl Cancer Inst. 2002;94:545–6.

    Article  Google Scholar 

  32. Tuynman JB, Hulscher JB, Steller EP, van Lanschot JJ, Richel DJ. Cyclooxygenase (COX)-2-inhibition in the prevention and treatment of colorectal carcinoma. Ned Tijdschr Geneeskd. 2003;147:2207–12.

    CAS  PubMed  Google Scholar 

  33. Landen CN Jr, Mathur SP, Richardson MS, Creasman WT. Expression of cyclooxygenase-2 in cervical, endometrial, and ovarian malignancies. Am J Obstet Gynecol. 2003;188:1174–6.

    Article  CAS  Google Scholar 

  34. Hayes EC, Rock JA. COX-2 inhibitors and their role in gynecology. Obstet Gynecol Surv. 2002;57:768–80.

    Article  Google Scholar 

  35. Ferrandina G, Legge F, Ranelletti FO, Zannoni GF, Maggiano N, Evangelisti A, Mancuso S, Scambia G, Lauriola L. Cyclooxygenase-2 expression in endometrial carcinoma: correlation with clinicopathologic parameters and clinical outcome. Cancer. 2002;95:801–7.

    Article  CAS  Google Scholar 

  36. Nasir A, Boulware D. Cyclooxygenase-2 (COX-2) expression in human endometrial carcinoma and precursor lesions and its possible use in cancer chemoprevention and therapy. In Vivo. 2007;21:35–44.

    CAS  PubMed  Google Scholar 

  37. Li J, Lu Y, Ma D. Cyclooxygenase-2 expression in endometrium carcinoma. Zhonghua Fu Chan Ke Za Zhi. 2002;37:408–10.

    PubMed  Google Scholar 

  38. Cao QJ, Einstein MH, Anderson PS, Runowicz CD, Balan R, Jones JG. Expression of COX-2, Ki-67, Cyclin D1, and P21 in endometrial endometrioid carcinomas. Int J Gynecol Pathol. 2002;21:147–54.

    Article  Google Scholar 

  39. Lavie O, Pinchev M, Rennert HS, Segev Y, Rennert G. The effect of statins on risk and survival of gynecological malignancies. Gynecol Oncol. 2013;130:615–9.

    Article  CAS  Google Scholar 

  40. Sperling CD, Verdoodt F, Friis S, Dehlendorff C, Kjaer SK. Statin use and risk of endometrial cancer: a nationwide registry-based case-control study. Acta Obstet Gynecol Scand. 2017;96:144–9. https://doi.org/10.1111/aogs.13069.

    Article  CAS  PubMed  Google Scholar 

  41. Perez-Medina T, Bajo J, Folgueira G, Haya J, Ortega P. Atypical endometrial hyperplasia treatment with progestogens and gonadotropin-releasing hormone analogues: long-term follow-up. Gynecol Oncol. 1999;73:299–304.

    Article  CAS  Google Scholar 

  42. Zhang Z, Dong L, Sui L, Yang Y, Liu X, Yu Y, Zhu Y, Feng Y. Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression. Int J Gynecol Cancer. 2011;21:213–21.

    Article  Google Scholar 

  43. Zhao S, Chen X, Lu X, Yu Y, Feng Y. Epidermal growth factor receptor signaling enhanced by long-term medroxyprogesterone acetate treatment in endometrial carcinoma. Gynecol Oncol. 2007;105:45–54.

    Article  CAS  Google Scholar 

  44. Satyaswaroop PG, Clarke CL, Zaino RJ, Mortel R. Apparent resistance in human endometrial carcinoma during combination treatment with tamoxifen and progestin may result from desensitization following downregulation of tumor progesterone receptor. Cancer Lett. 1992;62:107–14.

    Article  CAS  Google Scholar 

  45. Zheng W, Baker HE, Mutter GL. Involution of PTEN-null endometrial glands with progestin therapy. Gynecol Oncol. 2004;92:1008–13.

    Article  Google Scholar 

  46. Shen ZQ, Zhu HT, Lin JF. Reverse of progestin-resistant atypical endometrial hyperplasia by metformin and oral contraceptives. Obstet Gynecol. 2008;112:465–7.

    Article  Google Scholar 

  47. Shibata T, Kokubu A, Saito S, Narisawa-Saito M, Sasaki H, Aoyagi K, Yoshimatsu Y, Tachimori Y, Kushima R, Kiyono T, Yamamoto M. NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer. Neoplasia. 2011;13:864–73.

    Article  CAS  Google Scholar 

  48. Jiang T, Chen N, Zhao F, Wang XJ, Kong B, Zheng W, Zhang DD. High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Res. 2010;70:5486–96.

    Article  CAS  Google Scholar 

  49. Mutter GL, Ince TA, Baak JP, et al. Molecular identification of latent precancers in histologically normal endometrium. Cancer Res. 2001;61:4311–4.

    CAS  PubMed  Google Scholar 

  50. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347:645–50.

    Article  CAS  Google Scholar 

  51. Kliewer SA, Umesono K, Noonan DJ, et al. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature. 1992;358:771–4.

    Article  CAS  Google Scholar 

  52. Clay CE, Monjazeb A, Thorburn J, et al. 15-Deoxy-delta12, 14-prostaglandin J2-induced apoptosis does not require PPAR-gamma in breast cancer cells. J Lipid Res. 2002;43:1818–28.

    Article  CAS  Google Scholar 

  53. Lu J, Imamura K, Nomura S, et al. Chemopreventive effect of peroxisome proliferator-activated receptor gamma on gastric carcinogenesis in mice. Cancer Res. 2005;65:4769–74.

    Article  CAS  Google Scholar 

  54. Grommes C, Landreth GE, Heneka MT. Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol. 2004;5:419–29.

    Article  CAS  Google Scholar 

  55. Teresi RE, Shaiu CW, Chen CS, et al. Increased PTEN expression due to transcriptional activation of PPAR-gamma by Lovastatin and Rosiglitazone. Int J Cancer. 2006;118:2390–8.

    Article  CAS  Google Scholar 

  56. Celestino J, Milam MR, et al. Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model. Int J Gynecol Cancer. 2008;18:329–38.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gupta, M. (2019). Chemoprevention for Endometrial Cancers. In: Mehta, S., Singla, A. (eds) Preventive Oncology for the Gynecologist. Springer, Singapore. https://doi.org/10.1007/978-981-13-3438-2_5

Download citation

  • DOI: https://doi.org/10.1007/978-981-13-3438-2_5

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-13-3437-5

  • Online ISBN: 978-981-13-3438-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics