Advertisement

Chemoprevention for Endometrial Cancers

  • Monisha Gupta
Chapter

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.

Keywords

Endometrial cancers Chemoprevention Lynch syndrome OCPs Metformin COX-2 inhibitors Statins Rosiglitazone 

References

  1. 1.
    MayoClinic.com. Endometrial cancer. http://www.mayoclinic.com/health/endometrial-cancer/DS00306. Updated 7 Dec 2004.
  2. 2.
    The American Cancer Society. Cancer facts and figures, 1998. Atlanta: The American Cancer Society; 1998.Google Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 5.
    Pike MC, Spicer DV. Oral contraceptives and cancer. In: Shoupe D, Haseltine F, editors. Contraception. New York: Springer; 1993. p. 67–84.CrossRefGoogle Scholar
  6. 6.
    Mueck AO, Seeger H, Rabe T. Hormonal contraception and risk of endometrial cancer: a systematic review. Endocr Relat Cancer. 2010;17:R263–71.CrossRefGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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. 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.CrossRefGoogle Scholar
  14. 14.
    Zhou X, Dowdy S, Podratz K, Jiang S. Epigenetic considerations for endometrial cancer prevention, diagnosis and treatment. Gynecol Oncol. 2007;107:143–53.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 20.
    Haslam DW, James WP. Obesity. Lancet. 2005;366:1197–209.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 22.
    Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–91.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 24.
    Del Barco S, Vazquez-Martin A, Cufi S, et al. Metformin: multi-faceted protection against cancer. Oncotarget. 2011;2:896–917.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 2011;9:33.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 34.
    Hayes EC, Rock JA. COX-2 inhibitors and their role in gynecology. Obstet Gynecol Surv. 2002;57:768–80.CrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 37.
    Li J, Lu Y, Ma D. Cyclooxygenase-2 expression in endometrium carcinoma. Zhonghua Fu Chan Ke Za Zhi. 2002;37:408–10.PubMedGoogle Scholar
  38. 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.CrossRefGoogle Scholar
  39. 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.CrossRefGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefGoogle Scholar
  42. 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.CrossRefGoogle Scholar
  43. 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.CrossRefGoogle Scholar
  44. 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.CrossRefGoogle Scholar
  45. 45.
    Zheng W, Baker HE, Mutter GL. Involution of PTEN-null endometrial glands with progestin therapy. Gynecol Oncol. 2004;92:1008–13.CrossRefGoogle Scholar
  46. 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.CrossRefGoogle Scholar
  47. 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.CrossRefGoogle Scholar
  48. 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.CrossRefGoogle Scholar
  49. 49.
    Mutter GL, Ince TA, Baak JP, et al. Molecular identification of latent precancers in histologically normal endometrium. Cancer Res. 2001;61:4311–4.PubMedGoogle Scholar
  50. 50.
    Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347:645–50.CrossRefGoogle Scholar
  51. 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.CrossRefGoogle Scholar
  52. 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.CrossRefGoogle Scholar
  53. 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.CrossRefGoogle Scholar
  54. 54.
    Grommes C, Landreth GE, Heneka MT. Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol. 2004;5:419–29.CrossRefGoogle Scholar
  55. 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.CrossRefGoogle Scholar
  56. 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.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Monisha Gupta
    • 1
    • 2
  1. 1.Department of Surgical OncologyMax Super Speciality Hospital, Shalimar BaghNew DelhiIndia
  2. 2.Department of Surgical OncologyMax Super Speciality Hospital, PitampuraNew DelhiIndia

Personalised recommendations