Get Adobe Flash player
Gynecologic Oncology Endometrial Cancer Other Potential Combinations with mTOR Inhibitors in Endometrial Carcinoma As described above, activation of the PI3K/AKT/mTOR pathway has been implicated as a mechanism of resistance to both trastuzumab and standard cytotoxic chemotherapy, and combining trastuzumab or chemotherapeutic agents with inhibitors of the pathway has overcome resistance in numerous reports. 36,37 Trials combining chemotherapy with mTOR inhibitors have been slow to emerge, in part because the toxicities of the combinations are not always easy to manage. 38 However Kollmannsberger et al. successfully developed a regimen combining carboplatin/paclitaxel with temsirolimus on a 2 out of 3-week schedule 39 and a trial testing this regimen in the GOG has been completed; results should be available soon. Another opportunity might be combinations with 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 44 Jemal A, Siegel R, Ward E, et al., Cancer Statistics, CA Cancer J Clin, 2006;56(2):106–30. Bokhman JV, Two pathogenetic types of endometrial carcinoma, Gynecol Oncol, 1983;15(1):10–17. Creasman WT, Odicino F, Maisonneuve P, et al., Carcinoma of the corpus uteri, Int J Gynaecol Obstet, 2003;83(Suppl. 1): 79–118. Abal M, Planaguma J, Gil-Moreno A, et al., Molecular pathology of endometrial carcinoma: transcriptional signature in endometrioid tumours, Histol Histopathol, 2006;21(2):197–204. Hecht JL, Mutter GL, Molecular and pathologic aspects of endometrial carcinogenesis, J Clin Oncol, 2006;24(29): 4783–91. Lax SF, Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular- based classification, Virchows Arch, 2004;444(3):213–23. Hamilton CA, Cheung MK, Osann K, et al., Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers, Br J Cancer, 2006;94(5):642–6. Rudd ML, Price JC, Fogoros S, et al., A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas, Clin Cancer Res, 2011;17(6):1331–40. Urick ME, Rudd ML, Godwin AK, et al., PIK3R1 (p85alpha) is somatically mutated at high frequency in primary endometrial cancer, Cancer Res, 2011;71(12):4061–7. Salvesen HB, Carter SL, Mannelqvist M, et al., Integrated genomic profiling of endometrial carcinoma associates aggressive tumours with indicators of PI3 kinase activation, Proc Natl Acad Sci U S A, 2009;106(12):4834–9. Singh M, Zaino RJ, Filiaci VJ, Leslie KK, Relationship of oestrogen and progesterone receptors to clinical outcome in metastatic endometrial carcinoma: a Gynecologic Oncology Group Study, Gynecol Oncol, 2007;106(2):325–33. Chaudhry P, Asselin E, Resistance to chemotherapy and hormone therapy in endometrial cancer, Endocr Relat Cancer, 2009;16(2):363–80. Thigpen JT, Brady MF, Alvarez RD, et al., Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group, J Clin Oncol, 1999;17(6):1736–44. Markman M, Hormonal therapy of endometrial cancer, Eur J Cancer, 2005;41(5):673–5. Lentz SS, Brady MF, Major FJ, et al., High-dose megestrol acetate in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study, J Clin Oncol, 1996;14(2):357–61. Bender D, Buekers T, Leslie KK, Hormones and receptors in endometrial cancer, Proc Obstet Gynecol, 2011;1(July):25. Rose PG, Brunetto VL, VanLe L, et al., A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study, Gynecol Oncol, 2000;78(2):212–16. Burnett AF, Bahador A, Amezcua C, Anastrozole, an aromatase inhibitor, and medroxyprogesterone acetate therapy in premenopausal obese women with endometrial cancer: a report of two cases successfully treated without hysterectomy, 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. trastuzumab. Endometrial carcinomas can both overexpress and amplify HER2; a phase II GOG trial of single-agent trastuzumab in HER2-positive endometrial cancer found an overall rate of 11.5  % amplification, with highest rates of amplifications in serous carcinomas (seven of 25; 25 %), clear cell carcinomas (three of eight; 38 %), and mixed carcinomas (three of 11, 27  %). The trial, which permitted unlimited prior chemotherapy regimens, reported no objective responses. However, given the preclinical data suggesting that PI3K/AKT pathway activation is associated with resistance to trastuzumab, and the encouraging clinical results of the everolimus/trastuzumab combination in breast cancer (described above), trials testing a similar combination in endometrial cancer are of interest. n Gynecol Oncol, 2004;94(3):832–4. Ma BB, Oza A, Eisenhauer E, et al., The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers – a study of the National Cancer Institute of Canada Clinical Trials Group, Int J Gynecol Cancer, 2004;14(4):650–58. Watanabe R, Wei L, Huang J, mTOR signaling, function, novel inhibitors, and therapeutic targets, J Nucl Med, 2011;52(4):497–500. Bae-Jump VL, Zhou C, Boggess JF, et al., Rapamycin inhibits cell proliferation in type I and type II endometrial carcinomas: a search for biomarkers of sensitivity to treatment, Gynecol Oncol, 2010;119(3):579–85. Oza AM, Elit L, Tsao MS, et al., Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group, J Clin Oncol, 2011;29(24):3278–85. Westin SN, Broaddus RR, Personalized therapy in endometrial cancer: Challenges and opportunities, Cancer Biol Ther, 2012;13(1):1–13. Oza AM, Poveda A, Clamp AR, et al., A randomized Phase II (RP2) trial of ridaforolimus (R) compared with progestin (P) or chemotherapy (C) in female adult patients with advanced endometrial carcinoma, J Clin Oncol, 2011;29(24):3278–85. Diaz-Padilla I, Duran I, Clarke BA, Oza AM, Biologic rationale and clinical activity of mTOR inhibitors in gynecological cancer, Cancer Treat Rev, 2012;38(6):767–75. Lee S, Choi EJ, Jin C, Kim DH, Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line, Gynecol Oncol, 2005;97(1):26–34. Steelman LS, Navolanic P, Chappell WH, et al., Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells, Cell Cycle, 2011;10(17):3003–15. Sokolosky ML, Stadelman KM, Chappell WH, et al., Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy, Oncotarget, 2011;2(7):538–50. Morrow PK, Wulf GM, Ensor J, et al., Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy, J Clin Oncol, 2011;29(23):3126–32. Baselga J, Campone M, Piccart M, et al., Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer, N Engl J Med, 2012;366(6):520–29. Temkin SM, Fleming G, Current treatment of metastatic endometrial cancer, Cancer Control, 2009;16(1):38–45. Gu C, Zhang Z, Yu Y, et al, Inhibiting the PI3K/Akt pathway reversed progestin resistance in endometrial cancer, Cancer Sci, 2011;102(3):557–64. Slomovitz BM, Brown J, Johnston TA, et al., Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma, J Clin Oncol, 29:2011 (Suppl.; abstr 5012). Tewari KKS, Monk BJ, American Society of Clinical Oncology 2011 Annual Meeting update: summary of selected gynecologic cancer abstracts, Gynecol Oncol, 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 2011;122(2):209–12. Fleming GF, Filiaci VL, Hanjani P, Hormone Therapy plus temsirolimus for endometrial carcinoma (EC): Gynecologic Oncology Group trial #248, J Clin Oncol, 29:2011 (suppl; abstr 5014). Fung AS, Wu L, Tannock IF, Concurrent and sequential administration of chemotherapy and the Mammalian target of rapamycin inhibitor temsirolimus in human cancer cells and xenografts, Clin Cancer Res, 2009;15(17):5389–95. Piguet AC, Semela D, Keogh A, et al., Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma, J Hepatol, 2008;49(1):78–87. Temkin SM, Yamada SD, Fleming GF, A phase I study of weekly temsirolimus and topotecan in the treatment of advanced and/or recurrent gynecologic malignancies, Gynecol Oncol, 2010;117(3):473–6. Kollmannsberger C, Hirte H, Siu LL, et al., Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumours: a NCIC-CTG, phase I, open-label dose-escalation study (IND 179), Ann Oncol, 2012;23(1):238–44. Thigpen JT, Brady MF, Alvarez RD, et al., Oral medroxyprogesterone acetate in advanced endometrial carcinoma, Anticancer Research, 1986;6(3):355. Thigpen T, Brady MF, Homesley HD, et al., Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study, J Clin Oncol, 2001; 19(2):364–7. Whitney CW, Brunetto VL, Zaino RJ, et al., Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study, Gynecol Oncol, 2004;92(1):4–9. Fiorica JV, Brunetto VL, Hanjani P, et al., Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study, Gynecol Oncol, 2004;92(1):10–14. Pandya KJ, Yeap BY, Weiner LM, et al., Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882), Am J Clin Oncol, 2001;24(1):43–6. Covens A, Thomas G, Shaw P, et al., A phase II study of leuprolide in advanced/recurrent endometrial cancer, Gynecol Oncol, 1997;64(1):126–9. Lhommé C, Vennin P, Callet N, et al., A multicenter phase II study with triptorelin (sustained-release LHRH agonist) in advanced or recurrent endometrial carcinoma: a French anticancer federation study, Gynecol Oncol, 1999;75(2):187–93. Asbury RF, Brunetto VL, Lee RB, et al., Goserelin acetate as treatment for recurrent endometrial carcinoma: a Gynecologic Oncology Group study, Am J Clin Oncol, 2002;25(6):557–60. Mackay H, Welch S, Tsao MS, Phase II Study of oral Ridaforolimus in patients with metastatic and/or locally advanced recurrent endometrial cancer: NCIC CTG IND 192, J Clin Oncol, 29:2011 (suppl; abstr 5013). Slomovitz BM, Lu KH, Johnston T, et al., A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma, Cancer, 2010;116(23):5415–19. Oncology & H ematology Review