{"paper_id":"ee521b2d-06af-4e5a-881e-573077911e64","body_text":"Hormone Therapy plus mTOR Inhibitors in the  \nTreatment of Endometrial Carcinoma \nErica M Stringer 1 and Gini F Fleming 2\n1. Fellow, 2. Professor of Medicine, Department of Medicine, Section of Hematology Oncology, University of Chicago Medical Center, Chicago, IL, US.\nAbstract\nHormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance \nto progestin therapy are not well understood. However, activation of the PI3K/AKT/ mammalian target of rapamycin ( mTOR) pathway has \nbeen associated with resistance to hormonal therapy and alterations in components of the PI3K/AKT/mTOR pathway, including inactivating \nmutations in PTEN, activating mutations in PIK3CA and mutations in PIK3R1, are very common in endometrial carcinomas. mTOR inhibitors, \nincluding temsirolimus, everolimus and ridaforolimus, are also known to be active against endometrial cancer, and interest has been \nstimulated in combinations of hormonal treatment with mTOR inhibitors, as both therapies have single-agent activity, and it is hypothesised \nthat mTOR inhibition would enhance sensitivity to hormonal therapy. \nKeywords\nEndometrial cancer, hormone therapy, progestin, mTOR inhibitor, temsirolimus, everolimus, ridaforolimus, letrozole\nDisclosure: The authors have no conflicts of interest to declare.\nReceived: 30 March 2012 Accepted: 21 May 2012 Citation: European Endocrinology, 2013;9(1):18–21\nCorrespondence: Gini F Fleming, University of Chicago Medical Center, 5841 South Maryland Ave MC2115, Chicago, IL 60637, US. E: gfleming@medicine.bsd.uchicago.edu\n18\nEndocrine Oncology  Endometrial Cancer\n© TOUCH MEDICAL MEDIA 2013\nEndometrial Carcinoma\nEndometrial cancer is the most common gynecologic malignancy in \ndeveloped countries. 1 According to Surveillance, Epidemiology and \nEnd Results (SEER) statistics the estimated incidence of cancers of the \nuterine corpus for US women in 2011 is 46,470 women. The age-adjusted \nmortality rate is 4.2 deaths per 100,000 women per year, with an estimated \n8,100 deaths in 2011. Median survival for women with recurrent or \nmetastatic disease is only 12 to 15 months. The most commonly used \nsystemic treatment for advanced disease at this time is platinum/taxane-\nbased chemotherapy, which has produced higher response rates and \nlonger median progression-free survivals than hormonal therapy, but \nprogestins remain useful, and occasionally produce prolonged disease \ncontrol. Mammalian target of rapamycin (mTOR) inhibitors have also \nrecently been shown to have modest single-agent activity.\nType I and Type II Endometrial Carcinoma\nEndometrial cancers are often divided into two conceptual categories: \ntype I and type II. 2 About 80 % of endometrial carcinomas are type I, \ni.e. of endometriod histology with low or intermediate grade. These \ncancers can arise in the setting of persistent unopposed oestrogen \nstimulation, and tend to occur in perimenopausal women. 3 They \nare generally preceded by endometrial hyperplasia and are usually \noestrogen and progesterone receptor (ER/PR) positive. Molecular \nalterations associated with type I tumours include deletions/\ninactivating mutations of the PTEN tumour suppressor gene (36–83 %), \nmicrosatellite instability (20–40  %), mutations of K-ras (15–30  %) and \ngain of function mutations in β-catenin (25–40 %). 4–6 By contrast, type II \ntumours are histologically nonendometriod e.g. serous or clear cell, and \nhave no association with excess endogenous or exogenous oestrogen. \nThey tend to occur in older women, and are aggressive with a proclivity \nfor lymphovascular invasion, distant spread and deep tissue invasion; \nthey account for nearly half of endometrial cancer deaths. 7 The \ngenetic alterations associated with type II tumours include aneuploidy, \np53 mutations (80–90  %), p16 inactivation (40  %), overexpression of \nhuman epidermal growth factor receptor 2 (HER-2)/neu (40–80 %) and \nE-cadherin alterations (80–90 %). 4–6 Mutations in PIK3CA (gene encoding \nthe catalytic subunit of PI3K) and PIK3R (which encodes the regulatory \nsubunit of PI3K) can occur in both subtypes, although they appear to \nbe more common in type I cancers. 8,9 Increased signalling of the PI3K/\nAKT/mTOR pathway is associated with a poor prognosis in both type I \nand type II carcinomas. 10 \nHormone Therapy in the Treatment of  \nAdvanced Endometrial Cancer (see Table 1 )\nSince the early studies by Kelly and Baker in 1965, progestin-based \ntherapy has played a role in the treatment of advanced endometrial \ncarcinoma.11,12 Trials in chemotherapy-naïve advanced endometrial \ncarcinoma patients have demonstrated response rates of 18–34 % to \nprogestins with median overall survivals of 6–14 months. 13 Commonly \nused regimens in the US include megestrol acetate (MA) 160 mg/day, \nor MA for three weeks alternating with tamoxifen (TAM) for 3 weeks. \nThe addition of TAM was hypothesised to increase the percentage \nof endometrial cells that contain PRs, as well as the concentration \nof surface receptors. 14 While this alternating regimen has not been \ncompared with single-agent megestrol therapy in a randomised trial, \nthe 27  % response rate reported is as high as or higher than that \nreported with any other hormonal regimen, and TAM causes less \nweight gain than MA. Dose escalations of MA to 1,000 mg/day did not \nimprove overall survival or progression-free survival. 15 In general, the \nhighest response rates are found in patients with well-differentiated \nhormone receptor positive tumours. 11 However, objective response \nrates as high as 17 % have reported in PR-negative tumours, making \nER/PR expression an inadequate predictor of benefit from hormone \ntherapy in clinical practice. This may be partly related to heterogeneity \nDOI:10.17925/EE.2013.09.01.18\n\nHormone Therapy plus mTOR Inhibitors in the Treatment of Endometrial Carcinoma\nEUROPEAN ENDOCRINOLOGY 19\nof receptor distribution within an individual tumour. The most common \nside effects of progestin-based therapy are weight gain in about 26 % \nand venous thrombosis in about 5 % of patients; 16 oedema can also \noccur. Selective oestrogen modulators, such as TAM or arzoxifene, \nhave also produced modest response rates, although lower than those \nseen with progestins. 13 Aromatase inhibitors including letrozole and \nanastrozole have shown response rates of less than 10 %. 17–19 Of note, \npatients on the trials of aromastase inhibitors were permitted to have \nhad prior hormonal therapy, although not prior chemotherapy. A small \nmulticentre phase II study of the National Cancer Institute of Canada \n(NCIC) Clinical Trials Group testing the use of letrozole found a 9.4 % \nresponse rate and no correlation between response and expression \nof the following biomarkers: PR (86 %), oestrogen receptor (OR) (86 %), \nPTEN (82 %), phosphorylated PKB/Akt (59 %), bcl-2 (49 %), p53 (32 %) \nand HER-2 (0 %). \nmTOR Inhibitor Therapy in Endometrial Cancer \nThe mTOR is a protein downstream of PI3Kinase that is activated by \noncogenic alterations of the pathway. mTOR regulates numerous cell \nfunctions, including protein translation, cell growth and apoptosis. \nThere are two mTOR complexes, mTORC1 and mTORC2, both of which \nhave downstream effects. 20 The rapamycin-analogue mTOR inhibitors \ncurrently available (temsirolimus, everolimus and ridaforolimus) all act \nvia binding to the cytosolic protein, FK binding-protein 12 (FKBP12) and \nprimarily inhibit mTORC1. As early in vitro work suggested that genetic \nabnormalities resulting in activation of the PI3K/AKT/mTOR pathway, \nincluding loss of PTEN function, were associated with anti-tumour \nefficacy of mTOR inhibitors, these agents were tested fairly early in \nendometrial cancer. Bae-Jump et al. demonstrated in vitro  activity \nof rapamycin in both type I and type II endometrial cancer tumour \nexplants21 and, indeed, clinical responses have been observed in both \ntype I and type II endometrial cancers.\nThe NCIC Clinical Trials Group performed two phase II studies \nevaluating single-agent temsirolimus, the first in women with recurrent \nor metastatic chemotherapy-naïve disease, and the second in women \nwho had prior chemotherapy. Temsirolimus 25  mg intravenously (IV) \nwas administered weekly. In the chemotherapy-naïve group, four of \n29 evaluable patients (14  %) had a partial response with a median \nresponse duration of 5.1 months and 20 (69 %) had stable disease with a  \nmedian duration of 9.7 months. In the group with prior chemotherapy, \nonly one of 25 evaluable patients (4 %) responded; 12 patients (48%) \nhad stable disease with a median duration of 3.7  months. 22 Neither \nabsence of PTEN by immunohistochemical staining, PTEN mutation nor \nmolecular markers of PI3K/Akt/mTOR pathway correlated with clinical \noutcomes.23 Toxicities were typical of those seen with mTOR-inhibitor \ntherapy, and included fatigue, rash, nausea, diarrhoea, mucositis and \npneumonitis. Asymptomatic mucositis was particularly common in this \nstudy (42 %) with five patients (8 %) having grade 3 pneumonitis. Low \nlevels of activity were also seen in phase II trials of ridaforolimus and \neverolimus in women with pretreated disease (see Table 2). \nMore recently a randomised phase II trial compared ridaforolimus \nwith progestin-based therapy and standard chemotherapy in 130 \nwomen with advanced disease who had received one or two prior \nchemotherapy regimens. Almost one-third of patients had tumours \nof serous histology, and more than 50  % had grade 3 tumours. \nRidaforolimus met the primary endpoint of the study by demonstrating \na progression-free survival of 3.6 versus 1.9 months with progestins. 24 \nToxicities with ridaforolimus included hyperglycaemia, fatigue, \ndiarrhoea, anemia and mucositis, but no grade 3 pneumonitis. 25 \nGiven the toxicities with mTOR-inhibitor therapy, a biologic indicator \nof which patients are most likely to benefit is clearly needed, but no \ngood predictive marker has emerged to date.\nRationale for Combination of mTOR Inhibitors \nwith Hormone Therapy\nThe PI3K/AKT/mTOR signalling cascade has been widely implicated in \nresistance to chemotherapy agents, molecularly targeted agents, such \nas trastuzumab or gefitinib, radiotherapy and hormonal therapy. 26–28 In \nbreast cancer, clinical data have begun to suggest that use of mTOR- \ninhibitor therapy can overcome acquired resistance to trastuzumab \nand to aromatase-inhibitor therapy. A phase I/II study reported a 15 % \nresponse rate and a 34 % clinical benefit rate with the combination of \ntrastuzumab plus everolimus in women with HER2 positive tumours that \nhad progressed on trastuzumab therapy. 29 More definitive evidence is \nin the setting of the combination of an mTOR inhibitor with hormonal \ntherapy. A randomised, double-blind, placebo-controlled phase III clinical \ntrial (BOLERO-2) randomly assigned 724 hormone receptor positive \nadvanced breast cancer patients who had recurrence or progression on \na nonsteroidal aromatase inhibitor to exemestane (a steroidal aromatase \ninhibitor) plus everolimus or placebo. The combination therapy showed a \nsuperior progression-free survival of 10.6 months versus 4.1 months with \nexemestane alone.30 The most common grade 3 or 4 adverse events with \nthe combination were stomatitis, anaemia, dyspnoea, hyperglycaemia, \nfatigue and pneumonitis (3 %).\nSpecifically in endometrial cancer, there are in vitro  data that mTOR \ninhibitors increase progesterone messenger RNA (mRNA) expression.21,31 \nIn addition, in vitro  and in vivo  xenograft mouse models suggest that \nTable 1: Hormone Therapy in Advanced  \nEndometrial Cancer\nAuthor Drug RR (%) Median Overall \nSurvival (mos)\nThigpen, 198640 MPA 150 mg/day 18 10.5\nLentz, 199615 MA 800 mg/day 24 7.6\nThigpen, 199913 MPA 200 mg/day\nMPA 1000 mg/day\n25\n15\n11.1 \n7.0 \nThigpen, 200141 TAM 40 mg/day 10 8.8\nWhitney, 200442 MPA 200 mg/day every \nother week and TAM \n40 mg daily\n33 13\nFiorica, 200443 MA 160 mg/day x 3 \nweeks followed by TAM \n40 mg/day x 3 weeks\n27 14\nPandya, 200144 MA 160 mg/day \n      \nMA mg/160 mg/day + \nTAM 20 mg/day\n20 \n19\n12.6 \n8.6 \nCovens, 199745 Leuprolide 7.5 mg q 28 \ndays\n0 6\nLhomme, 199946 Triptorelin 3.75 mg q 28 8.7 7.2\nAsbury, 200247 Goserelin 3.6 mg q day 11 7.3\nRose, 200017 Anastrozole 1 mg/day 9 6\nMa, 200419 Letrozole 2.5 mg/day 9.4 6.7\nMA= megestrol acetate; MPA= medroxyprogesterone acetate; RR = response rate; TAM= tamoxifen.                                               \n\n20\nEndocrine Oncology  Endometrial Cancer\nEUROPEAN ENDOCRINOLOGY\nMPA activates the PI3K/AKT pathway in progestin-resistant cells, and \nthat inhibiting this pathway reverses progestin resistance in these cell \nlines.32 Two phase II trials combining mTOR inhibitors with hormonal \ntherapy have been completed in endometrial cancer, and both have \nbeen reported in abstract form (see Table 2). The Gynecologic Oncology \nGroup (GOG) has completed GOG-0248, a randomised phase II trial in \nwomen with hormone therapy-naïve disease; one prior chemotherapy \nregimen was permitted (in the setting of stage I, II or III disease, or as \nradiation sensitiser for pelvic recurrence, or in setting of stage IV disease \nif patient was without evidence of disease at end of chemotherapy and \nat least six months elapsed prior to progression). Patients received either \nsingle-agent temsirolimus 25 mg IV weekly and or the temsirolimus given \nconcomitantly with MA 80 mg bid for three weeks alternating with TAM \n20  mg bid for three  weeks. Unfortunately, the arm with the combined \nregimen closed after the first stage due to an unacceptable rate of \nvenous thrombosis (seven events in 22 patients).34,35 Three of 21 patients \n(14  %) had a partial response at the time of the preliminary report. \nResults for the single agent are are pending. A two-institution, open-\nlabel, single-arm phase II study in patients with recurrent endometrial \ncancer who had received two or fewer prior chemotherapeutic regimens \nreceived the combination of letrozole 2.5 mg daily and everolimus 10 mg \ndaily. Four of 19 patients (21  %) had an objective response and eight \nof 19 (42  %) had clinical benefit, defined as complete response (CR), \npartial response (PR) or stable disease (SD) for at least eight weeks. This \nresponse rate appears better than the historic controls with hormone \ntherapy in a chemotherapy pretreated population, as well as better than \nresults obtained by the same authors in a single agent trial of everolimus \nin a similarly pretreated population (no objective responses), although \nthe rate of stable disease at eight weeks (43 %) was similar. The most \ncommon drug toxicities were fatigue, stomatitis, hypertriglyceridaemia, \nnausea and hyperglycaemia. 33 Given that response rates of over 10 % \nwith any agent in the setting of chemotherapy pretreated endometrial \ncancer are unusual, further development of hormone therapy and PI3K \npathway inhibitor combinations is clearly warranted.\nOther Potential Combinations with mTOR  \nInhibitors in Endometrial Carcinoma\nAs described above, activation of the PI3K/AKT/mTOR pathway has \nbeen implicated as a mechanism of resistance to both trastuzumab \nand standard cytotoxic chemotherapy, and combining trastuzumab or \nchemotherapeutic agents with inhibitors of the pathway has overcome \nresistance in numerous reports. 36,37 Trials combining chemotherapy \nwith mTOR inhibitors have been slow to emerge, in part because \nthe toxicities of the combinations are not always easy to manage. 38 \nHowever Kollmannsberger et al. successfully developed a regimen \ncombining carboplatin/paclitaxel with temsirolimus on a two out of \nthree week schedule 39 and a trial testing this regimen in the GOG has \nbeen completed; results should be available soon. Another opportunity \nmight be combinations with trastuzumab. Endometrial carcinomas can \nboth overexpress and amplify HER2; a phase II GOG trial of single-agent \nTable 2: Phase II Trials of Mammalian Target of Rapamycin Inhibitors in Endometrial Carcinoma\nType of Trial Drug Mechanism Patient Population Response Rates Prior Therapy\nPhase II single agent 48    R 40 mg x five days per week mTORi Recurrent/metastatic PR 7.7 % (2 patients chemo-\nnaïve)\nSD 58 % MD 6.6 months\nYes, adjuvant \nonly\nRandomised open-\nlabel phase II 24\nR 40 mg x five days per week \n(experimental arm)\nProgestin * or chemotherapy\n(control arm)\nmTORi,\nPBT , chemo\nAdvanced/metastatic PFS: 3.6 months for R vs \n1.9 months for PBT by IRR \n(HR=0.53; p=0.008)\nControl: PR/SD 4.3 %/17 % \nby IRR\nExperimental: PR/SD 0 %/35 % \nby IRR\nYes\nRandomised phase \nII22\nTEM 25 mg weekly mTORi Recurrent/metastatic Chemo-naïve\nPR 14 %, SD 69 %\n(MD 5.1 vs 9.7 months)\nChemo-treated\nPR 4 % **, SD 48 % (MD 4.3 vs \n3.7 months) \nYes\nRandomised phase \nII35\nTEM 25 mg weekly\nTEM 25 mg weekly + (MA \n80 mg bid x three weeks  \nalternating with TAM 20 mg \nbid x three weeks)\nmTORi, PBT\nSERM\nAdvanced/recurrent 14% objective responses \nreported in combination arm \nCombined arm closed due to \nvenous thrombosis\nYes\nSingle-institution, \nopen-label, single-\narm, phase II49\nEverolimus 10 mg/day mTORi Recurrent disease CBR 43 % at eight weeks\nCBR 21 % at 20 weeks\nYes\nTwo-institution, open-\nlabel, single-arm, \nphase II33\nEverolimus 10 mg/day + \nletrozole 2.5 mg/day\nmTORi, AI Recurrent disease CBR 42 %\nObjective RR 21 %\nYes\nAI = aromatase inhibitor, CBR = Clinical Benefit Response (CR, PR, or SD), IRR = independent radiology review, MA = megestrol acetate, MD = median duration, MPA = medroxyprogesterone acetate,  \nmTORi = mammalian target of rapamycin inhibitors; PR = partial response; PBT = progestin-based therapy; R = ridaforolimus; SERM = selective oestrogen modulator; TAM = tamoxifen;  \nTEM = temsirolimus. *Progestin (MPA 200 mg/day or MA 60 mg/day); **Independently confirmed.            \n\nHormone Therapy plus mTOR Inhibitors in the Treatment of Endometrial Carcinoma\nEUROPEAN ENDOCRINOLOGY 21\ntrastuzumab in HER2-positive endometrial cancer found an overall \nrate of 11.5  % amplification, with highest rates of amplifications in \nserous carcinomas (seven of 25; 25  %), clear cell carcinomas (three \nof eight; 38  %) and mixed carcinomas (three of 11, 27  %). The trial, \nwhich permitted unlimited prior chemotherapy regimens, reported no \nobjective responses. However, given the preclinical data suggesting \nthat PI3K/AKT pathway activation is associated with resistance to \ntrastuzumab, and the encouraging clinical results of the everolimus/\ntrastuzumab combination in breast cancer (described above), trials \ntesting a similar combination in endometrial cancer are of interest. n\n1. Jemal A, Siegel R, Ward E, et al., Cancer Statistics, CA Cancer \nJ Clin, 2006 Mar-Apr;56(2):106–30.\n2. Bokhman JV, Two pathogenetic types of endometrial \ncarcinoma, Gynecol Oncol, 1983;15(1):10–17.\n3. Creasman WT , Odicino F , Maisonneuve P , et al., Carcinoma  \nof the corpus uteri, Int J Gynaecol Obstet, 2003;83 \n(Suppl. 1):79–118.\n4. Abal M, Planaguma J, Gil-Moreno A, et al., Molecular \npathology of endometrial carcinoma: transcriptional \nsignature in endometrioid tumours, Histol Histopathol, \n2006;21(2):197–204.\n5. 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