***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background : Bevacizumab and temsirolimus are active agents in gynecologic tumors .  Temsirolimus attenuates upregulation of HIF-1α levels , a resistance mechanism for antiangiogenics , and targets the PI3-kinase/AKT/mTOR axis , commonly aberrant in these tumors Patients and Methods : We analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus .  Results : Median age of the 41 women was 60 years ( range , 33 - 80 years ) ; median number of prior systemic therapies was 4 ( 1 - 11 ) .  Grade 3 or 4 treatment-related toxicities included : thrombocytopenia ( 10 % ) , mucositis ( 2 % ) , hypertension ( 2 % ) , hypercholesterolemia ( 2 % ) , fatigue ( 7 % ) , elevated aspartate aminotransferase ( 2 % ) , and neutropenia ( 2 % ) . Twenty-nine patients ( 71 % ) experienced no treatment-related toxicity greater than grade 2 . Full FDA -approved doses of both drugs ( bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25 mg IV weekly ) were administered without dose-limiting toxicity . Eight patients ( 20 % ) achieved stable disease ( SD ) ≥ 6 months and 7 patients ( 17 % ) , a partial response ( PR ) [ total = 15/41 patients ( 37 % ) ] . Eight of 13 patients ( 62 % ) with high- grade serous histology ( ovarian or primary peritoneal ) achieved SD ≥ 6 months/PR . Conclusion : Bevacizumab and temsirolimus was well tolerated . Thirty-seven percent of heavily-pretreated patients achieved SD ≥ 6 months/PR , suggesting that this combination warrants further study Background : This open-label , multicentre , phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer . Methods : Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle . The primary end point was clinical benefit response , defined as an objective response or prolonged stable disease of 16 weeks or more . Results : In all , 45 patients were treated with single-agent ridaforolimus .  Clinical benefit was achieved by 13 patients ( 29 % ) , including 5 ( 11 % ) with confirmed partial responses and 8 ( 18 % ) with prolonged stable disease . All patients with clinical benefit response received ridaforolimus for more than 4 months . In this heavily pretreated population , the 6-month progression-free survival was 18 % . Ridaforolimus was generally well tolerated : adverse events were predictable and manageable , consistent with prior studies in other malignancies . Overall , the most common adverse events were diarrhoea ( 58 % ) and mouth sores ( 56 % ) ; most common grade 3 or higher adverse events were anaemia ( 27 % ) and hyperglycaemia ( 11 % ) . Conclusion : Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients . Further clinical evaluation of ridaforolimus is warranted OBJECTIVE Patients with persistent/recurrent epithelial ovarian cancer/ primary peritoneal cancer ( EOC/PPC ) have limited treatment options . AKT and PI3 K pathway activation is common in EOC/PPC , result ing in constitutive activation of downstream mTOR . The GOG conducted a phase II evaluation of efficacy and safety for the mTOR inhibitor , temsirolimus in EOC/PPC and explored circulating tumor cells ( CTC ) and AKT/mTOR/downstream tumor markers . METHODS Eligible women with measurable , persistent/recurrent EOC/PPC who had received 1 - 3 prior regimens were treated with 25 mg weekly IV temsirolimus until progression or intolerable toxicity . Primary endpoints were progression-free survival ( PFS ) ≥6-months , tumor response , and toxicity . Cell Search ® system was used to examine CTC , and AKT/mTOR/downstream markers were evaluated by archival tumor immunohistochemistry . Kendall 's tau-b correlation coefficient ( r ) and Cox regression modeling were used to explore marker associations with baseline characteristics and outcome . RESULTS Sixty patients were enrolled in a two-stage sequential design . Of 54 eligible and evaluable patients , 24.1 % ( 90 % CI 14.9%-38.6 % ) had PFS ≥6 months ( median 3.1 months ) , 9.3 % ( 90 % CI 3.7%-23.4 % ) experienced a partial response . Grade 3/4 adverse events included metabolic ( 8) , gastrointestinal ( 8) , pain ( 6 ) , constitutional ( 5 ) and pulmonary ( 4 ) . Suggested associations were between cyclin D1 and PFS ≥6 months , PFS or survival ; positive CTC pre-treatment and lack of response ; and high CTC expression of M30 and PFS ≥6 months/longer PFS . CONCLUSIONS Temsirolimus appears to have modest activity in persistent/recurrent EOC/PPC ; however , PFS is just below that required to warrant inclusion in phase III studies in unselected patients . Cyclin D1 as a selection marker and CTC measures merit further study OBJECTIVE This two-stage phase II study was design ed to assess the activity of the combination of temsirolimus and bevacizumab in patients with recurrent or persistent endometrial carcinoma ( EMC ) . METHODS Eligible patients had persistent or recurrent EMC after receiving 1 - 2 prior cytotoxic regimens , measurable disease , and Gynecologic Oncology Group performance status ≤ 2 . Treatment consisted of bevacizumab 10 mg/kg every other week and temsirolimus 25 mg IV weekly until disease progression or prohibitory toxicity . Primary end points were progression-free survival ( PFS ) at six months and overall response rate using RECIST criteria . RESULTS Fifty-three patients were enrolled . Forty-nine patients were eligible and evaluable . Median age was 63 years , and prior treatment consisted of one or two regimens in 40 ( 82 % ) and 9 ( 18 % ) , respectively . Twenty ( 41 % ) received prior radiation . Adverse events were consistent with those expected with bevacizumab and temsirolimus treatment . Two gastrointestinal-vaginal fistulas , one grade 3 epistaxis , two intestinal perforations and 1 grade 4 thrombosis/embolism were seen . Three patient deaths were possibly treatment related . Twelve patients ( 24.5 % ) experienced clinical responses ( one complete and 11 partial responses ) , and 23 patients ( 46.9 % ) survived progression free for at least six months . Median progression-free survival ( PFS ) and overall survival ( OS ) were 5.6 and 16.9 months , respectively . CONCLUSION Combination of temsirolimus and bevacizumab is deemed active based on both objective tumor response and PFS at six months in recurrent or persistent EMC . However , this treatment regimen was associated with significant toxicity in this pretreated group . Future study will be guided by strategies to decrease toxicity and increase response rates PURPOSE The prognosis for women with recurrent and metastatic endometrial cancer is poor , and improved therapies are needed . The mammalian target of rapamycin ( mTOR ) pathway is an important target , and mTOR inhibitors show clinical activity in endometrial cancer . PATIENTS AND METHODS An open-label , multicenter , r and omized , phase II trial of oral ridaforolimus compared with progestin or investigator choice chemotherapy ( comparator ) was undertaken in women with metastatic or recurrent endometrial cancer who had progressive disease following one or two lines of chemotherapy and no hormonal therapy .  The primary end point was progression-free survival ( PFS ) assessed by independent radiologic review . RESULTS One hundred thirty patients were enrolled ( 64 received ridaforolimus and 66 received the comparator ) , and median age was 66 years .  Treatment discontinuation as a result of adverse events was 33 % with ridaforolimus versus 6 % with the comparator , with common ( > 10 % ) grade 3 toxicities being hyperglycemia , anemia , and diarrhea . Thirty-eight percent ( ridaforolimus ) versus 71 % ( comparator ) of patients discontinued treatment as a result of disease progression . Median PFS at the protocol prespecified interim analysis with 58 PFS events ( primary end point ) was 3.6 months ( 95 % CI , 2.7 to 7.3 months ) for ridaforolimus and 1.9 months ( 95 % CI , 1.9 to 2.3 months ) for the comparator ( hazard ratio , 0.53 ; 95 % CI , 0.31 to 0.90 ; P = .008 ) . PFS rate for ridaforolimus versus comparator was 48 % versus 18 % at 16 weeks and 38 % versus 15 % at 24 weeks . Objective response rate for ridaforolimus versus comparator was 0 % versus 4 % ( P = .925 ) , and stable disease was achieved in 35 % versus 17 % of patients ( P = .021 ) . CONCLUSION Oral ridaforolimus shows encouraging activity in advanced endometrial cancer but is associated with significant toxicity . Inhibition of the PI3K/Akt/mTOR pathway may be a viable therapeutic target Background : Since PI3K/AKT/mTOR pathway activation diminishes the effects of hormone therapy , combining aromatase inhibitors ( anatrozole ) with mTOR inhibitors ( everolimus ) was investigated . Patients and Methods : We evaluated anastrozole and everolimus in 55 patients with metastatic estrogen ( ER ) and /or progesterone receptor (PR)-positive breast and gynecologic tumors . Endpoints were safety , antitumor activity and molecular correlates . Results : Full doses of anastrozole ( 1 mg PO daily ) and everolimus ( 10 mg PO daily ) were well tolerated . Twelve of 50 evaluable patients ( 24 % ) ( median = 3 prior therapies ) achieved stable disease ( SD ) ≥ 6 months/partial response (PR)/complete response ( CR ) ( n = 5 ( 10 % ) with PR/CR ) : 9 of 32 ( 28 % ) with breast cancer ( n=5 ( 16 % ) with PR/CR ) ; 2 of 10 ( 20 % ) , ovarian cancer ; and 1 of 6 ( 17 % ) , endometrial cancer . Six of 22 patients ( 27 % ) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR . Six of 8 patients ( 75 % ) with SD ≥ 6 months/PR/CR with molecular testing demonstrated at least one alteration in the PI3K/AKT/mTOR pathway : mutations in PIK3CA ( n=3 ) and AKT1 ( n=1 ) or PTEN loss ( n=3 ) . All three responders ( CR ( n = 1 ) ; PR ( n=2 ) ) who had next generation sequencing demonstrated additional alterations : amplifications in CCNE1 , IRS2 , MCL1 , CCND1 , FGFR1 and MYC and a rearrangement in PRKDC . Conclusions : Combination anastrozole and everolimus is well tolerated at full approved doses , and is active in heavily-pretreated patients with ER and /or PR-positive breast , ovarian and endometrial cancers . Responses were observed in patients with multiple molecular aberrations . Clinical Trails Included : Background : Patients with recurrent/metastatic endometrial cancer that progresses after chemotherapy have limited treatment options and poor outcomes . Pre clinical data suggest the oral mammalian target of rapamycin inhibitor everolimus may provide clinical benefit in these patients . Methods : In this multicenter , open-label , phase 2 study , patients with advanced or metastatic endometrial cancer refractory to one or two previous chemotherapy regimens received everolimus 10 mg per day until progression or unacceptable toxicity . Primary end point was the non-progressive disease rate at 3 months . Secondary end points included duration of response , progression-free , and overall survival ( OS ) , and safety . Results : Forty-four patients were enrolled ( median age , 65 years ) ; 66 % received one previous chemotherapy regimen . The 3-month non-progressive disease rate was 36 % ( 95 % confidence interval 22–52 % ) , including two patients ( 5 % ) with partial response ( PR ) . At 6 months , two additional patients experienced PR . Median duration of response was 3.1 months . Median progression-free and OS were 2.8 months and 8.1 months , respectively . The most common adverse events were anaemia ( 100 % ) , fatigue ( 93 % ) , hypercholesterolaemia ( 81 % ) 
    Output:
    
mTOR inhibitors seem to be a promising option in the second line management of advanced gynecological cancers with best safety and efficacy outcomes when given as a single agent or in combination with hormonal treatment .