***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: Introduction Activation of the phosphatidylinositol-3-kinase ( PI3 K ) and /or mitogen-activated protein kinase ( MAPK ) pathways results in anti-estrogen resistance in vitro , but a biomarker with clinical validity to predict intrinsic resistance has not been identified . In metastatic breast cancer patients with previous exposure to endocrine therapy  , the addition of a mammalian target of rapamycine ( mTOR ) inhibitor has been shown to be beneficial . Whether or not patients on adjuvant endocrine treatment might benefit from these drugs is currently unclear . A biomarker that predicts intrinsic resistance could potentially be used as companion diagnostic in this setting . We tested the clinical validity of different downstream-activated proteins in the PI3 K and /or MAPK pathways to predict intrinsic tamoxifen resistance in postmenopausal primary breast cancer patients . Methods We recollected primary tumor tissue from patients who participated in a r and omized trial of adjuvant tamoxifen ( 1–3 years ) versus observation .  After constructing a tissue micro-array , cores from 563 estrogen receptor α positive were immunostained for p-AKT(Thr308 ) , p-AKT(Ser473 ) , p-mTOR , p-p706SK and p-ERK1/2 . Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interactions between these markers and tamoxifen treatment efficacy . Results Interactions were identified between tamoxifen and p-AKT(Thr308 ) , p-mTOR , p-p70S6 K and p-ERK1/2 . Applying a conservative level of significance , p-p70S6 K remained significantly associated  with tamoxifen resistance . Patients with p-p70S6 K negative tumors derived significant benefit from tamoxifen ( HR 0.24 , P < 0.0001 ) , while patients whose tumor did express p-p70S6 K did not ( HR = 1.02 , P = 0.95 ) , P for interaction 0.004 . In systemically untreated breast cancer patients , p-p70S6 K was associated with a decreased risk for recurrence . Conclusions Patients whose tumor expresses p-p70S6 K , as a marker of downstream PI3 K and /or MAPK pathway activation , have a favorable prognosis , but do not benefit from adjuvant tamoxifen . A potential benefit from inhibitors of the PI3K/Akt/mTOR pathway in these patients needs to be further explored Background and purpose There are scarce data available on the prognostic/predictive value of p-Akt and p-mTOR protein expression in patients with high-risk early breast cancer . Patients and methods Formalin-fixed paraffin-embedded ( FFPE ) tumor tissue sample s from 997 patients participating in two adjuvant phase III trials were assessed for EGFR , PTEN , p-Akt , p-mTOR protein expression , and PIK3CA mutational status . These markers were evaluated for associations with each other and with selected patient and tumor characteristics , immunohistochemical subtypes , disease-free survival ( DFS ) , and overall survival ( OS ) . Results  p-mTOR protein expression was negatively associated with EGFR and positively associated with PTEN , with p-Akt473 , and with the presence of PIK3CA mutations . EGFR expression was positively associated with p-Akt473 , p-Akt308 , and PIK3CA wild-type tumors . Finally , p-Akt308 was positively associated with p-Akt473 expression . In univariate analysis , EGFR ( p = 0.016 ) and the coexpression of EGFR and p-mTOR ( p = 0.015 ) were associated with poor OS . Among patients with p-Akt308-negative or low-expressing tumors , those treated with hormonal therapy were associated with decreased risk for both relapse and death ( p = 0.013 and p < 0.001 , respectively ) . In the subgroup of patients with locoregional relapse , positive EGFR and mTOR protein expression was found to be associated with increased ( p = 0.034 ) and decreased ( p < 0.001 ) risk for earlier relapse , respectively . In multivariate analysis , low levels of p-Akt308 and the coexpression of EGFR and p-mTOR retained their prognostic value . Conclusion Low protein expression of p-Akt308 was associated with improved DFS and OS among patients treated with hormonal therapy following adjuvant chemotherapy .  Coexpression of EGFR and p-mTOR was associated with worse OS.ZusammenfassungHintergrundGeringe Date n existieren über den prognostischen/prädiktiven Wert der p-Akt- und p-mTOR-Proteinexpression bei Patienten mit “ High-risk”-Mammakarzinom i m Frühstadium . Patienten und Method enFormalinfixierte und in Paraffin eingebettete ( FFPE ) Tumorgewebeproben von 997 Patienten , welche i m Rahmen von 2 adjuvanten Phase-III-Studien zytostatisch beh and elt wurden , wurden auf EGFR , PTEN , p-Akt , pmTOR und PIK3CA-Mutationsstatus untersucht . Diese Marker wurden in Assoziation mit ausgewählten Patienten- und Tumorcharakteristika , immunhistochemischen Mammakarzinomsubtypen , dem krankheitsfreien Überleben ( DFS ) sowie dem Gesamtüberleben ( OS ) evaluiert . ErgebnisseDie Expression von p-mTOR war negativ mit der Expression von EGFR , jedoch signifikant positiv mit PTEN und p-Akt473 sowie dem Nachweis von PIK3CA-Mutationen assoziiert . Die EGFR-Expression war signifikant positiv mit der Proteinexpression von p-Akt473 und p-Akt308 sowie PIK3CA-Wildtyp-Tumoren assoziiert . Die p-Akt308-Expression war ebenfalls signifikant positiv mit der Expression von p-Akt473 assoziiert . In der univariaten Analyse war sowohl die EGFR ( p = 0,016 ) , als auch die Koexpression von EGFR und p-mTOR ( p = 0,015 ) mit einem schlechteren OS assoziiert . Unter den Patienten mit p-Akt308-negativen oder gering exprimierenden Tumoren konnte bei denjenigen , die mit einer Hormontherapie beh and elt wurden , ein signifikant vermindertes Risiko für ein Rezidiv als auch für den Tod ( jeweils p = 0,013 und p < 0,001 ) nachgewiesen werden . In der Subgruppenanalyse von Patienten mit lokoregionärem Rezidiv konnte eine Assoziation von positivem EGFR-Status sowie mTOR-Expression mit einem jeweils erhöhten ( p = 0,034 ) bzw . verminderten ( p < 0,001 ) Risiko für das Auftreten von Frührezidiven nachgewiesen werden . In der multivariaten Analyse behielten die niedrigen p-Akt308-Werte und die Koexpression von EGFR und p-mTOR ihren prognostischen Wert . FazitEine niedrige Expression von p-Akt308 bei Patienten , die eine Hormontherapie nach einer adjuvanten Chemotherapie erhielten , war mit einem verbesserten DFS und OS assoziiert . Die Koexpression von EGFR und p-mTOR war mit einem schlechteren OS assoziiert In a phase 3 , double-blind , r and omized , international study ( the BOLERO-2 ) , the addition of mTOR inhibitor everolimus to exemestane was evaluated in postmenopausal women with estrogen-receptor-positive ( ER⁺ ) advanced/recurrent breast cancer that was refractory to any nonsteroidal aromatase inhibitor ( NSAI ) . This report presents the safety and up date d ( 18- month ) efficacy results from the Japanese subset ( n=106 ) of BOLERO-2 . After a median follow-up of 18 months , the median progression-free survival time was 8.5 months with everolimus plus exemestane compared to 4.2 months with placebo plus exemestane . The most common adverse events ( AEs ) with everolimus plus exemestane were stomatitis , rash , dysgeusia , and non-infectious lung disease . The AEs reported with the combination therapy were mostly of grade 1 or 2 and manageable with appropriate intervention . In conclusion , this combination could be a useful addition to the armamentarium of treatments for Japanese postmenopausal women with ER⁺ advanced/recurrent breast cancer progressing on NSAIs BACKGROUND Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin ( mTOR ) intracellular signaling pathway . In early studies , the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity . METHODS In this phase 3 , r and omized trial , we compared everolimus and exemestane versus exemestane and placebo ( r and omly assigned in a 2:1 ratio ) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease ( or both ) . The primary end point was progression-free survival . Secondary end points included survival , response rate , and safety . A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed . RESULTS Baseline characteristics were well balanced between the two study groups . The median age was 62 years , 56 % had visceral involvement , and 84 % had hormone-sensitive disease . Previous therapy included letrozole or anastrozole ( 100 % ) , tamoxifen ( 48 % ) , fulvestrant ( 16 % ) , and chemotherapy ( 68 % ) . The most common grade 3 or 4 adverse events were stomatitis ( 8 % in the everolimus-plus-exemestane group vs. 1 % in the placebo-plus-exemestane group ) , anemia ( 6 % vs. < 1 % ) , dyspnea ( 4 % vs. 1 % ) , hyperglycemia ( 4 % vs. < 1 % ) , fatigue ( 4 % vs. 1 % ) , and pneumonitis ( 3 % vs. 0 % ) . At the interim analysis , median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane , according to assessment s by local investigators ( hazard ratio for progression or death , 0.43 ; 95 % confidence interval [ CI ] , 0.35 to 0.54 ; P<0.001 ) . Median progression-free survival was 10.6 months and 4.1 months , respectively , according to central assessment ( hazard ratio , 0.36 ; 95 % CI , 0.27 to 0.47 ; P<0.001 ) . CONCLUSIONS Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors . ( Funded by Novartis ; BOLERO-2 Clinical Trials.gov number , NCT00863655 . ) BACKGROUND Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway . We aim ed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to trastuzumab . METHODS In this r and omised , double-blind , placebo-controlled , phase 3 trial , we recruited women with HER2-positive , trastuzumab-resistant , advanced breast carcinoma who had previously received taxane therapy . Eligible patients were r and omly assigned ( 1:1 ) using a central patient screening and r and omisation system to daily everolimus ( 5 mg/day ) plus weekly trastuzumab ( 2 mg/kg ) and vinorelbine ( 25 mg/m(2 ) ) or to placebo plus trastuzumab plus vinorelbine , in 3-week cycles , stratified by previous lapatinib use . The primary endpoint was progression-free survival ( PFS ) by local assessment in the intention-to-treat population . We report the final analysis for PFS ; overall survival follow-up is still in progress . This trial is registered with Clinical Trials.gov , number NCT01007942 . FINDINGS Between Oct 26 , 2009 , and May 23 , 2012 , 569 patients were r and omly assigned to everolimus ( n=284 ) or placebo ( n=285 ) . Median follow-up at the time of analysis was 20.2 months ( IQR 15.0 - 27.1 ) . Median PFS was 7.00 months ( 95 % CI 6.74 - 8.18 ) with everolimus and 5.78 months ( 5.49 - 6.90 ) with placebo ( hazard ratio 0.78 [ 95 % CI 0.65 - 0.95 ] ; p=0.0067 ) . The 
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Our findings suggested that p-mTOR overexpression was not significantly related to prognosis in breast carcinoma regarding OS and disease recurrence .