***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 Immunohistochemistry of primary breast cancer is routinely used to guide changes in therapy at the time of relapse . Retrospective review s suggest that the estrogen receptor ( ER ) , progesterone receptor ( PR ) and human epidermal growth factor receptor type 2 ( HER2 ) receptor may differ between the primary and loco-regional recurrence or distant metastases . The Breast Recurrence In Tissues Study ( BRITS ) was a large , multicentre , prospect i ve study to examine changes in ER , PR and HER2 . Methods Matched primary and recurrent breast cancer tissue sample s were prospect ively collected from 205 women attending 20 institutions . Central laboratory immunohistochemical analysis of core biopsies and tissue microarrays of ER and PR using the Allred and Quickscore methods and HER2 ( confirmed by fluorescence in situ hybridisation ( FISH ) for HER2 2 + ) were performed . Results From 205 consenting women , 18 ( 8.8 % ) did not have recurrent disease on biopsy , 35 were ineligible , 13 had insufficient paired tissue and 2 were excluded for safety reasons . Paired sample s from 137 women , mean age 62.6 years ( range 27 - 87 years ) , 83/137 ( 60.6 % ) postmenopausal with a median 92.2 months ( range 5 - 327 months ) from primary to recurrence and 88 ( 64.2 % ) as locoregional recurrence were successfully analysed . A switch in receptor status , in either direction , by Allred score , was identified for ER in 14 patients ( 10.2 % ; P = 0.983 Wilcoxon sign rank test ) , PR in 34 ( 24.8 % ; P = 0.003 Wilcoxon sign rank test ) and HER2 in 4 ( 2.9 % ; P = 0.074 Wilcoxon sign rank test ) . There was no difference between locoregional or distant recurrence in the proportion who switched . The switch in receptor status led to a change in the subsequent treatment plan for 24 patients ( 17.5 % ) . Conclusions This prospect i ve study confirms retrospective evidence that the management of relapsed breast cancer should include confirmatory tissue sampling and identify switches of ER , PR or HER2 which change therapeutic management for one in six patients PURPOSE To investigate whether dose escalation of megestrol acetate ( MA ) improves response rate and survival in comparison with st and ard doses of MA . PATIENTS AND METHODS Three hundred sixty-eight patients with metastatic breast cancer , positive and /or unknown estrogen and progesterone receptors , zero or one prior trial of hormonal therapy , and no prior chemotherapy for metastatic disease were prospect ively r and omized into three groups . The groups of patients received either MA 160 mg/d ( one tablet per day ) , MA 800 mg/d ( five tablets per day ) , or MA 1,600 mg/d ( 10 tablets per day ) . RESULTS Patient characteristics were well balanced in the three treatment groups . Three hundred sixty-six patients received treatment and were included in the analyses . The response rates were 23 % , 27 % , and 27 % for the 160-mg , 800-mg , and 1,600-mg arms , respectively . Response duration correlated inversely with dose . Median duration s of response were 17 months , 14 months , and 8 months for the 160-mg , 800-mg , and 1,600-mg arms , respectively . No significant differences in the treatment arms were noted for time to disease progression or for survival ; survival medians were 28 months ( low dose ) , 24 months ( mid dose ) and 29 months ( high dose ) . The most frequent and troublesome toxicity , weight gain , was dose-related , with approximately 20 % of patients on the two higher-dose arms reporting weight gain of more than 20 % of their pre study weight , compared with only 2 % in the 160-mg dose arm . CONCLUSION With a median follow-up of 8 years , these results demonstrate no advantage for dose escalation of MA in the treatment of metastatic breast cancer 155 Background : The phase III BOLERO-2 study at 18 months ' median follow-up showed that everolimus ( EVE ) + exemestane ( EXE ) significantly improved progression-free survival ( PFS ) vs EXE alone in 724 patients with hormone receptor-positive ( HR+ ) advanced breast cancer ( ABC ) with recurrence/progression during/after nonsteroidal aromatase inhibitor ( NSAI ) therapy . A higher rate of grade 3/4 adverse events was noted with EVE + EXE but was not associated with deterioration in quality of life ( QOL ) based on the EORTC QLQ-C30 Global Health Status scale . Additional patient-reported post hoc analyses of QOL are reported herein . METHODS During BOLERO-2 , QOL ( EORTC QLQ-C30 and QLQ-BR23 ) was assessed at baseline and q 6 wk thereafter until progression or discontinuation . Physical , emotional , and social functioning subscales of QLQ-C30 were analyzed . Time to definitive deterioration ( TTD ) was defined based on either a 5 % ( protocol -specified ) or a 10-point ( more stringent ) decrease from baseline for each subscale and analyzed by Kaplan-Meier methods . The difference between treatments was assessed by a log-rank test stratified by r and omization factors . RESULTS QLQ-C30 compliance was > 80 % at week 48 . Among the 3 protocol -specified QLQ-C30 subscales , analyses based on a 5 % decrease in QOL showed a longer TTD for both physical and emotional functioning in the EVE + EXE group vs EXE alone ( log-rank p = 0.0120 and p = 0.0277 , respectively ) . The TTDs for social functioning were similar in both treatment arms ( log-rank p = 0.3374 ) . Analyses based on a 10-point decrease indicated a longer TTD for physical functioning in the EVE + EXE group ( 15.2 mo ) vs EXE alone ( 9.7 mo ; log-rank p = 0.0211 ) . The TTDs for emotional and social functioning were similar between EVE + EXE and EXE alone : 13.9 vs 13.8 , respectively ( log-rank p = 0.4023 ) , and 11.5 vs 9.5 , respectively ( log-rank p = 0.2507 ) . CONCLUSIONS The treatment goal for ABC is to maximize clinical benefit with minimal negative effects on QOL . These additional BOLERO-2 QOL analyses confirmed that the more than doubling of PFS with EVE + EXE was accompanied by maintained physical , emotional , and social functioning compared with EXE alone in patients with HR+ ABC progressing after NSAI . CLINICAL TRIAL INFORMATION NCT00863655 The aromatase inhibitors exemestane and anastrozole are approved in Japan for first-line treatment of postmenopausal patients with advanced , hormone-receptor-positive breast cancer . This phase 3 , r and omized , double-blind study directly compared time to progression ( TTP ) for exemestane and anastrozole therapy in this patient population . Eligible patients were r and omized to receive exemestane 25 mg or anastrozole 1 mg , each once daily . The primary endpoint was TTP based on assessment by an expert radiologic images review committee ( ERIRC ) . Secondary endpoints included investigator-assessed TTP , time to treatment failure , overall survival , objective response rate , clinical benefit rate , and safety .  A total 298 patients were r and omized to receive exemestane ( n = 149 ; mean age 63.4 years ) or anastrozole ( n = 149 ; mean age 64.0 years ) .  Median ERIRC-assessed TTP was 13.8 and 11.1 months ( hazard ratio = 1.007 ; 95 % confidence interval [ CI ] : 0.771 , 1.317 ) and median investigator-assessed TTP was 13.8 and 13.7 months ( hazard ratio = 1.059 ; 95 % CI : 0.816 , 1.374 ) in the exemestane and anastrozole arms , respectively . Median overall survival was 60.1 months in the anastrozole arm and was not reached in the exemestane arm at data cutoff . The objective response rate was 43.9 % ( 95 % CI : 35.3 , 52.8 ) and 39.1 % ( 95 % CI : 30.6 , 48.1 ) in the exemestane and anastrozole arms , respectively . Treatment-related adverse events grade ≥3 occurred in 9.4 and 6.0 % of patients , and treatment-related serious adverse events occurred in 4.0 and 3.4 % of patients in the exemestane and anastrozole arms , respectively . In this study , the efficacy and safety profiles of exemestane were similar to those of anastrozole in Japanese patients with advanced , hormone-receptor-positive breast cancer ; however , TTP non-inferiority of exemestane versus anastrozole was not confirmed BACKGROUND FINDER1 compared efficacy , tolerability and pharmacokinetics ( PK ) of three fulvestrant dose regimens in postmenopausal Japanese women with estrogen receptor (ER)-positive locally advanced/metastatic breast cancer recurring or progressing after prior endocrine therapy . PATIENTS AND METHODS The primary end point of this r and omised , multicentre , phase II study was objective response rate ( ORR ) and the secondary end points included time to progression ( TTP ) , clinical benefit rate ( CBR ) , PK profiles and tolerability .  Postmenopausal women with ER-positive advanced breast cancer were r and omised to 28-day cycles of fulvestrant approved dose ( AD ) , loading dose ( LD ) or high dose ( HD ) until disease progression . RESULTS Hundred and forty-three patients ( median age 61 years ) received fulvestrant AD ( n = 45 ) , LD ( n = 51 ) or HD ( n = 47 ) . ORR was similar across dose regimens : 11.1 % , 17.6 % and 10.6 % for AD , LD and HD , respectively , with overlapping confidence intervals . TTP and CBR were also similar between groups ( median TTP : 6.0 , 7.5 and 6.0 months , respectively ; CBR : 42.2 % , 54.9 % and 46.8 % for AD , LD and HD , respectively ) . C(max ) and area under the plasma concentration-time curve were dose proportional and PK steady state was reached earlier with LD and HD than with AD . All three doses were well tolerated , with a similar adverse-event profile and no emerging safety concerns . CONCLUSION Fulvestrant AD , LD and HD had similar efficacy and tolerability profiles in postmenopausal Japanese women with ER-positive advanced breast cancer PURPOSE To test whether combining bevacizumab , an anti-vascular endothelial growth factor treatment , with endocrine therapy ( ET ) could potentially delay the emergence of resistance to ET . PATIENTS AND METHODS A multicenter , r and omized , open-label , phase III , binational ( Spain and Germany ) study added bevacizumab ( 15 mg/kg every 3 weeks ) to ET ( ET-B ; letrozole or fulvestrant ) as first-line therapy in postmenopausal patients with human epidermal growth factor receptor 2 ( HER2 ) -negative and hormone receptor-positive advanced breast cancer . We compared progression-free survival ( PFS ) , overall survival ( OS ) , overall response rate ( ORR ) , response duration ( RD ) , time to treatment failure ( TTF ) , clinical benefit rate ( CBR ) , and safety . RESULTS From 380 patients recruited ( 2007 to 2011 ) , 374 were analyzed by intent to-treat ( 184 patients on ET and 190 patients on ET-B ) . Median age was 65 years , 270 patients ( 72 % ) had Eastern Cooperative Oncology Group performance status of 0 , 178 patients ( 48 % ) had visceral metastases , and 171 patients ( 46 % ) and 195 patients ( 52 % ) had received prior chemotherapy or ET , respectively . Median PFS was 14.4 months in the ET arm and 19.3 months in the ET-B arm ( hazard ratio , 0.83 ; 95 % CI , 0.65 to 1.06 ; P = .126 ) . ORR , CBR , and RD with ET versus ET-B were 22 % versus 41 % ( P < .001 ) , 67 % versus 77 % ( P = .041 ) , and 13.3 months versus 17.6 months ( P = .434 ) , respectively . TTF and OS were comparable in both arms . Grade 3 to 4 hypertension , aminotransferase elevation , and proteinuria were significantly higher in the ET-B arm . Eight patients ( 4.2 % ) receiving ET-B died during study or within 30 days of end of treatment . CONCLUSION The addition of bevacizumab 
    Output:
    
Among patients with HR-positive , human epidermal growth factor receptor 2-positive MBC , human epidermal growth factor receptor 2-targeted therapy plus an AI can be effective for those who are not chemotherapy c and i date