***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: Purpose To compare overall survival ( OS ) for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer . Patients and Methods The Fulvestrant First-Line Study Comparing Endocrine Treatments ( FIRST ) was a phase II , r and omized , open-label , multicenter trial . Postmenopausal women with estrogen receptor – positive , locally advanced/metastatic breast cancer who had no previous therapy for advanced disease received either fulvestrant 500 mg ( days 0 , 14 , 28 , and every 28 days thereafter ) or anastrozole 1 mg ( daily ) . The primary end point ( clinical benefit rate [ 72.5 % and 67.0 % ] ) and a follow-up analysis ( median time to progression [ 23.4 months and 13.1 months ] ) have been reported previously for fulvestrant 500 mg and anastrozole , respectively . Subsequently , the protocol was amended to assess OS by unadjusted log-rank test after approximately 65 % of patients had died . Treatment effect on OS across several subgroups was examined . Tolerability was evaluated by adverse event monitoring . Results In total , 205 patients were r and omly assigned ( fulvestrant 500 mg , n = 102 ; anastrozole , n = 103 ) . At data cutoff , 61.8 % ( fulvestrant 500 mg , n = 63 ) and 71.8 % ( anastrozole , n = 74 ) had died . The hazard ratio ( 95 % CI ) for OS with fulvestrant 500 mg versus anastrozole was 0.70 ( 0.50 to 0.98 ; P = .04 ; median OS , 54.1 months v 48.4 months ) . Treatment effects seemed generally consistent across the subgroups analyzed . No new safety issues were observed . Conclusion There are several limitations of this OS analysis , including that it was not planned in the original protocol but instead was added after time-to-progression results were analyzed , and that not all patients participated in additional OS follow-up . However , the present results suggest fulvestrant 500 mg extends OS versus anastrozole . This finding now awaits prospect i ve confirmation in the larger phase III FALCON ( Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast Cancer ) trial ( Clinical Trials.gov identifier : NCT01602380 ) 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 to ET in first-line treatment failed to produce a statistically significant increase in PFS or OS in women with HER2-negative/hormone receptor-positive advanced breast cancer BACKGROUND The BOLERO-2 study previously demonstrated that adding everolimus ( EVE ) to exemestane ( EXE ) significantly improved progression-free survival ( PFS ) by more than twofold in patients with hormone-receptor-positive ( HR(+ ) ) , HER2-negative advanced breast cancer that recurred or progressed during/after treatment with nonsteroidal aromatase inhibitors ( NSAIs ) . The overall survival ( OS ) analysis is presented here . PATIENTS AND METHODS BOLERO-2 is a phase III , double-blind , r and omized international trial comparing EVE 10 mg/day plus EXE 25 mg/day versus placebo ( PBO ) + EXE 25 mg/day in postmenopausal women with HR(+ ) advanced breast cancer with prior exposure to NSAIs . The primary end point was PFS by local investigator assessment ; OS was a key secondary end point . RESULTS At the time of data cutoff ( 3 October 2013 ) , 410 deaths had occurred and 13 patients remained on treatment .  Median OS in patients receiving EVE + EXE was 31.0 months [ 95 % confidence interval ( CI ) 28.0 - 34.6 months ] compared with 26.6 months ( 95 % CI 22.6 - 33.1 months ) in patients receiving PBO + EXE ( hazard ratio = 0.89 ; 95 % CI 0.73 - 1.10 ; log-rank P = 0.14 ) . Post study treatments were received by 84 % of patients in the EVE + EXE arm versus 90 % of patients in the PBO + EXE arm . Types of post study therapies were balanced across arms , except for chemotherapy ( 53 % EVE + EXE versus 63 % PBO + EXE ) . No new safety concerns were identified . CONCLUSIONS In BOLERO-2 , adding EVE to EXE did not confer a statistically significant improvement in the secondary end point OS despite producing a clinical ly meaningful and statistically significant improvement in the primary end point , PFS ( 4.6-months prolongation in median PFS ; P < 0.0001 ) . Ongoing translational research should further refine the benefit of mTOR inhibition and related pathways in this treatment setting . TRIAL REGISTRATION NUMBER NCT00863655 Fulvestrant fIRst-line Study comparing endocrine Treatments is a phase II , r and omized , open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line endocrine therapy for postmenopausal women with hormone receptor-positive ( HR+ ) advanced breast cancer . At data cut-off , only 36 % of patients had progressed and the median time to progression ( TTP ) had not been reached for fulvestrant . Here , we report follow-up data for TTP for fulvestrant 500 mg versus anastrozole 1 mg . Key inclusion criteria were postmenopausal women with estrogen receptor-positive and /or progesterone receptor-positive locally advanced or metastatic breast cancer and no prior endocrine therapy . Key exclusion criteria were presence of life-threatening metastases and prior treatment with a non-approved drug .  Fulvestrant was administered 500 mg/month plus 500 mg on day 14 of month 1 ; anastrozole was administered 1 mg/day . TTP was defined by modified Response Evaluation Criteria in Solid Tumors v1.0 before data cut-off for the primary analysis , and investigator opinion after data cut-off . Best overall response to subsequent therapy and serious adverse events are also reported . In total , 205 patients received fulvestrant 500 mg ( n = 102 ) or anastrozole ( n = 103 ) . Follow-up analysis was performed when 79.5 % of patients had discontinued study treatment . Median TTP was 23.4 months for fulvestrant versus 13.1 months for anastrozole ; a 34 % reduction in risk of progression ( hazard ratio 0.66 ; 95 % confidence interval : 0.47 , 0.92 ; P = 0.01 ) . Best overall response to subsequent therapy and clinical benefit rate for subsequent endocrine therapy was similar between the treatment groups . No new safety concerns for fulvestrant 500 mg were documented . These longer-term , follow-up results confirm efficacy benefit for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for HR+ advanced breast cancer in terms of TTP , and , importantly , show similar best overall response rates to subsequent endocrine therapy Introduction Effective treatments for hormone-receptor-positive ( HR+ ) breast cancer ( BC ) following relapse/progression on nonsteroidal aromatase inhibitor ( NSAI ) therapy are needed . Initial Breast Cancer Trials of OraL EveROlimus-2 ( BOLERO-2 ) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival ( PFS ) versus placebo plus exemestane alone in this patient population . Methods BOLERO-2 is a phase 3 , double-blind , r and omized , international trial comparing everolimus ( 10 mg/day ) plus exemestane ( 25 mg/day ) versus placebo plus exemestane in postmenopausal women with HR+ advanced BC with recurrence/progression during or after NSAIs . The primary endpoint was PFS by local investigator review , and was confirmed by independent central radiology review . Overall survival , response rate , and clinical benefit rate were secondary endpoints . Results Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [ investigator review : 7.8 versus 3.2 months , respectively ; hazard ratio = 0.45 ( 95 % confidence interval 0.38–0.54 ) ; log-rank P < 0.0001 ; central review : 11.0 versus 4.1 months , respectively ; hazard ratio = 0.38 ( 95 % confidence interval 0.31–0.48 ) ; log-rank P < 0.0001 ] in the overall population and in all prospect ively defined subgroups , including patients with visceral metastases , patients with recurrence during or within 12 months of completion of adjuvant therapy , and irrespective of age . The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials . Conclusion The addition of everolimus to exemestane markedly prolonged PFS in patients with HR+ advanced BC with disease recurrence/progression following prior NSAIs . These results further support the use of everolimus plus exemestane in this patient population . Clinical Trials.gov # NCT00863655 Background At the time of the initial analysis of overall survival ( OS ) for the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer ( CONFIRM ) r and omized , double-blind , phase III trial , approximately 50 % of patients had died . A final analysis of OS was subsequently planned for when 75 % of patients had died . Methods Patients were r and omly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on days 0 , 14 , and 28 and every 28 ( ±3 ) days thereafter or fulvestrant 250 mg administered as two 5-mL intramuscular injections ( one fulvestrant and one placebo [ identical in appearance to study drug ] ) on days 0 , 14 ( two placebo injections only ) , and 28 and every 28 ( ±3 ) days thereafter . OS was analyzed using an unadjusted log-rank test . No adjustments were made for multiplicity . Serious adverse events ( SAEs ) and best response to subsequent therapy were also reported . All statistical tests were two-sided . Results In total , 736 women ( median age = 61.0 years ) were r and omly assigned to fulvestrant 500 mg ( n = 362 ) or 250 mg ( n = 374 ) . At the final survival analysis , 554 of 736 ( 75.3 % ) patients had died . Median OS was 26.4 months for fulvestrant 500 mg and 22.3 months for 250 mg ( hazard ratio = 0.81 ; 95 % confidence interval = 0.69–0.96 ; nominal P = .02 ) . There were no clinical ly important differences in SAE profiles between the treatment groups ; no clustering of SAEs could be detected in either treatment group . Type of first subsequent therapy and objective 
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Overall survival ( OS ) improved with the use of mTOR inhibitors and a SERD ; however , studies were not powered for an OS endpoint .
Study discontinuation rates and toxicity-related deaths were highest with VEGF inhibitors in combination with endocrine therapy , limiting their use in hormone receptor positive breast cancer .
CDK4/6 inhibitors and mTOR inhibitors appeared to have activity in both first and second line setting s , but required additional monitoring for common toxicities .
The activity of epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors was limited to the first-line setting and treatment discontinuation rates were higher than with mTOR inhibitors and SERDs .
Overall , PFS benefit appears to be greatest when agents acting on CDK4/6 , mTOR and Pi3 K pathways , and SERDs are added to st and ard endocrine therapy .