***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: The article presents final analyses of overall survival from a phase III trial of lapatinib and capecitabine in patients with human epidermal growth factor receptor 2–positive locally advanced or metastatic breast cancer that progressed following prior therapy including trastuzumab 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 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 A r and omized Phase II study evaluated the activity of weekly paclitaxel versus its combination with trastuzumab for treatment of patients with advanced breast cancer overexpressing HER-2 . Patients and methods Among 124 patients r and omized , 123 are assessable for toxicity and 118 for response . Patients received weekly paclitaxel single agent ( 80 mg/m2 ) or combined with trastuzumab ( 4 mg/kg loading dose , then weekly 2 mg/kg ) . HER-2 overexpression was determined by immunohistochemistry ( IHC ) . Patients with 2+/3 + IHC scores were eligible . IHC was compared with HER-2 serum extracellular domain ( ECD ) . Results Patient characteristics were similar in the two arms . Both treatments were feasible and well tolerated with no grade 4 hematologic toxicity . No patient developed cardiac toxicity . The combined treatment was statistically significant superior for overall response rate ( ORR ) ( 75 % vs. 56.9 % ; P = 0.037 ) , particularly in the subset of IHC 3 + patients ( 84.5 % vs. 47.5 % ; P = 0.00050 ) . A statistically significant better median time to progression was seen in the subgroup with IHC 3 + ( 369 vs. 272 days ; P = 0.030 ) and visceral disease ( 301 vs. 183 days ; P = 0.0080 ) treated with combination . Multivariable analysis of predictive factors showed that only IHC score retained statistically significant value for ORR ( P = 0.0035 ) . Conclusion Weekly paclitaxel plus trastuzumab is highly active and safe and it is superior to paclitaxel alone in patients with IHC score of 3 + BACKGROUND mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss , by sensitising PTEN-deficient tumours to trastuzumab . The BOLERO-1 study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer . METHODS In this phase 3 , r and omised , double-blind trial , patients were enrolled across 141 sites in 28 countries . Eligible patients were aged 18 years or older , with locally assessed HER2-positive advanced breast cancer , with Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 - 1 , who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of r and omisation , had measurable disease as per Response Evaluation Criteria in Solid Tumors ( RECIST ) or bone lesions in the absence of measurable disease , without previous systemic treatment for advanced disease except endocrine therapy . Patients were r and omly assigned ( 2:1 ) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m(2 ) on days 1 , 8 , and 15 of each 4 week cycle . R and omisation was stratified according to previous use of trastuzumab and visceral metastasis . Patients and investigators were masked to the assigned treatments . Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging , labelling , appearance , and administration schedule . The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline ; the latter was added during the course of the study , before unmasking based on new clinical and biological findings from other studies . All efficacy analyses were based on the intention-to-treat population . Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here . This trial is registered with Clinical Trials.gov , number NCT00876395 . FINDINGS Between Sept 10 , 2009 , and Dec 16 , 2012 , 719 patients were r and omly assigned to receive everolimus ( n=480 ) or placebo ( n=239 ) . Median follow-up was 41·3 months ( IQR 35·4 - 46·6 ) . In the full population , median progression-free survival was 14·95 months ( 95 % CI 14·55 - 17·91 ) with everolimus versus 14·49 months ( 12·29 - 17·08 ) with placebo ( hazard ratio 0·89 , 95 % CI 0·73 - 1·08 ; p=0·1166 ) . In the HR-negative sub population ( n=311 ) , median progression-free survival with everolimus was 20·27 months ( 95 % CI 14·95 - 24·08 ) versus 13·08 months ( 10·05 - 16·56 ) with placebo ( hazard ratio 0·66 , 95 % CI 0·48 - 0·91 ; p=0·0049 ) ; however , the protocol -specified significance threshold ( p=0·0044 ) was not crossed . The most common adverse events with everolimus were stomatitis ( 314 [ 67 % ] of 472 patients in the everolimus group vs 77 [ 32 % ] of 238 patients in the placebo group ) , diarrhoea ( 267 [ 57 % ] vs 111 [ 47 % ] patients ) , and alopecia ( 221 [ 47 % ] vs 125 [ 53 % ] ) . The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia ( 117 [ 25 % ] vs 35 [ 15 % ] ) , stomatitis ( 59 [ 13 % ] vs three [ 1 % ] ) , anaemia ( 
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Albeit small , the gain in months of median PFS and median OS was significant .
Importantly , the results reported show large variation , and thus routinely applying a personalized approach seems warranted