***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 Neratinib , an irreversible tyrosine-kinase inhibitor of HER1 , HER2 , and HER4 , has clinical activity in patients with HER2-positive metastatic breast cancer . We aim ed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer . METHODS We did this multicentre , r and omised , double-blind , placebo-controlled , phase 3 trial at 495 centres in Europe , Asia , Australia , New Zeal and , and North and South America . Eligible women ( aged ≥18 years , or ≥20 years in Japan ) had stage 1 - 3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before r and omisation . Inclusion criteria were amended on Feb 25 , 2010 , to include patients with stage 2 - 3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously . Patients were r and omly assigned ( 1:1 ) to receive oral neratinib 240 mg per day or matching placebo . The r and omisation sequence was generated with permuted blocks stratified by hormone receptor status ( hormone receptor-positive [ oestrogen or progesterone receptor-positive or both ] vs hormone receptor-negative [ oestrogen and progesterone receptor-negative ] ) , nodal status ( 0 , 1 - 3 , or ≥4 ) , and trastuzumab adjuvant regimen ( sequentially vs concurrently with chemotherapy ) , then implemented central ly via an interactive voice and web-response system . Patients , investigators , and trial sponsors were masked to treatment allocation . The primary outcome was invasive disease-free survival , as defined in the original protocol , at 2 years after r and omisation . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00878709 . FINDINGS Between July 9 , 2009 , and Oct 24 , 2011 , we r and omly assigned 2840 women to receive neratinib ( n=1420 ) or placebo ( n=1420 ) . Median follow-up time was 24 months ( IQR 20 - 25 ) in the neratinib group and 24 months ( 22 - 25 ) in the placebo group . At 2 year follow-up , 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group ( stratified hazard ratio 0·67 , 95 % CI 0·50 - 0·91 ; p=0·0091 ) . The 2-year invasive disease-free survival rate was 93·9 % ( 95 % CI 92·4 - 95·2 ) in the neratinib group and 91·6 % ( 90·0 - 93·0 ) in the placebo group . The most common grade 3 - 4 adverse events in patients in the neratinib group were diarrhoea ( grade 3 , n=561 [ 40 % ] and grade 4 , n=1 [ < 1 % ] vs grade 3 , n=23 [ 2 % ] in the placebo group ) , vomiting ( grade 3 , n=47 [ 3 % ] vs n=5 [ < 1 % ] ) , and nausea ( grade 3 , n=26 [ 2 % ] vs n=2 [ < 1 % ] ) . QT prolongation occurred in 49 ( 3 % ) patients given neratinib and 93 ( 7 % ) patients given placebo , and decreases in left ventricular ejection fraction ( ≥ grade 2 ) in 19 ( 1 % ) and 15 ( 1 % ) patients , respectively . We recorded serious adverse events in 103 ( 7 % ) patients in the neratinib group and 85 ( 6 % ) patients in the placebo group . Seven ( < 1 % ) deaths ( four patients in the neratinib group and three patients in the placebo group ) unrelated to disease progression occurred after study drug discontinuation . The causes of death in the neratinib group were unknown ( n=2 ) , a second primary brain tumour ( n=1 ) , and acute myeloid leukaemia ( n=1 ) , and in the placebo group were a brain haemorrhage ( n=1 ) , myocardial infa rct ion ( n=1 ) , and gastric cancer ( n=1 ) . None of the deaths were attributed to study treatment in either group . INTERPRETATION Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer . Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained . FUNDING Wyeth , Pfizer , Puma Biotechnology PURPOSE To evaluate the prognostic and predictive significance of plasma levels of the epidermal growth factor receptor ( EGFR ) lig and s , transforming growth factor α ( TGF-α ) and amphiregulin , in patients with non-small-cell lung cancer ( NSCLC ) enrolled in NCIC Clinical Trials Group BR.21 comparing erlotinib with placebo . PATIENTS AND METHODS TGF-α and amphiregulin were assessed retrospectively by enzyme-linked immunosorbent assay from available prospect ively collected baseline plasma sample s in 565 of 731 BR.21 patients . Cutoff points were determined for both amphiregulin ( low , < 10 pg/mL ; high , ≥10 pg/mL ) and TGF-α ( low , ≤12 pg/mL ; high , > 12 pg/mL ) using a graphical method . Cox regression models were used to correlate biomarker data and baseline characteristics with outcomes including overall ( OS ) and progression-free survival ( PFS ) . RESULTS High TGF-α and amphiregulin were associated with poorer performance status ( P=.06 and P<.0001 , respectively ) and no prior platinum therapy ( P=.06 and P=.02 , respectively ) . High amphiregulin was also associated with anemia ( P=.001 ) , increased lactate dehydrogenase ( P=.03 ) , ever-smokers ( P=.04 ) , and non-Asian ethnicity ( P=.001 ) . Patients on the placebo arm with high amphiregulin had poorer OS than patients with low amphiregulin ( hazard ratio [HR]=1.88 ; 95 % CI , 1.34 to 2.64 ; P=.0002 ) , which remained significant in multivariate  analysis . Amphiregulin levels did not predict for benefit from erlotinib ( interaction P=.87 ) . Conversely , TGF-α levels did not have prognostic significance , but high TGF-α predicted lack of benefit from erlotinib compared with low TGF-α ( TGF-α low , OS HR=0.66 ; 95 % CI , 0.54 to 0.81 ; P<.0001 ; high , OS HR=1.32 ; 95 % CI , 0.73 to 2.39 ; P=.36 ; interaction P=.04 ) . CONCLUSION High baseline amphiregulin is a poor prognostic factor , whereas high baseline TGF-α predicts for lack of benefit from erlotinib in advanced NSCLC Introduction Breast cancer is the most common type of cancer seen in women in western countries . Thus , diagnostic modalities sensitive to early-stage breast cancer are needed . Antibody-based array platforms of a data -driven type , which are expected to facilitate more rapid and sensitive detection of novel biomarkers , have emerged as a direct , rapid means for profiling cancer-specific signatures using small sample s. In line with this concept , our group constructed an antibody bead array panel for 35 analytes that were selected during the discovery step . This study was aim ed at testing the performance of this 35-plex array panel in profiling signatures specific for primary non-metastatic breast cancer and validating its diagnostic utility in this independent population . Methods Thirty-five analytes were selected from more than 50 markers through screening steps using a serum bank consisting of 4,500 sample s from various types of cancer .  An antibody-bead array of 35 markers was constructed using the Luminex ™ bead array platform .  A study population consisting of 98 breast cancer patients and 96 normal subjects was analysed using this panel . Multivariate classification algorithms were used to find discriminating biomarkers and vali date d with another independent population of 90 breast cancer and 79 healthy controls . Results Serum concentrations of epidermal growth factor , soluble CD40-lig and and proapolipoprotein A1 were increased in breast cancer patients . High-molecular-weight-kininogen , apolipoprotein A1 , soluble vascular cell adhesion molecule-1 , plasminogen activator inhibitor-1 , vitamin-D binding protein and vitronectin were decreased in the cancer group . Multivariate classification algorithms distinguished breast cancer patients from the normal population with high accuracy ( 91.8 % with r and om forest , 91.5 % with support vector machine , 87.6 % with linear discriminant analysis ) . Combinatorial markers also detected breast cancer at an early stage with greater sensitivity . Conclusions The current study demonstrated the usefulness of the antibody-bead array approach in finding signatures specific for primary non-metastatic breast cancer and illustrated the potential for early , high sensitivity detection of breast cancer . Further validation is required before array-based technology is used routinely for early detection of breast cancer BACKGROUND Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer ( NSCLC ) with activating EGFR mutations . We aim ed to assess the safety and efficacy of erlotinib compared with st and ard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC . METHODS We undertook the open-label , r and omised phase 3 EURTAC trial at 42 hospitals in France , Italy , and Spain . Eligible participants were adults ( > 18 years ) with NSCLC and EGFR mutations ( exon 19 deletion or L858R mutation in exon 21 ) with no history of chemotherapy for metastatic disease ( neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed ) . We r and omly allocated participants ( 1:1 ) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of st and ard intravenous chemotherapy of cisplatin 75 mg/m(2 ) on day 1 plus docetaxel ( 75 mg/m(2 ) on day 1 ) or gemcitabine ( 1250 mg/m(2 ) on days 1 and 8) . Carboplatin ( AUC 6 with docetaxel 75 mg/m(2 ) or AUC 5 with gemcitabine 1000 mg/m(2 ) ) was allowed in patients unable to have cisplatin . Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status ( 0 vs 1 vs 2 ) . The primary endpoint was progression-free survival ( PFS ) in the intention-to-treat population . We assessed safety in all patients who received study drug ( ≥ 1 dose ) . This study is registered with Clinical Trials.gov , number NCT00446225 . FINDINGS Between Feb 15 , 2007 , and Jan 4 , 2011 , 174 patients with EGFR mutations were enrolled . One patient received treatment before r and omisation and was thus withdrawn from the study ; of the remaining patients , 86 were r and omly assigned to receive erlotinib and 87 to receive st and ard chemotherapy . The preplanned interim analysis showed that the study met its primary endpoint ; enrolment was halted , and full evaluation of the results was recommended . At data cutoff ( Jan 26 , 2011 ) , median PFS was 9·7 months ( 95 % CI 8·4 - 12·3 ) in the erlotinib group , compared with 5·2 months ( 4·5 - 5·8 ) in the st and ard chemotherapy group ( hazard ratio 0·37 , 95 % CI 0·25 - 0·54 ; p < 0·0001 ) . Main grade 3 or 4 toxicities were rash ( 11 [ 13 % ] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group ) , neutropenia ( none vs 18 [ 22 % ] ) , anaemia ( one [ 1 % ] vs three [ 4 % ] ) , and increased amino-transferase concentrations ( two [ 2 % ] vs 0 ) . Five ( 6 % ) patients on erlotinib  had treatment-related severe adverse events compared with 16 patients ( 20 % ) on chemotherapy . One patient in the erlotinib group and two in the st and ard chemotherapy group died from treatment-related causes . INTERPRETATION Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors . FUNDING Spanish Lung Cancer Group , Roche Farma , Hoffmann-La Roche , and Red Temática de 
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Twelve studies evaluated EGFR , whereas five studies evaluated one or more of the EGFR-lig and s. Current evidence indicates associations between low baseline serum-EGFR and shorter survival or reduced response to treatment in patients with advanced breast cancer , especially in patients with estrogen and /or progesterone receptor positive tumors .
This is the first systematic review evaluating the utility of EGFR and EGFR-lig and s as predictive and prognostic biomarkers in blood in breast cancer .