***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 : All patients with EGF receptor (EGFR)–mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors ( TKI ) . Smaller series have identified various mechanisms of resistance , but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted . Experimental Design : Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib  enrolled onto a prospect i ve biopsy protocol and underwent a rebiopsy after the development of acquired resistance . Histology was review ed . Sample s underwent genotyping for mutations in EGFR , AKT1 , BRAF , ERBB2 , KRAS , MEK1 , NRAS and PIK3CA , and FISH for MET and HER2 . Results : Adequate tumor sample s for molecular analysis were obtained in 155 patients . Ninety-eight had second-site EGFR T790 M mutations [ 63 % ; 95 % confidence interval ( CI ) , 55%–70 % ] and four had small cell transformation ( 3 % , 95 % CI , 0%–6 % ) . MET amplification was seen in 4 of 75 ( 5 % ; 95 % CI , 1%–13 % ) . HER2 amplification was seen in 3 of 24 ( 13 % ; 95 % CI , 3%–32 % ) . We did not detect any acquired mutations in PIK3CA , AKT1 , BRAF , ERBB2 , KRAS , MEK1 , or NRAS ( 0 of 88 , 0 % ; 95 % CI , 0%–4 % ) . Overlap among mechanisms of acquired resistance was seen in 4 % . Conclusions : This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy . We identified EGFR T790 M as the most common mechanism of acquired resistance , whereas MET amplification , HER2 amplification , and small cell histologic transformation occur less frequently . More comprehensive methods to characterize molecular alterations in this setting are needed to improve our underst and ing of acquired resistance to EGFR-TKIs . Clin Cancer Res ; 19(8 ) ; 2240–7 . © 2013 AACR BACKGROUND Previous , uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer . METHODS In this phase 3 , open-label study , we r and omly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib ( 250 mg per day ) ( 609 patients ) or carboplatin ( at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute ) plus paclitaxel ( 200 mg per square meter of body-surface area ) ( 608 patients ) . The primary end point was progression-free survival . RESULTS The 12-month rates of progression-free survival were 24.9 % with gefitinib and 6.7 % with carboplatin-paclitaxel . The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority , as compared with carboplatin-paclitaxel , with respect to progression-free survival in the intention-to-treat population ( hazard ratio for progression or death , 0.74 ; 95 % confidence interval [ CI ] , 0.65 to 0.85 ; P<0.001 ) . In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene ( EGFR ) mutation , progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel ( hazard ratio for progression or death , 0.48 ; 95 % CI , 0.36 to 0.64 ; P<0.001 ) , whereas in the subgroup of 176 patients who were negative for the mutation , progression-free survival was significantly longer among those who received carboplatin-paclitaxel ( hazard ratio for progression or death with gefitinib , 2.85 ; 95 % CI , 2.05 to 3.98 ; P<0.001 ) . The most common adverse events were rash or acne ( in 66.2 % of patients ) and diarrhea ( 46.6 % ) in the gefitinib group and neurotoxic effects ( 69.9 % ) , neutropenia ( 67.1 % ) , and alopecia ( 58.4 % ) in the carboplatin-paclitaxel group . CONCLUSIONS Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia . The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib . ( Clinical Trials.gov number , NCT00322452 . OBJECTIVES Epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKIs ) have been shown to be effective for the treatment of EGFR mutation-positive non-small cell lung cancer ( NSCLC ) in clinical trials . However , there is a lack of data from routine clinical practice . This study determined treatment and outcomes in patients with EGFR mutation-positive NSCLC treated in a real world setting . MATERIAL S AND METHODS Clinical characteristics , information about NSCLC treatment regimens and survival outcomes data were obtained retrospectively from 17 medical centers across Japan . In addition to overall survival ( OS ) , subgroup analyses were conducted based on first- and second-line treatments and combinations , and for patients who had survived > 5 years from initiation of first-line treatment . RESULTS The full analysis set comprised 1656 patients ( mean 67 years , 80.6 % with performance status 0 or 1 ) . Median follow-up was 29.5 months and median OS was 29.7 months ; 3- and 5-year survival rates were 41.2 % and 21.5 % , respectively . Significant predictors of OS were younger age , no smoking history , histological diagnosis of adenocarcinoma , less advanced clinical stage , good performance status and major EGFR-activating mutation . Despite some imbalances in baseline characteristics , patients who received first-line chemotherapy had numerically higher 5-year survival rates than those who received first-line EGFR-TKIs . CONCLUSIONS This large , long-term analysis of EGFR mutation-positive NSCLC patients provides useful information about treatment outcomes in clinical practice . Up date d analyses are required to determine real world outcomes for NSCLC patients treated with the latest available agents , including immunotherapies OBJECTIVE To study the clinical and demographic factors associated with delays in the diagnosis of lung cancer . PATIENTS AND METHODS A 2-year prospect i ve study of patients admitted to the respiratory medicine ward with a suspected diagnosis of lung cancer . We studied  demographic factors , health care received , place of residence  , and  delays  in carrying out  diagnostic procedures . The following diagnostic time periods were defined : consultation ( from first symptom to first medical visit ) , middle period ( from first medical visit to hospital admission ) and diagnostic ( from hospital admission to histological diagnosis and clinical staging ) . RESULTS One hundred thirteen patients with a mean age of 65 years ( range , 36 - 90 ) , 103 men and 10 women , were studied . The most frequent symptoms leading to consultation were coughing ( 10.6 % ) , hemoptysis ( 19.5 % ) , chest pain ( 26.5 % ) , and shortness of breath ( 9.7 % ) . First visits were to a primary care physician for 72 % , to the hospital emergency room for 22 % , or to a pulmonologist for 6 % . Forty-four percent of the patients visited the doctor 2 or 3 times . The mean SD , numbers of days for the different time periods were as follows : consultation , 30.3 60 ; diagnosis , 18.6 19 ; middle period 37.9 63 . The mean total time from first symptom to diagnosis was 85.7 87 days . The middle period , the time in hospital until diagnosis , and the total time were shorter when patients were referred by the primary care physician to the emergency room or were directly admitted to the hospital ( P<.001 ) . Only 25.7 % of the staged lung cancers were operable . CONCLUSIONS Delays in lung cancer diagnosis are long . The attitudes of primary care physicians and their relations with specialized care providers are crucial for reducing delays Background and objective An adjusted indirect comparison was conducted to assess efficacy outcomes , particularly overall survival ( OS ) , of osimertinib versus platinum-based doublet chemotherapy in patients with epidermal growth factor receptor-mutated ( EGFRm ) T790 M mutation-positive non-small-cell lung cancer ( NSCLC ) who had progressed following an EGFR tyrosine kinase inhibitor ( TKI ) . Analysis of treatment effect from two separate trials had the potential to more accurately estimate the magnitude of OS benefit due to absence of confounding due to treatment switching from the control arm to the osimertinib arm of the ongoing r and omized control trial , AURA3 . Methods Two non-r and omized individual data sets were compared : pooled patients from the AURA extension and AURA2 trials ( osimertinib 80 mg , n = 405 , with a confirmed T790 M mutation using tissue sample s ) , and patients from the control arm of the IMPRESS study ( platinum-based doublet chemotherapy , n = 61 , with a confirmed T790 M mutation using plasma circulating tumour DNA [ ctDNA ] ) . A propensity score-based approach was used to account for differences in baseline demographics and disease characteristics . Results After adjustment for baseline differences between the two groups , osimertinib demonstrated a statistically significant improvement in progression-free survival ( PFS )  versus platinum-based doublet chemotherapy ( hazard ratio [ HR ] = 0.278 , 95 % confidence interval [ CI ] 0.188–0.409 , p < 0.0001 ; median PFS 10.9 vs. 5.3 months ) . Improvements were also observed for objective response rate ( ORR ) and disease control rate ( DCR ) ( ORR : 64.3 vs. 33.3 % ; odds ratio [ OR ] = 5.31 , 95 % CI 2.47–11.40 , p < 0.001 ; DCR : 92.1 vs. 75.0 % ; OR = 4.72 , 95 % CI 1.92–11.58 , p < 0.001 ) . Similar results were obtained for patients who received osimertinib as second-line treatment only . A statistically significant improvement in OS was observed for the osimertinib group ( HR = 0.412 , 95 % CI 0.273–0.622 , p < 0.0001 ) . Median OS for osimertinib was not reached . Conclusions In this indirect comparison , osimertinib showed a statistically significant improvement in efficacy outcomes versus platinum-based doublet chemotherapy in patients with EGFRm T790 M NSCLC who had progressed after EGFR-TKI therapy BACKGROUND Nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , disrupts PD-1-mediated signaling and may restore antitumor immunity . METHODS In this r and omized , open-label , international phase 3 study , we assigned patients with nonsquamous non-small-cell lung cancer ( NSCLC ) that had progressed during or after platinum-based doublet chemotherapy  to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS Overall survival was longer with nivolumab than with docetaxel .  The median overall survival was 12.2 months ( 95 % confidence interval [ CI ] , 9.7 to 15.0 ) among 292 patients in the  nivolumab group and 9.4 months ( 95 % CI , 8.1 to 10.7 ) among 290 patients in the docetaxel group ( hazard ratio for death , 0.73 ; 96 % CI , 0.59 to 0.89 ; P=0.002 ) . At 1 year , the overall survival rate was 51 % ( 95 % CI , 45 to 56 ) with nivolumab versus 39 % ( 95 % CI , 33 to 45 ) with docetaxel . With additional follow-up , the overall survival rate at 18 months was 39 % ( 95 % CI , 34 to 45 ) with nivolumab versus 23 % ( 95 % CI , 19 to 28 ) with docetaxel . The response rate was 19 % with nivolumab versus 12 % with docetaxel ( P=0.02 ) . Although progression-free survival did not favor nivolumab over docetaxel ( median , 2.3 months and 4 
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Our analyses showed that , when considering costs and effects directly related to testing , liquid biopsy ( as a triage test , which means patients who test negative undergo a follow-up tissue biopsy , or alone , which means using only liquid biopsy ) was less costly than tissue biopsy alone and led to fewer tissue biopsies .
Using liquid biopsy as a triage test produced the most correct treatment decisions and greatest number of people who were given osimertinib .
When considering long-term costs ( i.e. , treatment and care ) and effects ( i.e. , life-years and quality -adjusted life-years [ QALYs ] ) , liquid biopsy as a triage test was the most effective and most costly strategy followed by liquid biopsy alone .
Tissue biopsy alone was the least effective and least costly strategy .
We estimated that the total annual budget impact of publicly funding liquid biopsy as a triage test in Ontario over the next 5 years would range from approximateily $ 60,000 in year 1 to $ 3 million in year 5.People with lung cancer with whom we spoke said that liquid biopsy would likely be an appropriate test for people with NSCLC given their frail condition and because it would avoid the pain and anxiety associated with tissue biopsy .
Conclusions As a minimally invasive test , liquid biopsy identifies a high proportion of people with the EGFR T790 M resistance mutation .
This identification could better guide treatment for people with advanced NSCLC .
However , its relatively low negative predictive value means it is best used as a triage test ( i.e. , followed by tissue biopsy if the liquid biopsy does not identify a resistance mutation ) .
Liquid biopsy as a triage test is likely more effective than tissue biopsy alone .
However , owing to the high cost of treatment , liquid biopsy may not be cost-effective .