***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: Research methods for biomarker evaluation lag behind those for evaluating therapeutic treatments . Although a phased approach to development of biomarkers exists and guidelines are available for reporting study results , a coherent and comprehensive set of guidelines for study design has not been delineated . We describe a nested case – control study design that involves prospect i ve collection of specimens before outcome ascertainment from a study cohort that is relevant to the clinical application . The biomarker is assayed in a blinded fashion on specimens from r and omly selected case patients and control subjects in the study cohort . We separately describe aspects of the design that relate to the clinical context , biomarker performance criteria , the biomarker test , and study size . The design can be applied to studies of biomarkers intended for use in disease diagnosis , screening , or prognosis . Common biases that pervade the biomarker research literature would be eliminated if these rigorous st and ards were followed Background A high- quality programmed cell-death lig and 1 ( PD-L1 ) diagnostic assay may help predict which patients are more likely to respond to  anti-programmed cell death-1 (PD-1)/PD-L1 antibody-based  cancer therapy . Here we describe a PD-L1 immunohistochemical ( IHC ) staining protocol developed by Ventana Medical Systems Inc. and key analytical parameters of its use in formalin-fixed , paraffin-embedded ( FFPE ) sample s of non-small cell lung cancer ( NSCLC ) and head and neck squamous cell carcinoma ( HNSCC ) . Methods An anti-human PD-L1 rabbit monoclonal antibody ( SP263 ) was optimized for use with the VENTANA OptiView DAB IHC Detection Kit on the automated VENTANA BenchMark ULTRA platform . The VENTANA PD-L1 ( SP263 ) Assay was vali date d for use with FFPE NSCLC and HNSCC tissue sample s in a series of studies addressing sensitivity , specificity , robustness , and precision . Sample s from a subset of 181 patients from a Phase 1/2 study of durvalumab ( NCT01693562 ) were analyzed to determine the optimal PD-L1 staining cut-off for enriching the probability of responses to treatment . The scoring algorithm was defined using statistical analysis of clinical response data from this clinical trial and PD-L1 staining parameters in HNSCC and NSCLC tissue . Inter-reader agreement was established by three pathologists who evaluated 81 NSCLC and 100 HNSCC sample s across the range of PD-L1 expression levels . Results The VENTANA PD-L1 ( SP263 ) Assay met all pre-defined acceptance criteria . For both cancer types , a cut-off of 25 % of tumor cells with PD-L1 membrane staining of any intensity best discriminated responders from nonresponders . Sample s with staining above this value were deemed to have high PD-L1 expression , and those with staining below it were deemed to have low or no PD-L1 expression . Inter-reader agreement on PD-L1 status was 97 and 92 % for NSCLC and HNSCC , respectively . Conclusions These results highlight the robustness and reproducibility of the VENTANA PD-L1 ( SP263 ) Assay and support its suitability for use in the evaluation of NSCLC and HNSCC FFPE tumor sample s using the devised ≥25 % tumor cell staining cut-off in a clinical setting . The clinical utility of the PD-L1 diagnostic assay as a predictive biomarker will be further vali date d in ongoing durvalumab studies .Trial registration Clinical Trials.gov : 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 4.2 months , respectively ) , the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel ( 19 % and 8 % , respectively ) . Nivolumab was associated with even greater efficacy  than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression ( ≥1 % , ≥5 % , and ≥10 % ) of the PD-1 lig and . Treatment-related adverse events of grade 3 or 4 were reported in 10 % of the patients in the nivolumab group , as compared with 54 % of those in the docetaxel group . CONCLUSIONS Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy  , overall survival was longer with nivolumab than with docetaxel . ( Funded by Bristol-Myers Squibb ; CheckMate 057 Clinical Trials.gov number , NCT01673867 . ) Introduction : The Blueprint Programmed Death Lig and 1 ( PD‐L1 ) Immunohistochemistry ( IHC ) Assay Comparison Project is an industrial‐academic collaborative partnership to provide information on the analytical and clinical comparability of four PD‐L1 IHC assays used in clinical trials . Methods : A total of 39 NSCLC tumors were stained with four PD‐L1 IHC assays ( 22C3 , 28‐8 , SP142 , and SP263 ) , as used in the clinical trials . Three experts in interpreting their respective assays independently evaluated the percentages of tumor and immune cells staining positive at any intensity . Clinical diagnostic performance was assessed through comparisons of patient classification above and below a selected expression cutoff and by agreement using various combinations of assays and cutoffs . Results : Analytical comparison demonstrated that the percentage of PD‐L1–stained tumor cells was comparable when the 22C3 , 28‐8 , and SP263 assays were used , whereas the SP142 assay exhibited fewer stained tumor cells overall . The variability of immune cell staining across the four assays appears to be higher than for tumor cell staining . Of the 38 cases , 19 ( 50.0 % ) were classified above and five ( 13 % ) were classified below the selected cutoffs of all assays . For 14 of the 38 cases ( 37 % ) , a different PD‐L1 classification would be made depending on which assay/scoring system was used . Conclusions : The Blueprint PD‐L1 IHC Assay Comparison Project revealed that three of the four assays were closely aligned on tumor cell staining whereas the fourth showed consistently fewer tumor cells stained . All of the assays demonstrated immune cell staining , but with greater variability than with tumor cell staining . By comparing assays and cutoffs , the study indicated that despite similar analytical performance of PD‐L1 expression for three assays , interchanging assays and cutoffs would lead to “ misclassification ” of PD‐L1 status for some patients . More data are required to inform on the use of alternative staining assays upon which to read different specific therapy‐related PD‐L1 cutoffs The identification of biomarkers associated with response to therapeutic agents is central to optimizing patient outcomes . Expression of the immune checkpoint proteins PD-1/L1 , and DNA mismatch repair deficiency ( dMMR ) status may be predictive response biomarkers for immunotherapies , but their overlap requires further study . We prospect ively conducted PD-L1 and MMR immunohistochemistry ( IHC ) on 430 consecutive patients with advanced gastrointestinal ( GI ) cancers , genitourinary ( GU ) cancers or rare cancers between June 2012 and March 2016 . Overall 393/430 ( 91.4 % ) patients were evaluable for PD-L1 expression by IHC . The frequency of tumor PD-L1 positivity ( PD-L1 + ) was 16.5 % ( 65/393 ) . Among anatomic tumor sites PD-L1 + was 28.6 % in melanoma , 22.2 % in GC , 20.9 % in CRC , 12.5 % in BTC , 7.1 % in GU cancer , 6.7 % in HCC , 0 % in pancreatic cancer and 0 % in sarcoma . Among the 394 evaluable for MLH1/MSH2 expression cases , 18 patients ( 4.5 % ) had dMMR tumors . The dMMR was most common in GC ( 7.1 % ) followed by 6.7 % in HCC , 4.4 % in CRC , and 2.7 % in sarcoma . Of the 365 patients evaluable for both PD-L1 and MLH1/MSH2 expression , there was a significant association between the PD-L1 expression and MLH1/MSH2 loss ( P = 0.01 ) , but not with overall survival within tumor types . PD-L1 status and dMMR are overlapping putative response biomarkers in immunoncology . Clinical trials with biomarker enrichment restricted to PD-L1 + or dMMR may be inadequate to capture the subset of patients who may benefit from immune mediated therapies . More robust immunotherapy biomarkers and careful clinical trial design are warranted The efficacy of trastuzumab for metastases coupled with the relatively poor prognosis of patients with node-positive , HER2-positive breast cancer has led to the evaluation of trastuzumab as an adjuvant therapy . A prospect i ve , r and omized , three-arm , phase III trial is being conducted by the Breast Intergroup ( N9831 ) for women with primary , operable , histologically confirmed , node-positive breast carcinoma that strongly overexpresses ( 3 + ) HER2 protein and /or displays HER2/neu gene amplification , as determined by local laboratory testing . The protocol requires confirmatory central testing of HER2 status using the HercepTest immunohistochemistry and the Vysis PathVysion fluorescence in situ hybridization ( FISH ) assays . Tumor specimens from the first 119 patients enrolled in N9831 were central ly tested ; 74 % were found to be HercepTest 3 + and 66 % were found to have HER2 gene amplification . Only six of nine ( 67 % ) of the specimens su bmi tted by local laboratories as FISH positive could be confirmed by central assays . The concordance for central HercepTest and central FISH assays was 92 % . The poor concordance ( 74 % ) between local and central testing for HER2 status has led to modifications in the eligibility criteria for N9831 This article introduces the approach of GRADE to rating  quality of evidence .  GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence ABSTRACT Introduction : Immune checkpoint inhibitors targeting programmed death protein 1 ( PD-1 ) receptor and its lig and , PD-L1 , have recently led to significant and durable improvements in the clinical outcomes of some types of cancers including lung cancer . Areas covered : Pembrolizumab was approved by the US FDA for the treatment of advanced or metastatic NSCLC whose disease has progressed after other treatments and with tumors that express PD 
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Results of our study suggest that , when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s ) for PD-L1 assessment for its specific clinical purpose ( s ) , it is better to develop a properly vali date d laboratory developed test for the same purpose ( s ) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic , than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose