Top-level MET gene copy number gain defines a subtype of poorly differentiated pulmonary adenocarcinomas with poor prognosis.

BACKGROUND: MET amplifications occur in human tumors, including non-small cell lung cancer (NSCLC). MET inhibitors have demonstrated some clinical activity in MET amplified NSCLC, presumably with a gene dose effect. However, the definition of MET positivity or MET amplification as a potential oncogenic driver is still under debate. In this study, we aimed to establish the molecular subgroup of NSCLC with the highest unequivocal MET amplification level and to describe the prevalence, and histologic and clinical phenotype of this subgroup. METHODS: A total of 373 unselected patients with NSCLC were consecutively tested for MET gene copy number (GCN) by FISH. Mean GCN, MET/CEN7 ratio and other FISH parameters were identified and correlated with morphological and molecular pathological characteristics of the tumors as well as with clinical data. RESULTS: Based on the variability of obtained data a top-level category of MET amplification was newly defined (>90th percentile of average GCN; ≥10 MET gene copies per tumor cell). This criterion was fulfilled in 2% of analyzed tumors. These tumors were exclusively poorly differentiated adenocarcinomas with a predominant solid subtype and pleomorphic features. Rarely, co-alterations were detected (KRAS mutation or MET exon 14 skipping mutation). In this top-level group, there were no EGFR mutations or ALK or ROS1 alterations. The most important clinical feature was a significantly shortened overall survival (HR 3.61; median OS 8.2 vs. 23.6 months). Worse prognosis did not depend on initial stage or treatment. CONCLUSIONS: The newly defined top-level category of MET amplification in NSCLC defines a specific subgroup of pulmonary adenocarcinoma with adverse prognosis and characteristic morphological features. Lower levels of MET gene copy number seem to have probably no specific value as a prognostic or predictive biomarker.

ReadMax-a novel reading and scoring approach for EGFR gene copy number to predict therapeutic benefit of erlotinib treatment in EGFR wild-type non-small-cell lung cancer.

EGFR mutation testing is now well established as a means of selecting the optimal first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). However, deciding on the correct treatment for EGFR wild-type NSCLC remains a challenge. EGFR fluorescence in-situ hybridization (FISH) testing of gene copy number has been a promising marker, but has provided mixed results despite attempts to standardize the reading and scoring process. The novel ReadMax reading and scoring system focuses on the most aberrant cells, to identify oncogene addiction, rather than taking a representative reading as in the Colorado method. The methodology was developed using historical samples from the TRUST and MERIT studies, followed by re-reading of the samples from the SATURN trial. Analysis of samples using the ReadMax methodology revealed that progression-free survival (PFS) and overall survival (OS) were improved in patients with ReadMax FISH-positive (RM FISH+) tumours, compared with those whose tumours were not RM FISH+: PFS hazard ratios (HRs) were 0.52 for RM FISH+ versus 0.93 for not RM FISH+; OS HRs were 0.69 and 0.92, respectively. For PFS, HR for RM FISH+ versus not RM FISH+ in the SATURN erlotinib group was 0.53 (p = 0.003). The PFS and OS results were also similar in the EGFR wild-type population (PFS HRs were 0.63 and 0.96; OS HRs were 0.61 and 0.84, respectively), although amplification of the EGFR gene in patients with EGFR wild-type disease was not found to be predictive of treatment outcomes, which was unexpected but not unprecedented. KRAS status was not found to affect outcomes. Further experience is required to refine the ReadMax methodology and fully establish its validity and robustness. In conclusion, the ReadMax scoring system to identify patients with EGFR FISH-positive NSCLC is a promising technique, which could improve treatment options and outcomes for patients with advanced NSCLC, in particular for EGFR wild-type tumours.

Pooled analysis of clinical outcome for EGFR TKI-treated patients with EGFR mutation-positive NSCLC.

Patients with non-small-cell lung cancer (NSCLC) appear to gain particular benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKI) if their disease tests positive for EGFR activating mutations. Recently, several large, controlled, phase III studies have been published in NSCLC patients with EGFR mutation-positive tumours. Given the increased patient dataset now available, a comprehensive literature search for EGFR TKIs or chemotherapy in EGFR mutation-positive NSCLC was undertaken to update the results of a previously published pooled analysis. Pooling eligible progression-free survival (PFS) data from 27 erlotinib studies (n = 731), 54 gefitinib studies (n = 1802) and 20 chemotherapy studies (n = 984) provided median PFS values for each treatment. The pooled median PFS was: 12.4 months (95% accuracy intervals [AI] 11.6-13.4) for erlotinib-treated patients; 9.4 months (95% AI 9.0-9.8) for gefitinib-treated patients; and 5.6 months (95% AI 5.3-6.0) for chemotherapy. Both erlotinib and gefitinib resulted in significantly longer PFS than chemotherapy (permutation testing; P = 0.000 and P = 0.000, respectively). Data on more recent TKIs (afatinib, dacomitinib and icotinib) were insufficient at this time-point to carry out a pooled PFS analysis on these compounds. The results of this updated pooled analysis suggest a substantial clear PFS benefit of treating patients with EGFR mutation-positive NSCLC with erlotinib or gefitinib compared with chemotherapy.

Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: pooled analysis.

Non-small-cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR) is a distinct subgroup of NSCLCs that is particularly responsive to EGFR tyrosine-kinase inhibitors (TKIs). A weighted pooled analysis of available studies was performed to evaluate clinical outcome in patients with EGFR-mutated NSCLC who were treated with chemotherapy or EGFR TKIs. Median progression-free survival (PFS) times were pooled from prospective or retrospective studies that evaluated chemotherapy or single-agent EGFR TKIs (erlotinib or gefitinib) in patients with NSCLC and EGFR mutations. Among the studies identified for inclusion in the analysis, 12 evaluated erlotinib (365 patients), 39 evaluated gefitinib (1069 patients) and 9 evaluated chemotherapy (375 patients). Across all studies, the most common EGFR mutations were deletions in exon 19 and the L858R substitution in exon 21. In the weighted pooled analysis, the overall median PFS was 13.2 months with erlotinib, 9.8 months with gefitinib and 5.9 months with chemotherapy. Using a two-sided permutation, erlotinib and gefitinib produced a longer median PFS versus chemotherapy, both individually (P= 0.000 and P= 0.002, respectively) and as a combined group (EGFR TKI versus chemotherapy, P= 0.000). EGFR TKIs appear to be the most effective treatment for patients with advanced EGFR-mutant NSCLC. Ongoing prospective trials comparing the efficacy of first-line chemotherapy and EGFR TKIs in EGFR-mutant disease should provide further insight into the most appropriate way to treat this specific group of patients.

Short- and long-term biological variation in cardiac troponin I measured with a high-sensitivity assay: implications for clinical practice.

BACKGROUND: The improved detection limit and precision in new-generation commercial assays for cardiac troponin I (cTnI) have lowered the 99th-percentile cutoff value, yielding higher frequencies of positive test results. Because serial testing is important in interpreting low concentrations, we evaluated the biological variation of cTnI in both the short (hours) and long (weeks) terms and determined reference change values (RCVs) and the index of individuality (II) for cTnI. METHODS: To assess short- and long-term variation, we collected blood from 12 healthy volunteers hourly for 4 h and from 17 healthy individuals once every other week for 8 weeks, measured cTnI with a high-sensitivity assay (detection limit, 0.2 ng/L), and computed analytical, intraindividual, interindividual, and total CVs (CV(A), CV(I), CV(G), and CV(T), respectively; CV(T) = CV(A) + CV(I) + CV(G)) as well as the II. Because of the slight right-skewness of the data, RCVs were calculated with a lognormal approach. RESULTS: Within-day CV(A), CV(I), and CV(G) values were 8.3%, 9.7%, and 57%, respectively; the corresponding between-day values were 15%, 14%, and 63%. Within- and between-day IIs were 0.21 and 0.39, respectively. Lognormal within-day RCVs were 46% and -32%, respectively; the corresponding between-day values were 81% and -45%. CONCLUSIONS: The low II indicates that population-based reference intervals are less useful for interpreting cTnI values than following serial changes in values in individual patients. This criterion is particularly important for interpreting results from patients who show cTnI increases at low concentrations measured with very high-sensitivity assays, from patients presenting with chest pain (short term), and for evaluating drugs for cardiotoxicity (long term).

N-terminal pro-B-type natriuretic peptide concentrations predict the risk of cardiovascular adverse events from antiinflammatory drugs: a pilot trial.

BACKGROUND: we investigated whether higher concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts cardiovascular adverse events (CV-AEs) in patients with osteoarthritis treated with antiinflammatory drugs. METHODS: NT-proBNP was measured in baseline samples from 433 patients enrolled in a prospective randomized study designed to test the therapeutic effect of a novel metalloproteinase inhibitor. We monitored CV-AEs and retrospectively investigated their relationship to the concomitant use of selective cyclooxygenase-2 inhibitors (coxibs), traditional nonsteroidal antiinflammatory drugs (tNSAIDs), and glucocorticoids. CV-AEs included myocardial infarction, stroke, new or worsening of preexisting arterial hypertension, congestive heart failure, and several less severe CV-AEs. RESULTS: we observed 82 mild to serious CV-AEs during an observational period of 200 days. The risk of such events was 1.95-fold higher in patients who were taking tNSAIDs, glucocorticoids, or coxibs (i.e., any inhibitor) and who had NT-proBNP concentrations > or = 100 ng/L than in patients taking any inhibitor who had NT-proBNP values <100 ng/L (P < 0.05). Patients taking coxibs (alone or in addition to tNSAIDs or glucocorticoids) with baseline NT-proBNP values > or = 100 ng/L had a 7.41-fold higher risk for CV-AEs than those with baseline values <100 ng/L (P < 0.01). Patients who were taking 2 or more antiinflammatory drugs and had NT-proBNP values > or = 100 ng/L had a 3.74-fold higher risk for CV-AEs than those with NT-proBNP values <100 ng/L (P < 0.05). An NT-proBNP value <100 ng/L was associated with negative predictive values of >85% across all treatment groups. CONCLUSIONS: NT-proBNP may be a useful marker for anticipating cardiovascular risk associated with the use of antiinflammatory drugs for osteoarthritis.

Measures of morbidity in clinical studies with recurrent skeletal complications.

Double-blind placebo-controlled clinical trials in metastatic bone disease considered counts of morbid events as the clinical outcome measure. These (recurrent) skeletal events were derived from a composite endpoint based on the necessity of medical interventions against bone pain or incident fractures. The trials were conducted for regulatory approval of therapy with bisphosphonates and were intended to demonstrate that an active treatment reduces the occurrence of skeletal events. The advanced morbidity of the patients led to a substantial amount of premature discontinuations, because of early death or because of progression of the basic disease. In some trials the discontinuations were unbalanced between treatment arms, where there were more dropouts under placebo. These effects contribute to a high portion of patients with no morbidity events. This background presents difficulties for the task of defining statistics that validly quantify skeletal morbidity in these trials while keeping the necessary simplicity so as to be accepted by health authorities and a clinical audience. Guided by this regulatory context, this paper compares the performance of five (simple) approaches to quantifying skeletal morbidity. Key criteria are bias and validity under different dropout scenarios, as well as the capability to demonstrate treatment effects. Based on theoretical considerations, two simulation studies, and real data results, a morbidity measure in the form of a smoothed rate was favored: this is a rate estimate in the individual patient of the form (y + c)(T + d)(-1), where y is the count of events, T is the patient's observation time, and c, d are constants to be appropriately chosen. This morbidity measure performed well in the simulation studies and showed a wanted insensitivity to dropout patterns. It outperforms the simple rate y/T due to the high portion of patients without events. Rates of this type were used before in the quantal bioassay and have a strong relationship to Bayesian approaches. Hence, these measures represent a good approach to handle the inherent difficulties of morbid event data in severely diseased patient populations, still offering sufficient simplicity.