VeriStrat is a blood-based proteomic test with predictive and prognostic significance in second-line treatments for non-small cell lung cancer (NSCLC). This trial was designed to investigate the role ...of VeriStrat in first-line treatment of advanced NSCLC with standard chemotherapy. Here we present the results for 76 non-squamous patients treated with a combination of carboplatin or cisplatin with pemetrexed.
The test-assigned classifications of VeriStrat Good or VeriStrat Poor to samples collected at baseline. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and objective response. Exploratory analyses of end points separately in carboplatin/pemetrexed and cisplatin/pemetrexed subgroups were also conducted.
Patients classified as VeriStrat Good had longer PFS and OS than VeriStrat Poor: 6.5 vs 1.6 months and 10.8 vs 3.4 months, respectively; the corresponding hazard ratios (HRs) were 0.36 (P<0.0001) and 0.26 (P<0.0001); they were also more likely to achieve objective response. Prognostic significance of VeriStrat was confirmed in multivariate analysis. Significant differences in OS and PFS between Veristrat classifications were also found when treatment subgroups were analysed separately.
The trial demonstrated clinical utility of VeriStrat as a prognostic test for standard first-line chemotherapy of non-squamous advanced NSCLC.
The serum proteomic test VeriStrat has been shown to be able to classify advanced non-small cell lung cancer (NSCLC) patients for overall survival (OS) after treatment with epidermal growth factor ...receptor (EGFR) tyrosine kinase inhibitors (TKIs). In this study, VeriStrat was evaluated as a pre-treatment stratification tool in patients with advanced stage NSCLC for treatment with the combination of erlotinib and sorafenib, considering both OS and progression-free survival (PFS) as end points.
Serum samples from 50 patients treated within the context of a phase II trial of first-line erlotinib and sorafenib were analysed with VeriStrat, a fully locked mass spectrometry-based test that identifies patients likely to have good or poor outcome on EGFR therapy based on eight distinct features in mass spectra. Analysis was performed fully blinded to all clinical data, and then the outcome data were analysed with respect to the obtained serum classifications.
VeriStrat classified pre-treatment samples into two groups, VeriStrat Good and VeriStrat Poor, which were significantly different in OS (hazard ratio (HR) 0.30, log-rank P=0.009) and in PFS (HR 0.40, log-rank P=0.035).
VeriStrat has shown its potential for stratification of unselected, advanced stage NSCLC patients treated in first line with a combination of erlotinib and sorafenib.
The maximum cross‐correlation (MCC) method reconstructs the surface advective velocity fields from the displacements of spatial patterns in pairs of sequential satellite (normally infrared) images. ...However, the performance of the conventional MCC method is not always satisfactory. One of the main reasons for this is the fact that the method can correctly estimate only the velocity component parallel to the gradient of the property depicted in the images, while any small displacement perpendicular to the gradient (i.e., directed along the isolines) essentially maps the spatial pattern onto itself and therefore can not be detected using the conventional MCC technique. In the present work we propose a modification of the MCC method that allows circumventing this basic deficiency and improving the performance of the MCC technique. In this approach, the “cross‐isoline” components of the velocity field are obtained as in the conventional MCC scheme; however, the “along‐isoline” components derived from the MCC are disregarded as unreliable. Instead, the “true” along‐isoline components are then reconstructed from the given cross‐isoline velocity field based on the continuity requirement and on the condition of no normal flow at solid boundaries. This inverse problem is solved by constructing the two‐dimensional stream function in the curvilinear coordinate frame associated with the image isolines. The method is illustrated using AVHRR images from the southwestern Atlantic Ocean and the Black Sea. The results are compared with some direct drifter and current meter measurements and geostrophic estimates.
Abstract
Background: In EGF30008 the addition of lapatinib (La) to first-line treatment with letrozole (Le) significantly improved progression-free survival (PFS) in patients (pts) with hormone ...receptor positive (HR+), HER2 positive (HER2+) metastatic breast cancer (hazard ratio (HR) = 0.71; p=0.019), but not in HR+, HER2 negative (HER2−) pts. This study assessed the ability of VeriStrat (VS), a mass-spectrometry blood-based pretreatment assay correlating with clinical outcome from EGFR-TKI therapy, to stratify pt outcome in EGF30008. The VS assay assigns VS Good (Good), VS Poor (Poor), or Indeterminate labels to a serum sample based on a specific 8-peak signature in the mass-spectra (Taguchi F et al., JNCI 2007).
Methods: Blinded to clinical data, pretreatment serum was analyzed using standard VS procedurei. Statistical analyses were performed using Mantel-Haenszel and Cox proportional hazards methods; correlations were evaluated using Fisher's exact and χ2 tests.
Results: Of the 1286 pts randomized (HER2+=219; HER2−=952; HER2 unknown=115), 1163 pts had serum available; a VS label was assigned to 1046 pts (961 Good; 80 Poor; 5 Indeterminate); 117 were not evaluable (hemolyzed). In the overall population there was no significant difference in PFS between Good and Poor groups within the Le+La arm (p=0.53). In contrast, PFS of the Good group was longer than that of the Poor group within the Le only arm (HR=0.36, p<0.001) and comparable with that of Good pts within the Le+La arm (median PFS 10.8 mo vs 11.0 mo). An interaction test showed significantly different HRs for PFS in Good vs Poor between treatment arms (p=0.002).
In the HER2+ population both Good (n= 169) and Poor (n= 13) groups received significant PFS benefit from addition of La to Le: in Good HR=0.71, p=0.046, medians 3.0 mo (Le) vs 8.0 mo (Le+La); in Poor HR=0.17, p=0.02, medians 2.3 mo (Le) vs 8.6 mo (Le+La). In the HER2− population median PFS for the Poor group (n=58) increased from 3.1 to 11.0 mo (HR=0.57, p=0.068) with addition of La to Le, whereas the Good group (n=702) received no significant benefit, median 13.6 mo on Le and 13.8 mo on Le+La (PFS HR= 0.85, p=0.09).
In multivariate analysis VS remained independently significant and predictive of differential treatment effect in the overall population. No significant correlation of VS classification with HER2 status (p=0.35) or prior adjuvant hormonal therapy (p=0.33) was found. VeriStrat was also not significantly correlated with baseline HER2 ECD levels (low <15 ng/ml vs. high ≥15 ng/ml), p = 0.23, or ER expression (H-score:lower quartile:<160 vs. rest), p=0.18.
Conclusions:
In the overall population VeriStrat predicted PFS in Le alone but not in the Le+La combination, with a significant differential treatment effect. VeriStrat identified a subset of pts with inferior PFS on Le therapy. Adding La to Le improved outcome in HER2+ pts, and interestingly suggested an improvement in the VS Poor subset of HER2− pts. HER2− VS Good pts do not gain benefit with the addition of La. No correlation between VS and investigated predictors of benefit from the addition of La to Le in HER2− pts was observed. If these results can be validated in a prospective study, the addition of La to Le may be a potential treatment option for HER2− HR+ VS poor pts.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-4.
Monoclonal antibodies of two clones reacting with the nonnative forms of d-glyceraldehyde-3-phosphate dehydrogenase, EC 1.2.1.12 (GAPDH), were obtained. Antibodies of clone 6C5 belonged to IgG1 ...subtype; antibodies of clone 6G7 belonged to IgM type. The interaction of antibodies of both clones with the immobilized and soluble enzyme was studied. The specificity of antibodies to the definite oligomeric forms was demonstrated on immobilized monomers, dimers, and tetramers of GAPDH. The affinity of antibodies to monomeric and dimeric forms of GAPDH, either active or not, was demonstrated. At the same time the antibodies did not react with the tetrameric enzyme. The binding of antibodies had no influence on the enzymatic activity. However, the addition of antibodies to the denatured enzyme blocked the spontaneous renaturation of GAPDH. The immobilized antibodies of both clones were successfully used for the purification of GAPDH solution from the denatured admixtures.
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are the major forms of autoimmune liver diseases each characterized by the destruction of a ...specific liver cell type and the presence of differing auto-antibodies. We took a proteomic approach utilizing in situ matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) to obtain profiles directly from liver samples of patients with PBC, PSC, AIH and controls. The ability to precisely localize the region for acquisition of MALDI MS allowed us to obtain profiles from bile ducts, inflammatory infiltrates and hepatocytes from each biopsy sample. Analysis tools developed to identify peaks and compare peaks across diseases and cell types were used to develop models to classify the samples. Using an initial set of testing samples from PBC patients and controls, we identified unique peaks present in bile ducts, inflammatory infiltrates and hepatocytes that could classify samples in a validation cohort with 88-91% accuracy. Interestingly, profiles of PSC and AIH did not differ significantly from PBC. Identification of proteins in these peaks may represent novel autoantigens or effector molecules. These findings illustrate the potential of a proteomic approach to autoimmune diseases with in situ MALDI MS.
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