Lower cutoff points with Dako antibody provided the best discrimination between EGFR-positive and EGFR-negative individuals for survival hazard ratios comparing gefitinib to placebo, with a significant treatment/cutoff point connection for 10% cutoff point (= .049). with Dako antibody assorted between 8% and 12%, and with Zymed antibody Sodium dichloroacetate (DCA) between 10% and 13%. Lower cutoff points with Dako antibody offered the best discrimination between Rabbit Polyclonal to MPHOSPH9 EGFR-positive and EGFR-negative individuals for survival hazard ratios comparing gefitinib to placebo, with a significant treatment/cutoff point connection for 10% cutoff point (= .049). A similar but less apparent trend was mentioned for Zymed antibody, even though discrimination between risk ratios was not significant for any cutoff point analyzed. CONCLUSIONS Assessment with the Dako PharmDx kit and percentage of cells with positive staining may provide more accurate prediction of differential effect on survival Sodium dichloroacetate (DCA) with gefitinib than assessment with Zymed antibody and staining index. Using higher cutpoints to define positivity does not improve test discrimination. Keywords: nonsmall-cell lung malignancy, epidermal growth element receptor, immunohistochemistry, phase 3 trial, cutoff point Epidermal growth element receptor tyrosine kinase inhibitors (EGFR TKIs, gefitinib and erlotinib) are active inside a subset of nonsmall-cell lung malignancy (NSCLC) individuals. The response rates and disease control rates reported in medical tests of EGFR TKIs in advanced pretreated NSCLC individuals in Western populations are 10% to 20% and 40%, respectively,1C3 indicating that a proportion of NSCLC individuals do not derive any benefit from EGFR TKIs. A major research effort over the last decade focused on the recognition of predictive biomarkers for response and survival benefit to EGFR TKIs, and many of these studies analyzed EGFR protein manifestation by immunohistochemistry as the most applicable method to assess the presence of molecular target in the tumor. Results of the ISEL (Iressa Survival Evaluation in Lung malignancy) phase 3 medical trial in advanced NSCLC individuals who have been refractory to or intolerant of their latest chemotherapy regimen showed some improvement in survival with gefitinib (plus best supportive care), which failed to reach statistical significance compared with placebo (plus best supportive care), in the overall human population and in individuals with adenocarcinoma.4 Preplanned subgroup analysis of the ISEL demonstrated a statistically significant increase in survival with gefitinib in individuals of Asian ethnicity and in individuals who experienced never smoked. A biomarker analysis of this study demonstrated a nonsignificant 23% reduction in the risk of death for gefitinib-treated individuals who indicated EGFR protein as assessed from the EGFR Dako PharmDx kit having a cutoff point of 10% of cells exhibiting the staining of at least minor intensity.5 No benefit was observed in the subset of patients who have been classified as EGFR protein-negative. The National Tumor Institute of Canada BR.21 clinical trial that shown a significant improvement in survival of erlotinib versus placebo-treated advanced NSCLC patients who failed at least 1 chemotherapy regimen6 showed a 32% reduction in the risk of death for patients with EGFR protein-positive tumor samples.7 No survival advantage was seen among individuals with EGFR protein-negative tumor samples. This study also used a cutoff point of 10% stained cells and the Dako PharmDx kit. Inside a retrospective evaluation of gefitinib-treated NSCLC individuals, Cappuzzo et al.8 used Zymed anti-EGFR monoclonal antibody and a staining index that takes into account the percent of positive cells and staining intensity, scored from 0 to 4. Using a cutpoint of 200 within the level from 0 to 400, superior survival was shown in EGFR protein-positive versus bad individuals Sodium dichloroacetate (DCA) (= .01). However, other studies performed on tumor samples from phase 3 clinical tests investigating the combination of gefitinib or erlotinib with chemotherapy failed to display any predictive value of EGFR protein manifestation for either medical response or survival.9,10 Also, there was no association with EGFR protein expression and survival for NSCLC individuals who received gefitinib monotherapy in the phase 2 clinical studies IDEAL1 and 2 (Iressa Dose Evaluation in Advanced Lung cancer).11 Clinical tests of cetuximab, a monoclonal antibody targeted against the EGFR in both lung and colorectal cancer needed EGFR protein expression in tumor samples for study entry in most tests. EGFR protein manifestation was evaluated from the EGFR PharmDx kit with cutoff points of at least 1+ (at least 1% or at least 10% of cells with fragile staining relating to individual study). More than 90% of screened individuals were obtained as EGFR protein-positive in phase 2 clinical studies with cetuximab in lung malignancy12C14 and >75% in phase 2 or 3 3 colorectal malignancy tests.15,16 Because these trials were performed largely in.
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