Paul A. Bunn

TL;DR: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations.

TL;DR: Increased copy number of the HER2 gene is associated with gefitinib sensitivity in EGFR-positive patients, supporting use of HER2 FISH analysis for selection of patients for TKI therapy.

TL;DR: MALDI-TOF MS of pretreatment serum may aid with the identification of subsets of NSCLC Pts that will benefit from treatment with gefitinib.

Abstract: 1667 Substitutions and deletions in exons in the tyrosine kinase domain of the EGFR gene (exons 18 to 24) in lung tumors have been associated with sensitivity to molecular target therapeutic agents classified as tyrosine kinase inhibitors (TKIs) Among the TKIs are gefitinib and erlotinib, which produce objective responses in 10-20% of advanced NSCLC patients after chemotherapy Erlotinib prolongs survival in these patients The relationship between mutation and response and survival is imperfect, suggesting that other factors may play a role in determining sensitivity to TKIs Recently we found EGFR amplification to be frequent in NSCLC (13%) and to be related to gefitinib response and survival In this report, we examined genomic DNAs from 78 NSCLC and 20 SCLC lung cancer cell lines Exons 18-21 of the tyrosine kinase domain were amplified and sequenced for the presence of mutations Mutations were found in none of the SCLC lines and 8 of 78 NSCLC lines (10%), namely NCI-H820, NCI-H1650, NCI-H1975, NCI-H3255, HCC827, HCC2279, HCC2935 and HCC4006 These cell lines were initiated from 7 Caucasian patients and one of Oriental origin Most patients were light or never smokers Six of the mutations were deletions in exon 19 and two were the L858R point mutation in exon 21 Dual color fluorescence in situ hybridization analysis was performed in 35 NSCLC lines using the EGFR/CEP 7 probe (Vysis/Abbott) EGFR gene amplification was identified in 7 of these lines, all carrying EGFR mutations H3255, HCC827, HCC2259, and HCC4006 had large, clustered gene amplification in all cells; H1650 had focal gene amplification with large gene clusters in approximately 30% of cells; NCI-H820 and HCC2935 showed small gene clusters in interphase nuclei and apparently normal metaphase chromosomes, supporting the hypothesis that rearranged chromosomes harbor gene duplications The remaining mutated line, NCI-1975 had no evidence of amplification Chromosomes harboring large amplicons including EGFR were distinct among the lines H3255 showed gene clusters in two distinct chromosomes, a large der(7) with three layers of gene clusters and a large metacentric with numerous layers of gene clusters in both arms HCC827, HCC4006 and H1650 carried the EGFR amplification in the long arm of der(7) with large gene clusters interspaced by centromeric sequences Preliminary in vitro testing showed that the majority of the mutated lines were sensitive to gefitinib and that there was a correlation between gefitinib sensitivity and the degree of gene amplification These results identified gene amplification as frequently associated with mutations in the tyrosine kinase domain of the EGFR gene in NSCLC cell lines and support the role of both amplification and mutation in the sensitivity to TKIs

TL;DR: This study tested the ability of the serum mass spectrometry classifier of clinical benefit from gefitinib to classify pre-treatment sera and plasma samples from non-small ce...