RRC ID 45129
Author Ålgars A, Avoranta T, Österlund P, Lintunen M, Sundström J, Jokilehto T, Ristimäki A, Ristamäki R, Carpén O.
Title Heterogeneous EGFR gene copy number increase is common in colorectal cancer and defines response to anti-EGFR therapy.
Journal PLoS One
Abstract Anti-EGFR therapy is commonly used to treat colorectal cancer (CRC), although only a subset of patients benefit from the treatment. While KRAS mutation predicts non-responsiveness, positive predictive markers are not in clinical practice. We previously showed that immunohistochemistry (IHC)-guided EGFR gene copy number (GCN) analysis may identify CRC patients benefiting from anti-EGFR treatment. Here we tested the predictive value of such analysis in chemorefractory metastatic CRC, elucidated EGFR GCN heterogeneity within the tumors, and evaluated the association between EGFR GCN, KRAS status, and anti-EGFR antibody response in CRC cell lines. The chemorefractory patient cohort consisted of 54 KRAS wild-type (WT) metastatic CRC patients. EGFR GCN status was analyzed by silver in situ hybridization using a cut-off value of 4.0 EGFR gene copies/cell. KRAS-WT and KRAS mutant CRC cell lines with different EGFR GCN were used in in vitro studies. The chemorefractory CRC tumors with EGFR GCN increase (≥4.0) responded better to anti-EGFR therapy than EGFR GCN (<4.0) tumors (clinical benefit, P = 0.0004; PFS, HR = 0.23, 95% CI 0.12-0.46). EGFR GCN counted using EGFR IHC guidance was significantly higher than the value from randomly selected areas verifying intratumoral EGFR GCN heterogeneity. In CRC cell lines, EGFR GCN correlated with EGFR expression. Best anti-EGFR response was seen with KRAS-WT, EGFR GCN = 4 cells and poorest response with KRAS-WT, EGFR GCN = 2 cells. Anti-EGFR response was associated with AKT and ERK1/2 phosphorylation, which was effectively inhibited only in cells with KRAS-WT and increased EGFR GCN. In conclusion, IHC-guided EGFR GCN is a promising predictor of anti-EGFR treatment efficacy in chemorefractory CRC.
Volume 9(6)
Pages e99590
Published 2014-1-1
DOI 10.1371/journal.pone.0099590
PII PONE-D-14-02187
PMID 24940619
PMC PMC4062406
MeSH Adult Aged Cell Line, Tumor Cohort Studies Colorectal Neoplasms / drug therapy* Colorectal Neoplasms / genetics* Disease-Free Survival Drug Resistance, Neoplasm ErbB Receptors / antagonists & inhibitors* ErbB Receptors / genetics* Female Gene Dosage* Gene Expression Regulation, Neoplastic Genetic Heterogeneity Humans Immunohistochemistry In Situ Hybridization Kaplan-Meier Estimate Male Middle Aged Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins p21(ras) Reproducibility of Results Treatment Outcome ras Proteins / genetics
IF 2.74
Times Cited 14
Human and Animal Cells CW-2(RCB0778)