Epidermal Growth Factor Amplification Research Articles

Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma.

BackgroundClinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small. A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC.ResultsDual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6). EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 %) tumours, with high polysomy in 22 (13.8 %) and amplification in 10 (6.3 %). Two independent operator scores for FISH positivity were 100 % concordant. EGFR FISH positive status was not associated with clinic-pathological features. EGFR amplification was associated with worse survival (HR = 2.64, 95 % CI 1.04 to 6.71, p = 0.03).ConclusionOur FISH scoring system for EGFR in advanced EC identifies a significant subgroup (20.0 %) of FISH positive patients. EGFR amplification, which is found in 6.3 %, is associated with poor survival. It is not known if there is a role for EGFR targeted treatment in this subgroup of patients, however we are now utilising this EGFR FISH assay and scoring system in biopsies from clinical trials utilising anti-EGFR targeted therapies.

Final results of a randomized phase III trial of nimotuzumab for the treatment of newly diagnosed glioblastoma in addition to standard radiation and chemotherapy with temozolomide versus standard radiation and temoziolamide.

2033 Background: The receptor for epidermal growth factor (EGF-R) has consistently been found expressed or overexpressed in human malignant glioma disease. Therapeutic targeting of the EGF-R has shown mixed responses which appear to be restricted by specific features of the tumor cells.Nimotuzumab binds preferentially to highly over expressing cells, a phase III trial was initiated to test efficacy in glioma. Methods: Nimotuzumab was tested in an open label, randomized, multicenter Phase III trial in patients with histologically confirmed, newly diagnosed glioblastoma. 12 consecutive weekly infusions of 400mg during standard radiotherapy with Temozolomide followed by biweekly infusions of 400mg arm A was randomized against standard radio chemotherapy alone arm B. Primary endpoint was PFS as determined by centralized neuro-imaging review. OS as secondary endpoint with quality of life, safety as additional parameters.MGMT and EGF-R were assessed where sufficient materials could be retrieved as well as tumor hypoxia. Results: Between 2007 and 2010, 149 patients were randomized and 142 were available for analysis. Stratification according to resection status resulted in 40 pts in the treatment arm and 41 in the control arm with residual tumor and 31 vs 30 pts without residual tumor. PFS: 12 month was 25.5% arm A vs 20.3% in arm B (p = 0.78) and OS: 679 days vs 596 days. For non - methylated MGMT the difference was most notable: OS arm A 28 pats: 19.6 months vs arm B 28 pats 15.0 months EGF-R amplification, gave no clear signal, neither was there a statistically significant treatment effect between with or without residual tumor. Tumor hypoxia does not appear to have predictive value in the overall group but possibly in subgroups.AEs and SAEs did not reveal a new specific toxicity profile beyond the known side effects from glioma treatment with current standard. Conclusions: Nimotuzumab shows a clear trend towards efficacy in MGMT non-methylated glioblastoma patients. Safety profile and indications for subgroup efficacy potentially justify focused evaluation of antibody therapy against glioblastoma.

MET Gene Copy Number in Non-small Cell Lung Cancer: Molecular Analysis in a Targeted Tyrosine Kinase Inhibitor Naïve Cohort

Recent clinical success of epidermal growth factor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) have raised hopes that targeting other deregulated growth factor signaling, such as the hepatocyte growth factor/MET pathway, will lead to new therapeutic options for NSCLC. Furthermore, NSCLC present secondary EGFR-TKIs resistance related to exons 20 and 19 EGFR mutations or more recently to MET amplification. The aim of this study was to determine MET copy number related to EGFR copy number and K-Ras mutations in a targeted TKI naive NSCLC cohort. We investigated 106 frozen tumors from surgically resected NSCLC patients. Genes copy number of MET and EGFR were assessed by quantitative relative real-time polymerase chain reaction and K-Ras mutations by sequencing. MET is amplified in 22 cases (21%) and deleted in nine cases (8.5%). EGFR is amplified in 31 cases (29%). K-Ras is mutated in 11 cases (10.5%). As observed for EGFR amplification, MET amplification is never associated with K-Ras mutation. MET amplification could be associated with EGFR amplification. MET amplification is not related to clinical and pathologic features. MET amplification and EGFR amplification showed a trend toward poor prognosis in adenocarcinomas. In EGFR-TKIs naive NSCLC patients, MET amplification is a frequent event, which could be associated with EGFR amplification, but not with K-Ras mutation. MET amplification may identify a subset of NSCLC for new targeted therapy. It will also be important to evaluate MET copy number to properly interpret future clinical trials.

The combination of the HER2 antibody trastuzumab, the EGFR tyrosine kinase inhibitor gefitinib, and docetaxel as first-line therapy in patients with HER2 overexpressing stage IV breast carcinoma

1057 Background: Interference with both HER2 and epidermal growth factor (EGFR) dependent pathways may improve therapeutic efficacy of docetaxel (doc) in pts with HER2 overexpressing (+) BC. Methods: Patients (pts) without prior chemotherapy (Rx) exposure for stage IV HER-2 + BC were enrolled. Prior hormonal or adjuvant Rx inclusive of taxane or trastuzumab (tras) were allowed. A left ventricular ejection fraction of > 45% and ECOG performance status of ≥ 2 were required. Pts were to receive doc 75 m2, tras every 3 weeks, and gefitinib (gef) 250 mg daily. BC samples from 12 pts were analyzed by FISH for HER2 and EGFR amplification (amp), and topoisomerase II (topo II) amp or loss. IHC was to be performed to examine p-Src, p-STAT3, Ki67 and survivin expression. Results: The median age was 49 (range, 34–67) and ECOG performance status 0.5 (0–1). The first 9 patients received gef 250 mg daily; 2 pts received dox 75 mg/m2 and developed grade 3 febrile neutropenia (neu), hence, additional pts received doc at 60 mg/m2: 3 more episodes of grade 3 neu were seen. Gef was held due to grade 3 dermatitis (2 pts) and diarrhea (2 pts). Pts received a median of 6 cycles (3–10). Gef schedule then was changed, and was prescribed on days 2–14, only. Three of the next 9 pts experienced grades 3 or 4 neu, and we observed 3 cases of grade 3 gastrointestinal toxicities; pts were able to receive 11 + (range; 5–25+) cycles on this schedule (p<0.04). There were 4 complete (CR)and 6 partial R (23 % CR, 59 % overall R), and 3 pts had stable disease (SD; all R and SD confirmed); 3 pts progressed at 4, 4, and 5 mos, 1 pt was inevaluable. The median time to progression is 12 + mos. Samples from 3 pts revealed topo II amplification and one pt sample showed loss of one topo II allele; none were amplified for EGFR. Outcome will be correlated with IHC defined signal trasduction status and proliferation rates. Conclusions: The combination of doc, tras, and short course of gef is feasible, with encouraging R and SD rates and time to progression. Further exploration of simultaneous blockage of multiple signal transduction pathways is indicated in combination with chemoRx. Supported by NCI CA33572 and by a grant from AstraZeneca. No significant financial relationships to disclose.