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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Tumor gene mutations and messenger RNA expression: correlation with clinical response to icotinib hydrochloride in
Guan-Jun Ren1, Yuan-Yuan Zhao, Yu-Jia Zhu
1Department of Respiration, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China.
Background:
Molecular targeted drugs is now widely used in non-small cell lung cancer (NSCLC) clinical treatment. Icotinib hydrochloride is a new type of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs). In this study, we examined the role of EGFR, K-RAS, B-RAF somatic mutations and EGFR mRNA expression in tumor specimens from advanced NSCLC patients as predicators of the efficacy of icotinib hydrochloride.
Methods:
We analyzed tumor paraffin-embedded specimens, which were obtained from 14 of 40 patients with advanced NSCLC who enrolled in the stage I clinical trial of icotinib hydrochloride. Somatic mutations were evaluated by mutant-enriched liquidchip (MEL) technology, and EGFR mRNA expression was measured by branched DNA liquidchip (MBL) technology.
Results:
In the 14 specimens, seven patients showed EGFR mutations, exon 19 deletion (3/7) and exon 21 point mutation (4/7); and two patients showed K-RAS mutation. No mutations in EGFR exon 20 or B-RAF were detected. In patients with EGFR mutation, one patient developed progress disease (PD), three patients had stable disease (SD), two patients had partial responses (PR) and one patient had a complete response (CR). In patients with wild-type EGFR, four patients had PD, three patients acquired SD, and none had PR/CR (P = 0.0407). EGFR mutations were associated with better progress-free survival (PFS) (141 days vs. 61 days) but without a statistically significant difference (P = 0.8597), and median overall survival (OS) (≥ 449 days vs. 140 days). EGFR mRNA expression levels were evaluated (three high, eight moderate, one low, and two that can not be measured due to insufficient tumor tissue) and no statistically significant relationships was observed with response, PFS or OS.
Conclusions:
The EGFR mutation rate was consistent with that reported in the Asian population, so the MEL technology is reliable for measuring EGFR mutation with high throughput and rapidity. EGFR exon 19 deletions and exon 21 point mutation are predictive biomarkers for response to icotinib hydrochloride as second line treatment or above.
Insights
Epidermal growth factor receptor (EGFR) mutations, specifically exon 19 deletions and exon 21 point mutations, predict a positive response to icotinib hydrochloride in advanced non-small cell lung cancer (NSCLC) patients. This finding supports EGFR mutations as key biomarkers for targeted therapy efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacogenomics
Background:
- Molecular targeted drugs, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), are integral to non-small cell lung cancer (NSCLC) treatment.
- Icotinib hydrochloride is an oral EGFR-TKI used in advanced NSCLC.
- Identifying predictive biomarkers is crucial for optimizing targeted therapy selection.
Purpose of the Study:
- To investigate the predictive value of EGFR, K-RAS, and B-RAF somatic mutations, as well as EGFR mRNA expression, for icotinib hydrochloride efficacy in advanced NSCLC patients.
- To assess the reliability of mutant-enriched liquidchip (MEL) technology for EGFR mutation detection.
Main Methods:
- Analysis of tumor paraffin-embedded specimens from 14 advanced NSCLC patients treated with icotinib hydrochloride in a Phase I clinical trial.
- Somatic mutation analysis using mutant-enriched liquidchip (MEL) technology.
- EGFR mRNA expression measurement via branched DNA liquidchip (MBL) technology.
Main Results:
- Seven out of 14 patients harbored EGFR mutations (3 with exon 19 deletion, 4 with exon 21 point mutation); two had K-RAS mutations.
- Patients with EGFR mutations showed significantly higher response rates (P = 0.0407) and improved median overall survival (OS) (≥ 449 days vs. 140 days) compared to those with wild-type EGFR.
- EGFR mRNA expression levels did not show a statistically significant correlation with treatment response, progression-free survival (PFS), or OS.
Conclusions:
- EGFR exon 19 deletions and exon 21 point mutations are reliable predictive biomarkers for response to icotinib hydrochloride in advanced NSCLC, particularly in the Asian population.
- MEL technology is a validated, high-throughput, and rapid method for detecting EGFR mutations.
- EGFR mutation status is a key determinant of treatment efficacy for icotinib hydrochloride in NSCLC.
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