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Updated: Aug 9, 2026
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
HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients
F Cappuzzo1, L Toschi, I Domenichini
1Department of Medicine/Medical Oncology and Pathology, University of Colorado Cancer Center, Campus Box 8117; PO Box 6511, Aurora, CO 80045, USA.
Abstract:
In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH+ pattern was significantly associated with female gender (P=0.02) and never smoking history (P=0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P=0.04) than patients with HER3- tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P=0.03) and time to progression (7.7 vs 2.7 months, P=0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3- tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.
Insights
Genomic gain of HER3 was not associated with improved response or survival in non-small-cell lung cancer (NSCLC) patients treated with gefitinib. HER3 status did not predict TKI therapy outcomes in this patient cohort.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Sensitivity to tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) is linked to epidermal growth factor receptor (EGFR) mutations and gain.
- Preclinical studies suggested that HER3 overexpression might enhance TKI sensitivity.
Purpose of the Study:
- To investigate the association between HER3 genomic gain and TKI treatment outcomes in NSCLC patients.
- To determine if HER3 genomic gain serves as a predictive marker for gefitinib therapy.
Main Methods:
- 82 NSCLC patients treated with gefitinib were assessed for EGFR, HER2, and HER3 genomic gain using fluorescence in situ hybridization (FISH) and DNA sequencing.
- Immunohistochemistry was used to evaluate Phospho-Akt status.
Main Results:
- HER3 genomic gain was associated with female gender and never-smoking history.
- Patients with HER3 genomic gain showed a longer time to progression but not improved response rates or survival.
- Combined EGFR and HER3 positivity correlated with higher objective response rates and longer time to progression, but not improved survival.
Conclusions:
- Genomic gain for HER3 is not a reliable marker for predicting response or resistance to TKI therapy in advanced NSCLC.
- HER3 status alone or in combination with EGFR/HER2 does not significantly alter clinical outcomes in gefitinib-treated NSCLC patients.
