Clinical Significance of Epidermal Growth Factor Receptors in Non-small Cell Lung Cancer and a Prognostic Role for HER2 Gene Copy Number in Female Patients

Introduction: To compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting HER2 alterations and to investigate the prevalence and prognostic significance of Erb family members in non-small cell lung cancer (NSCLC). Methods: Stage I to IIIA tumors from 335 patients with NSCLC were immunohistochemically tested for protein expression of all Erb family members. Membranous HER2 expression was compared with its gene copy number by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with clinicopathological variables. Results: Synchronous high immunohistochemical expression of all Erb family members was seen in 8% of tumor samples. There was a significant correlation between the HER2 gene copy number and HER2 protein expression (p = 0.003). High nuclear HER3 expression correlated significantly with high HER2 gene copy numbers (p = 0.015). In univariate analyses, high HER2 gene copy number was a highly significant negative prognostic indicator for disease-specific survival in women (p = 0.005), whereas it did not show prognostic influence in men (p = 0.9). Neither polysomy of chromosome 17 nor the IHC expression of Erb family member proteins as singles or pairs correlated significantly with survival. In the multivariate analysis, high HER2 gene copy number in tumor epithelial cells (p = 0.03) was an independent prognostic factor for disease-specific survival in female patients. Conclusions: IHC does not consistently identify patients likely to have a poor prognosis, whereas SISH provides superior prognostic information for female patients with NSCLC. High HER2 gene copy number in tumor epithelial cells is an independent predictor of inferior survival in female patients with primary NSCLC.