Correlation of genes associated with drug response to prognosis of large cell lung carcinoma

Abstract

Platinum-based chemotherapy remains the main treatment of advanced lung cancer. However, platinum resistance has become a major treatment obstacle. Novel therapies, particularly tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKI) and agents that target vascular endothelial growth factor (VEGF), have improved the treatment. Both chemotherapy and targeted therapy have their molecular mechanisms. This study aimed to determine the mutation, amplification, or expression status and interrelationships of the epidermal growth factor receptor (EGFR), K-Ras proto-oncogene, excision repair cross-complementation group 1 (ERCC1), and VEGF genes as well as their correlations to prognosis of large cell lung carcinoma (LCLC) after EGFR-targeted therapy, chemotherapy, and anti-VEGF therapy. EGFR and K-Ras mutations in 60 specimens of LCLC were detected by direct DNA sequencing. EGFR, ERCC1, and VEGF protein expression was detected by immunohistochemistry (IHC). EGFR gene copy number was detected by fluorescence in situ hybridization (FISH). One (1.7%) patient had an EGFR L858M point mutation in exon 21, 3 (5.0%) had K-Ras mutations, and 10 (19.6%) had EGFR amplification (FISH positive). Positive rates of EGFR, ERCC1, and VEGF proteins were 38.3%, 56.7%, and 70.0%, respectively. EGFR amplification was positively correlated to EGFR protein expression (r = 0.390, P = 0.005). The positive rate of VEGF protein was significantly higher in patients with lymph node metastasis than in those without (84.6% vs. 58.8%, P = 0.046). No significant correlations were observed among the EGFR, K-Ras, ERCC1, and VEGF genes. EGFR gene amplification and the low rate of EGFR mutation suggest that patients with LCLC are likely to obtain little benefit from anti-EGFR therapies.

Figure 1.. Kaplan-Meier overall survival curves of patients with large cell lung cancer.

A, the overall survival rate of patients with lymph node metastasis is lower than that of patients without lymph node metastasis; B, the overall survival rate of patients with early TNM stage disease is higher than that of patients with advanced stage disease.

Figure 2.. Epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1), and vascular endothelial growth factor (VEGF) protein expression detected by immunohistochemistry and EGFR amplification detected by fluorescence in situ hybridization in large cell lung cancer.

A, positive immunoreactivity of EGFR (in yellow) is evident in the membrane of tumor cells (×400). B, positive expression of ERCC1 protein was detected in the nuclei of cancer cells (×400). C, immunoreactivity for VEGF was detected predominantly in the cytoplasm of tumor cells (×400). D, EGFR amplification was detected by dual-color FISH assay with probes for EGFR (red) and chromosome 7 (CEP7, green). FISH-negative tumor cells show two red and two green signals (×1000). E, cells with amplification show an excess of red signals (×1000).