Prognostic value of acquired resistance-related molecules in Japanese patients with NSCLC treated with an EGFR-TKI

Hidetaka Uramoto, Tadaaki Yamada, Seiji Yano, Nobuyuki Kondo, Seiki Hasegawa, Fumihiro Tanaka
Anticancer Research 2012, 32 (9): 3785-90

BACKGROUND: Most patients with lung cancer experience relapse, although epidermal growth factor receptor (EGFR) of tyrosine kinase inhibitor (TKI) has an astounding effect on tumors with EGFR-activating mutations. It is therefore critical to determine the mechanisms of resistance against agents and the prognostic value of acquired resistance-related molecules to EGFR-TKI.

MATERIALS AND METHODS: Tumor specimens were obtained from 19 matched specimens before and after treatment with gefitinib. A retrospective multi-institutional study analyzed the correlation between patients' survival and acquired resistance-related molecules in non-small cell lung cancer (NSCLC) samples, that possessed sensitive EGFR mutations (7 cases: exon 19 deletion, and 12 cases: exon 21 point mutation). The status of the epidermal growth factor receptor (EGFR) and KRAS genes were investigated by polymerase chain reaction (PCR)-based analyses. Real-time PCR assays were also used to evaluate MET gene amplification. The expression of hepatocyte growth factor (HGF) and changes in the epithelial-mesenchymal transition (EMT) status including the expression of E-cadherin and γ-catenin as epithelial markers, and those of vimentin and fibronectin as mesenchymal markers, were evaluated by immunohistochemistry.

RESULTS: Eight of the gefitinib refractory tumors exhibited a secondary threonine-to-methionine mutation at codon 790 in EGFR (T790M). All of the tumors had wild type KRAS gene expression. No MET amplification was detected in any of the samples. A strong expression of HGF was detected in eight of the specimens at post-treatment. A change in the EMT status between pre-and post-treatment was found in five cases. The 5-year survival rate of patients with and without T790M was 86.7% and 13.3%, respectively (p=0.020). The 5-year overall survival (OS) rate for patients with overexpresion and for those with weak expression of HGF was 75.0% and 22.2%, respectively (p=0.259). In addition, the 5-year OS rate for patients with unchanged and changed EMT status was 83.3% and 40.0%, respectively (p=0.123).

CONCLUSION: The current results showed that the presence of T790M is associated with favorable survival. On the other hand, the patients with weak HGF expression and EMT change tend to have a poor survival. The current patients' selection might be changed by discrimination of acquired resistance-related molecules in patients with NSCLC treated with an EGFR-TKI.


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