Abstract:

Background and purpose: EGFR-TKI (EGFR-tyrosine kinase inhibitors), represented by gefitinib and erlotinib, have exhibited significant antiproliferative effects against non-small cell lung cancer (NSCLC) with low toxicity. EGFR gene mutation was discovered to be a predictive biomarker for EGFR–TKI treatment. Although the efficacy of EGFR-TKI is limited to EGFR wild-type patients, it is still noticeable suggesting that some other mechanisms are responsible for it. The current study is aimed at evaluating the expression of phosphorylated EGFR in advanced NSCLC, investigating its relationship with EGFR mutations and EGFR-TKI efficacy. Methods: EGFR gene mutations were detected by denaturing high performance liquid chromatography (DHPLC) in 205 stage ⅢB-ⅣNSCLC patients. The expressions of phosphorylated tyrosine 1068 (pTyr1068) and 1173 (pTyr1173) were detected by immunohistochemistry. Results: The positive expressions of pTyr1068 and pTyr1173 were 80.0% (164/205) and 57.6% (95/165) respectively. None of them were related to clinical pathological characteristics (age, gender, pathological type, smoking status, disease stage). EGFR gene mutation rate was 44.9% (92/205), which was only related to smoking status (P=0.024) compared to other clinical pathological characteristics. EGFR gene mutations were poorly related to pTyr1068 expression (P<0.001) and not related to pTyr1173 expression (P=0.297). The objective response rate (ORR), disease control rate (DCR), and progressive free survival (PFS) of EGFR-TKI treatment in patients with EGFR mutations were 48.3% (43/89), 80.9% (72/89) and 8 months (95%CI: 6.11-11.42) respectively, which were significantly higher than that of EGFR wild-type patients [ORR=16.2% (17/105, P<0.001); DCR=56.2% (59/105, P<0.001); Median PFS: 2.1 months, (95%CI: 0.89-3.24; P=0.001)]. Superior ORR: DCR and PFS appeared in patients with pTyr1068 positive expression compared to negative [ORR: 37.7% (58/154) vs 5.0% (2/40, P<0.001); DCR: 74.7% (115/154) vs 40.0% (16/40, P<0.001); Median PFS: 7.0 months vs 1.2 months, P<0.001)]. Inversely, the patients with pTyr1173 positive expression had lower ORR, DCR and shorter PFS [ORR: 27.8% (25/90) vs 37.9% (25/66, P=0.123); DCR: 64.4% (58/90) vs 83.3% (55/66, P=0.007); Median PFS: 4.8 months vs 7.7 months (P=0.016)]. In subgroup of EGFR wild-type patients, positive expression of pTyr1068 was 69.0% (69/100). EGFR wild-type patients with pTyr1068 positive expression had a prolonged PFS and elevated ORR and DCR compared to negative [median PFS: 3.6 months vs 1.2 months (P<0.001); ORR: 23.2% vs 3.2% (P=0.010); DCR: 69.6% vs 35.5% (P=0.001)]. Sixteen patients with pTyr1068 positive expression who responded to EGFR-TKI treatment in this subgroup had a remarkable PFS [median PFS: 15.6 months (95%CI: 7.28-23.9)]. Multiple factor analysis showed that the expression of pTyr1068 was an independence predictor factor for EGFR-TKI treatment (OR=0.24, 95%CI: 0.16~0.37, P<0.001). Conclusion: Phosphorylation at Tyr1068 of EGFR might be a potential predictive factor for clinical response and survival of EGFR-TKI treatment in patients with advanced NSCLC, especially in EGFR wild-type patients.

Key words: Advanced non-small-cell lung cancer, Epidermal growth factor receptor phosphorylation, Epidermal growth factor receptor mutation, Epidermal growth factor receptor-tyrosine kinase inhibitors, Predictive factor.