Relationship between EGFR protein phosphorylation,EGFR mutation and EGFR-TKI efifcacy in advanced non-small cell lung cancer / 中国癌症杂志

ABSTRACT

Background and purpose:EGFR-TKI (EGFR-tyrosine kinase inhibitors), represented by geiftinib and erlotinib, have exhibited signiifcant 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 efifcacy of EGFR-TKI is limited toEGFR 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 withEGFR mutations and EGFR-TKI efifcacy.Methods:EGFR gene mutations were detected by denaturing high performance liquid chromatography (DHPLC) in 205 stageⅢB-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 withEGFR mutations were 48.3% (43/89), 80.9% (72/89) and 8 months (95%CI 6.11-11.42) respectively, which were signiifcantly higher than that ofEGFR 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 monthsvs 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 monthsvs 7.7 months (P=0.016)]. In subgroup ofEGFR 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 monthsvs 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%CI7.28-23.9)]. 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 inEGFR wild-type patients.