C. Zhao

T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients

BACKGROUND AND PURPOSE Continuous EGFR-TKI treatment beyond progression has shown promising benefit for some patients with acquired resistance to EGFR-TKIs. The aim of this study was to investigate the association of secondary T790M mutation at the time of progression with the efficacy of EGFR-TKI treatment beyond progression. METHODS From March 2011 to March 2013, patients with advanced NSCLC who developed acquired resistance to EGFR-TKI and where a re-biopsy was performed at Tongji University Cancer Institute were included into this study. Scorpion ARMS was used to detect EGFR mutation status. RESULTS A total of 54 patients were enrolled in this study with a median progression-free survival time (PFS1) of 10.9 months according to RECIST criteria. In all, 53.7% (29/54) had T790M mutation after the failure of EGFR-TKIs; PFS1 was not statistically significantly different between patients with T790M mutation and without (13.0 vs. 10.5 months, p = 0.894). In all, 41 patients received TKI treatment beyond progression, including 22 with local progression to receive additional local therapy and 19 with gradual progression to receive additional chemotherapy. The median progression-free survival time (PFS2) of patients who received EGFR-TKI beyond progression treatment was 3.5 months (95% CI, 2.689-4.311). Patients with T790M mutation had significantly longer PFS2 (6.3 vs. 2.6 months, p = 0.002) and overall survival (39.8 vs. 23.2 months, p = 0.044) than those without. CONCLUSION Patients with secondary T790M mutation at the time of progression having gradual or local progression after acquired resistance to EGFR-TKI benefit more from EGFR-TKI treatment beyond progression compared to those without T790M mutation.

Epithelial phenotype as a predictive marker for response to EGFR-TKIs in non-small cell lung cancer patients with wild-type EGFR.

Epithelial‐to‐mesenchymal transition (EMT) has profound impacts on cancer progression and also on drug resistance, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs). Nowadays, there is still no predictive biomarker identified for the use of EGFR‐TKIs in non‐small cell lung cancer (NSCLC) patients with wild‐type EGFR. To clarify the role of EMT phenotype as a predictive marker for EGFR‐TKI, we performed a retrospective study in 202 stage IV or recurrent NSCLC patients receiving gefitinib or erlotinib therapy from June 2008 to September 2012 in our institute. Clinical data and EGFR mutational status were collected, while epithelial, epithelial to mesenchymal, not specified or mesenchymal phenotype were classified according to EMT markers such as E‐cadherin, fibronectin, N‐cadherin and vimentin by immunohistochemistry. Epithelial phenotype was more frequently found in patients with EGFR mutation (p = 0.044). Epithelial phenotype was associated with a significantly higher objective response rate (23.5 vs. 11.1 vs. 0.0 vs. 2.4%, p = 0.011), longer progression‐free survival (4.4 vs. 1.9 vs. 1.7 vs. 1.0 months, p < 0.001) and longer overall survival (11.5 vs. 8.9 vs. 4.5 vs. 4.9 months, p < 0.001) compared to epithelial to mesenchymal, not specified and mesenchymal phenotype in the wild‐type EGFR subgroup. In the subgroup with EGFR mutation, the trend remained but without a statistically significant difference. In conclusion, epithelial phenotype was more likely expressed in patients with EGFR mutation and was associated with a better outcome in advanced NSCLC patients with wild‐type EGFR, which indicates that the EMT phenotype might be a potential marker to guide EGFR‐TKI therapy in this population.

202PCOEXISTENCE OF EGFR MUTATIONS WITH ALK, ROS1 OR RET REARRANGEMENTS IN LUNG ADENOCARCINOMA: A CLINICOPATHOLOGICAL ANALYSIS FROM 646 CHINESE PATIENTS WITH LUNG ADENOCARCINOMA

ABSTRACT Aim: We investigated the incidence of concomitant EGFR mutations and ALK, ROS1 or RET rearrangements in Chinese patients with lung adenocarcinoma and analyzed the clinicopathological characteristics of concomitant EGFR mutations with known fusion genes in lung adenocarcinoma. Methods: We screened 646 patients with lung adenocarcinoma for EGFR using amplification-refractory mutation system (ARMS) assay, and for ALK, ROS1 and RET status using RT-PCR assay. All positive samples were validated by direct sequencing. The clinicopathological characteristics of dual alterations was analyzed. Results: EGFR mutations were found to coexist with fusion genes in 27 (4.2%) patients with lung adenocarcinoma. Of these, EGFR/ALK, EGFR/ROS1 and EGFR/RET co-alterations were identified in 12, 7, and 8 samples, respectively. EGFR/ALK co-alterations were found in 3.2% EGFR-mutated patients and 24% ALK-rearranged patients. EGFR/ROS1 co-alterations were found in 1.9% EGFR-mutated patients and 33.3% ROS1-rearranged patients. EGFR/RET co-alterations were found in 2.2% EGFR-mutated patients and 57.1% RET-rearranged patients. The median age of patients with co-alteration were 56 (range from 28 to 75). Nineteen of 27 (70.4%) patients with dual alterations were female. There was no statistically significant difference in age, gender, smoking status, pathological stage, and adenocarcinoma subtype (according to the 2011 IASLC/ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma) between coexistence and non-coexistence groups. RET/EGFR co-alterations seem to be more common in lepidic predominant adenocarcinoma, and ALK/EGFR co-alterations might occur more frequently in patients with resectable lesion (I-IIIa stage), with a borderline statistical significance (p = 0.062). The median overall survival (mOS) was 74.5 months in non-coexistence group, and the mOS was not reached in coexistence group. Conclusions: EGFR mutations could coexist with ALK, ROS1 or RET rearrangements, with an incidence of 1.0-1.8% of Chinese patients with lung adenocarcinoma. Coexistence of EGFR mutations with fusion genes might be associated with lepidic predominant adenocarcinoma, which is being investigated. Patients with concomitant EGFR mutations and ALK, ROS1 or RET rearrangements might have a better prognosis. Disclosure: All authors have declared no conflicts of interest.