| Background and Objection:Epidermal growth factor receptor (EGFR) mutation status is one of the most critical factors for clinicians to develop multiple strategies in non-small cell lung cancer (NSCLC) patients. Previous studies had reported that EGFR mutation might promote the proliferation, invasion and metastasis of tumor cells though the signal pathways including MAPK, PI3K/Akt and Jak/Stat. These opinions was demonstrated in many preclinical studies gradually. However, whether EGFR mutation affect the proliferation, invasion and metastasis of tumor cells in human was still unknown. Here we conducted a retrospective study to outline the Whether EGFR mutations associated with more aggressive clinical characteristic. In addition, in the past decade, For patients with advanced NSCLC harbored an activating mutation in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR), targeted treatment of the EGFR-TK inhibitors (TKIs) such as gefitinib and erlotinib has been shown to be effective. Several clinical trials have demonstrated the superiority of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) over chemotherapy in the treatment of patients with advanced NSCLC harboring EGFR mutations2-6. Therefore, EGFR-TKIs have been recommended as the standard of care for first-line treatment for EGFR-mutant NSCLC. However, not all the patients who harbored a sensitive mutation showed dramatic response to EGFR-TKIs. Some patients had benefit from EGFR-TKIs for more than 2 years while some patients had a primary resistance to EGFR-TKIs when harbored sensitive EGFR mutation. To distinguish patients who are most likely to experience an expected response to EGFR-TKIs and who are not is now emerging as a crucial issue. Here, aimed to explore the correlation of epidermal growth factor receptor (EGFR) mutation with tumor node metastasis (TNM) stage in patients with non-small-cell lung cancer (NSCLC) and to find a predictor of the efficacy of EGFR-TKIs in EGFR-mutant non-small-cell lung cancer (NSCLC).Methods and materialsIn the first part of this study, we consecutively enrolled the patients diagnosed with NSCLC who underwent EGFR mutation status testing in Nanfang Hospital between July 2010 and June 2014. Patients’EGFR mutation status, clinical characteristics (including gender, age and family history), smoking history, tumor histology and imaging examination at initial diagnosis (including PET/CT, chest CT scan, abdominal CT or B ultrasounds, brain MRI, radionuclide bone imaging and so on). The 7th edition of American Joint Committee on Cancer (AJCC) was applied to evaluate the TNM stage for every patient. Tumor histology and TNM stages of patients were confirmed by at least two relevant experts who did not know the EGFR mutation status. All the patients enrolled should meet the following criterion:1. Patients should be diagnosed as non-small-cell lung cancer by histology or cytology diagnosis; 2. Have a complete clinical characteristical information; 3. None tumor-related therapy was done before imaging examination; 4. Have a complete imaging examination to evaluate the TNM stage. We analyzed the correlation between EGFR mutation status and TNM stage from different EGFR mutation status group.In the second part of this study, a total of 108 Chinese patients were enrolled from four medical centers in China including Nanfang hospital of Southern Medical University, the first affiliated hospital of Fujian Medical University, the second affiliated hospital of Fujian Medical University and Guangdong Province Traditional Medical Hospital. Criteria for the patients enrolled in this retrospective study are as follows:1. diagnosed with advanced NSCLC; 2. EGFR mutation test was performed in primary tissue; 3. The kit applied to test EGFR mutation status should be Human EGFR Gene Mutation Detection Kit (PCR Fluorescence Probe) (Shanghai Yuanqi Bio-Pharmaceutical Company Limited, Shanghai, China) 4. Patient harbored a drug sensitivity associated mutation site (19Del and L858R) tested by ARMS 5. Patient received treatment of EGFR-TKIs including gefitinib, erlotinib and icotinib as a monotherapy at any time. The data we collected of all patients were from the electronic medical record system in the four medical centers. Patients with a ACt value less than 1 harbored high ratio of EGFR mutation but the patients with a ACt value between 1 to cut-off AC tharbored low ratio of EGFR mutation in the tumor sample. The first end point was Progression-free survival (PFS) and the second end points were, objective response rate (ORR) and rate of primary resistance.Results:A total of 677 Chinese NSCLC patients enrolled in this study. EGFR mutations were found in 39.0% of the patients. EGFR mutations were found preferentially in females than males (57.7% vs 29.9%, P<0.001), never smokers than current or former smokers (53.9% vs 23.5%, P< 0.001) and adenocarcinomas than non-adenocarcinoma (46.4% vs 16.3%, P<0.001). Difference in EGFR mutation rate between patients detected by the methods of Sanger sequence and ARMS was not significant (40.9% vs 36.7%, P=0.256).We observed that the distribution of T and N stages between different EGFR mutation status was similar (T:P=0.468; N:P=0.053). However, data showed that the tumor size in EGFR mutation group was significantly smaller than the wild-type group (P<0.001). Further, data showed that patients had a higher rate of distant metastasis in patients with EGFR mutations than the wild type (58.7% vs 44.6%, P< 0.001). Of note, the rates of distant metastases in bone (32.2% vs 22.8%, P=0.007) and brain (16.3% vs 9.4%, P=0.008) were higher in patients with EGFR mutations than the wild type. However, data showed that distant metastases rates were similar in lung (17.0% vs 14.8, P=0.427), pleural (16.3% vs 11.1%, P=0.053), liver (5.7% vs 5.8%, P=0.944) and adrenal metastasis (6.1% vs 7.7%, P=0.404).In addition, in the IV stage NSCLC patients, we observed that EGFR mutant NSCLC patients in this stage still had a trend to smaller tumor size (P=0.023). However, the distribution of T, N, M stage in advance NSCLC between EGFR mutation and wild-type group was similar (P=0.928, P=0.497, P=0.053).We observed that the distribution of T and N stages between different EGFR mutation status was similar (T:P=0.468; N:P=0.168). However, data showed that the tumor size in EGFR mutation group was significantly smaller than the wild-type group (P\0.001). Further, patients with EGFR mutations were demonstrated significantly more frequent in patients with distant metastasis than non-metastasis (46.0 vs 33.2%, P=0.008). Further, data showed that patients had a higher rate of distant metastasis in patients with EGFR mutations than the wild type (58.5 vs 45.0%, P= 0.008). Of note, the rates of distant metastases in bone (34.6 vs 24.8%, P=0.034) and brain (15.7 vs 6.6%, P=0.003) were higher in patients with EGFR mutations than the wild type. However, data showed that distant metastases rates were similar in lung (16.4 vs 12.4%, P=0.264), pleural (16.4 vs 13.6%, P=0.453), liver (6.3 vs 7.9%, P=0.555) and adrenal metastasis (8.8 vs 10.7%, P=0.526;).Next, analyses were performed to explore the relationship between TNM stage and EGFR mutation status in stage IV NSCLC patients. Data showed that patients in EGFR mutation group had smaller tumor size and earlier N stage than the wild-type group, similar to the data we acquired in 401 NSCLC patients. In the 199 stage IV patients in our study,58 (29.2%) had at least three organs of metastases,59 (29.6%) patients had two organs of metastases, and 82 (41.2%) patients had only one organ of metastases. In the massive disordered data, we mainly did analysis in patients with brain, bone, liver or adrenals metastases (the most common extrathoracic metastases for NSCLC which could not find by chest CT scan) to explore the difference between EGFR mutations and wild type. Further, data showed that 20.9%of the patients with EGFR mutation had metastases in brain and bone, while the data in wild-type group were 7.5%(P=0.018). There was no similar result found in bone plus liver (P= 0.385), bone plus adrenals (P=0.826), brain plus liver (P= 0.796), brain plus adrenals (P=0.355) and liver plus adrenals (P= 0.523).A total of 108 patients who fully met the enrollment criteria were enrolled in present study.65 patients had a ACT value less than 1 (group L) and 43 patients equal or more than 1 (group H). The median of age was similar between the group L and group H (60 vs 61, P=0.499).47.7% of group L and 58.1% of group H was female (P=0.287). Rates of never smokers in group L and group H were similar (73.8% vs 67.4%, P=0.471),19Del was more frequent in group L than L858R mutation (70.2% vs 49.0%, P=0.025).96.9% of the patients in group L was adenocarcinoma and 97.7% in group H (P=1.00). TNM stage and line of TKI therapy were all well balanced between the two groups (P=0.716, P=0.520). (Table 1)Efficacy of different ACT value groupsAll the patients were received TKIs from Jan 2012 to Dec 2014 in the four hospitals. The last follow up date was Dec 31,2015. The median follow-up duration was 605 days (range,345 to 1392 days).83.3% of the patients experienced a disease progression. The Median PFS was 336 days (95%CI:292.2 to 379.8) in group L and 206 days (95%CI,148.2 to 263.8) in group H and the difference showed statistically significant (P<0.001). The rate of primary resistance in group H was significantly higher than the group L (23.3% versus 9.2%, P=0.045).The ORRs in group L was significant higher than the group H (60.0% vs 34.9%, P=0.011).21 (19.4%) patients had died at the last follow-up date. The median OS was not available.For patients harbored 19Del mutation, the median PFS was 320 days (95%CI: 256.4 to 383.53) in group L and 203 days (95%CI,164.3 to 247.7) in group H and the difference showed statistically significant (P=0.002). The ORRs in group L was higher than the group H (65.0% vs 47.1%, P=0.207). The rate of primary resistance in group H was not significantly lower than the group L (7.5% versus 5.9%, P=1.000).For patients harbored L858R mutation, the median PFS was 383 days (95%CI: 314.3 to 451.7) in group L and 185 days (95%CI,70.1 to 299.9) in group H and the difference showed statistically significant (P=0.001). The ORRs in group L was higher than the group H (56.0% vs 26.9%, P=0.035). The rate of primary resistance in group H was not significantly lower than the group L (5.9% versus 17.6%, P=0.057).Efficacy of EGFR 19Del and EGFR 21 L858R mutationThe PFS of patients harbored a 19Del mutation was 274 days (95%CI,229.6 to 318.4) and in patients harbored a L858R mutation the PFS was 323 days (95%CI, 258.4 to 387.6) and he difference between the two group was not significant (P=0.457). The ORRs in patients harbored a 19Del was higher than the patients harbored a L858R mutation and the difference showed statistically significant (59.6% vs 39.2%, P=0.034). However, the rate of primary resistance was significantly higher in patients with L858R mutation than the 19Del (23.5% vs 6.3%, P=0.018).In addition, for patients in Group L, the PFS of the patients harbored a 19Del was 320 days (95%CI,256.5 to 383.5) and the L858R was 383 days (95%CI,314.3 to 451.7) and the difference showed not significant (P=0.127). The ORR was similar between the 19Del and L858R mutated patients (65.0% vs 52.0%, P=0.298). Primary resistance rates of 19De1 and L858R was not significantly different too (7.5% vs 12.0%, P-0.542).For patients in Group H, the PFS of the patients harbored a 19Del was 206 days (95%CI,164.3 to 247.7) and the L858R was 185 days (95%CI,70.1 to 299.9) and the difference showed not significant (P=0.413). The ORR was not significantly different between the 19Del and L858R mutated patients (47.1% vs 26.9%, P=0.176). Primary resistance rates of 19De1 and L858R was not significantly different too (15.8% vs 34.6%, P=0.061).ConclusionIn conclusion, we found that EGFR mutations showed higher likelihood of suffering distant metastases, especially bone and brain metastases compared with the wild types in NSCLC. Of note, brain plus bone metastases were found more frequently in EGFR mutation group than the wildtype group at initial diagnosis, which suggested that clinicians should pay more attention on evaluation of distant metastases, especially in brain and bone when making diagnostic and preventive strategies for EGFR-mutant NSCLCs.In addition, our study suggests that the ACT value of EGFR mutations could predict the efficacy of EGFR-TKIs treatment in EGFR mutant NSCLC. We hope this indicator would contribute and more accurate technologies to evaluate the ratio of EGFR mutation in tumors were expected. |
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