Detecting Plasma Epidermal Growth Factor Receptor Mutations of 198 Patients with Surgically Resected Non-small Cell Lung Cancer by Amplification Refractory Mutation System_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

GUOKai ¹ , YANXiao-long ¹ , ZHANGZhi-pei ¹ , HANLu ² , FANLiang-bo ¹ , TONGLi-ping ¹ , ZHANGYong ¹ ,  LIXiao-fei ¹

1. Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an 710038, P.R.China;
2. Department of Ultrasound, Xijing Hospital, The Fourth Military Medical University, Xi’an 710038, P.R.China;

Corresponding author：

LIXiao-fei, Email: lxfchest@fmmu.edu.cn

Keywords：

Epidermal growth factor receptor(EGFR) mutations; Non-small cell lung caner; Plasma; Amplification refractory mutation system(ARMS); Targeted therapy; Survival rate; Survival factor

DOI：

10.7507/1007-4848.20160143

Video：

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Objective To reveal the true value of plasma detection of epidermal growth factor receptor (EGFR) mutation for early-stage non-small cell lung cancer (NSCLC) gene diagnosis and to predict survival prognosis. Methods Tissue samples of positive EGFR mutations by using amplification refractory mutation system (ARMS) method were surgically resected from 198 patients with stage I-IV NSCLC between February 2014 and June 2015 in Tangdu hospital. Paired blood samples were collected before surgery. And the cellfree DNA (cfDNA) in plasma was extracted, plasma EGFR mutations were detected by real-time polymerase chain reaction (PCR). Concentration of cfDNA was measured by ultraviolet spectrophotometry. Follow-up observation for stage Ⅲ_A patients was put into force after surgery. Kaplan-Meire was used in survival analysis. Results The sensitivity of EGFR mutation for the 198 paired tissues and plasma samples was 17.2%.The sensitivity was positively correlated with TNM stage and negatively correlated with tumor differentiation. The sensitivity of sage Ⅲ_A was 33.3%, significantly higher than that of the patients at stage Ⅰ_A (1.6%, P=0.000) and stage Ⅰ_B (7.9%, P=0.004). The sensitivity of poor differentiation was 36.8%, significantly higher than that of high differentiation (0.0%, P=0.000) and moderate differentiation (15.7%, P=0.010). There was no correlation between plasma cfDNA concentration and patient characteristics. Survival analysis showed that plasma detection was a vital factor for predicting postoperative survival prognosis of stage Ⅲ_A patients (P=0.014). Conclusion Tissue samples cannot be replaced by plasma samples for epidermal growth factor receptor (EGFR) mutation test in early-stage NSCLC patients, currently. When the sensitivity increases dramatically in the plasma samples of stage Ⅲ_A NSCLC and poor differentiation tumor, we recommend using plasma detection for gene diagnosis, dynamic monitoring of EGFR mutations in stage Ⅲ_A or poorly differentiated tumors, especially in NSCLC patients whose tissue samples cannot be obtained by surgery. And plasma EGFR detection is a valuable method of forecasting survival prognosis for locally advanced NSCLC patients.

Citation： GUOKai, YANXiao-long, ZHANGZhi-pei, HANLu, FANLiang-bo, TONGLi-ping, ZHANGYong, LIXiao-fei. Detecting Plasma Epidermal Growth Factor Receptor Mutations of 198 Patients with Surgically Resected Non-small Cell Lung Cancer by Amplification Refractory Mutation System. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2016, 23(6): 602-607. doi: 10.7507/1007-4848.20160143 Copy

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6.	Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med, 2010, 362(25):2380-2388.
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8.	尹迎春, 王新美, 李良, 等. 非小细胞肺癌胸腔积液细胞蜡块检测EGFR与K-ras基因突变和EML4-ALK融合基因及其临床病理特征. 中国胸心血管外科临床杂志, 2015, 22(9):870-874.
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11.	He C, Liu M, Zhou C, et al. Detection of epidermal growth factor receptor mutations in plasma by mutant-enriched PCR assay for prediction of the response to gefitinib in patients with non-small-cell lung cancer. Int J Cancer, 2009, 125(10):2393-2399.
12.	Zhao X, Han RB, Zhao J, et al. Comparison of epidermal growth factor receptor mutation statuses in tissue and plasma in stage I-IV non-small cell lung cancer patients. Respiration, 2013, 85(2):119-125.
13.	Ren J, Song GH, Zhang LJ, et al. Low correspondence of EGFR mutations in tumor tissue and paired serum of non-small-cell lung cancer patients. Chin J Cancer Res, 2010, 22(1):27-31.
14.	Robertson EG, Baxter G. Tumour seeding following percutaneous needle biopsy:the real story. Clin Radiol, 2011, 66(11):1007-1014.

1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin, 2011, 61(1):69-90.
2. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2007, 57(1):43-66.
3. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2006, 56(2):106-130.
4. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009, 361(10):947-957.
5. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405):an open label, randomised phase 3 trial. Lancet Oncol, 2010,11(2):121-128.
6. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med, 2010, 362(25):2380-2388.
7. Costa DB, Kobayashi S, Tenen DG, et al. Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer, 2007, 58(1):95-103.
8. 尹迎春, 王新美, 李良, 等. 非小细胞肺癌胸腔积液细胞蜡块检测EGFR与K-ras基因突变和EML4-ALK融合基因及其临床病理特征. 中国胸心血管外科临床杂志, 2015, 22(9):870-874.
9. Mok T, Wu YL, Lee JS, et al. Detection and dynamic changes of EGFR mutations from circulating tumor DNA as a predictor of survival outcomes in NSCLC patients treated with first-line intercalated erlotinib and chemotherapy. Clin Cancer Res, 2015, 21(14):3196-3203.
10. Brevet M, Johnson ML, Azzoli CG, et al. Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genotyping is predictive of tumor EGFR status and response to EGFR inhibitors. Lung Cancer, 2011, 73(1):96-102.
11. He C, Liu M, Zhou C, et al. Detection of epidermal growth factor receptor mutations in plasma by mutant-enriched PCR assay for prediction of the response to gefitinib in patients with non-small-cell lung cancer. Int J Cancer, 2009, 125(10):2393-2399.
12. Zhao X, Han RB, Zhao J, et al. Comparison of epidermal growth factor receptor mutation statuses in tissue and plasma in stage I-IV non-small cell lung cancer patients. Respiration, 2013, 85(2):119-125.
13. Ren J, Song GH, Zhang LJ, et al. Low correspondence of EGFR mutations in tumor tissue and paired serum of non-small-cell lung cancer patients. Chin J Cancer Res, 2010, 22(1):27-31.
14. Robertson EG, Baxter G. Tumour seeding following percutaneous needle biopsy:the real story. Clin Radiol, 2011, 66(11):1007-1014.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Detecting Plasma Epidermal Growth Factor Receptor Mutations of 198 Patients with Surgically Resected Non-small Cell Lung Cancer by Amplification Refractory Mutation System

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