EGFR plasma mutation in prediction models for resistance with EGFR TKI and survival of non-small cell lung cancer

Abstract

Background: This study aims to clarify the prognostic role of epidermal growth factor receptor (EGFR) mutations in plasma of non-small cell lung cancer (NSCLC) for resistance to tyrosine kinase inhibitor (TKI), in correlation with clinical characteristics. A total of 94 Adenocarcinoma, clinical stage IV NSCLC patients with either E19del or L858R mutation were admitted to the prospective study from Jan-2016 to Jul-2018. EGFR mutations in plasma were detected by scorpions ARMS method. The Kaplan-Meier and Cox regression methods were used to estimate and test the difference of progression-free survival (PFS) and overall survival (OS) between groups. The prognostic power of each factor was appraised by the Bayesian Model Averaging (BMA) method.

Results: Among 94 patients, 28 cases still are good responses according to the RECIST criteria and negative for EGFR mutations in plasma. Of 66 resistant patients, EGFR mutations were positive in plasma of 57 cases (86.4%) which was higher than the value of pre-treatment (48.5%). Of which, 17 patients (25.8%) have the occurrence of EGFR mutations in plasma earlier than progression 2.1 (0.6-7.9) months. The secondary T790M mutation was found in the plasma of 32 cases (48.5%). Median PFS and OS for the study subjects were 12.9 (11.0-14.2) and 29.5 (25.2-41.3) months, respectively. The post-treatment EGFR plasma test with brain and new metastasis were detected as independent prognostic factors for worse PFS (P = 0.008, 0.016 and 0.028, respectively). While EGFR plasma (P = 0.044) with bone metastasis at baseline (P = 0.012), new metastasis (P = 0.003), and high cfDNA concentration (P = 0.004) serve as the worse survival factors, surgery treatment helps to prolong OS in NSCLC treated with EGFR TKI (P = 0.012). BMA analysis identified EGFR plasma test as the strongest prognostic factor for both PFS and OS (possibility of 100% and 99.7%, respectively).

Conclusions: EGFR plasma test is the powerfully prognostic factor for early resistance with EGFR TKI and worse survival in NSCLC regardless of clinical characteristics.

Keywords: EGFR plasma mutation test; NSCLC; Secondary T790M; cfDNA.

Fig. 1

Patient groups and analysis flow

Fig. 2

Progression-free survival between groups: EGFR plasma after treatment (a^£, b^ǂ); secondary T790M mutation (c^£, d^ǂ); brain metastasis after treatment (e^£, f^ǂ). £: all patients; ǂ: the newly diagnosed group. EGFR epidermal growth factor receptor

Fig. 3

Progression-free survival between groups: new metastasis site (a^£, b^ǂ). £: all patients; ǂ: the newly diagnosed group

Fig. 4

The possibility that factors appear in prognostic models for PFS by the Bayesian Model Averaging method. EGFR mutations in post-treatment plasma (egfr.after) and new metastasis (new.met.site) factors present in most models (100% and 95%, respectively)

Fig. 5

Overall survival between groups: EGFR plasma at baseline (a); EGFR plasma after treatment (b); secondary T790M mutation (c^£, d^ǂ); bone metastasis at baseline (e^£, f^ǂ). £: all patients; ǂ: the newly diagnosed group. EGFR epidermal growth factor receptor

Fig. 6

Overall survival between groups: treatment method (a^£, b^ǂ); new metastasis site (c^£, d^ǂ); brain metastasis after treatment (e^£, f^ǂ). £: all patients; ǂ: the newly diagnosed group. TKI tyrosine kinase inhibitor, Sur surgery, Che chemotherapy, Ra radiotherapy

Fig. 7

Overall survival between groups: bone metastasis after treatment (a^£, b^ǂ); and cfDNA level (c^£, d^ǂ). £: all patients; ǂ: the newly diagnosed group

Fig. 8

The possibility that factors appear in prognostic models for OS by the Bayesian Model Averaging method. Bone metastasis at baseline (bone.base: 68.1%); EGFR plasma at baseline (egfr.base: 99.7%); cfDNA (cfdna: 73.4%); treatment method (treat.method: 83.5%); and new metastasis (new.met.site: 93.2%) factors present in most models