Epidermal growth factor receptor (EGFR) T790M mutation identified in plasma indicates failure sites and predicts clinical prognosis in non-small cell lung cancer progression during first-generation tyrosine kinase inhibitor therapy: a prospective observational study

Abstract

Introduction: Plasma circulating tumor DNA (ctDNA) is an ideal approach to detecting the epidermal growth factor receptor (EGFR) T790M mutation, which is a major mechanism of resistance to first-generation EGFR-tyrosine kinase inhibitor (TKI) therapy. The present study aimed to explore the association of ctDNA-identified T790M mutation with disease failure sites and clinical prognosis in non-small cell lung cancer (NSCLC) patients.

Methods: Patients who progressed on first-generation TKIs were categorized into failure site groups of chest limited (CF), brain limited (BF) and other (OF). Amplification refractory mutation system (ARMS) and droplet digital PCR (ddPCR) were used to identify the T790M mutation in ctDNA. Prognosis was analyzed with Kaplan-Meier methods.

Results: Overall concordance between the two methods was 78.3%. According to both ARMS and ddPCR, patients in the OF group had a significantly higher rate of T790M mutation than did patients in the BF and CF groups (P < 0.001), and a significantly higher T790M mutation rate was also observed in OF-group patients than in those in the CF and BF groups (P < 0.001). AZD9291 was found to be an excellent treatment option and yielded the longest survival for T790M+ patients in all groups who had progressed on EGFR-TKIs; for other treatments, the prognosis of T790M- patient subgroups varied.

Conclusions: The present study demonstrates that T790M mutation in ctDNA is associated with failure sites for NSCLC patients after EGFR-TKI therapy and indicates that both failure site and T790M mutational status greatly influence treatment selection and prognosis.

Keywords: Epidermal growth factor receptor; Failure sites; Non-small cell lung cancer; T790M; ctDNA.

Fig. 1

The scheme of the clinical trial design. TKI tyrosine kinase inhibitor, ctDNA circulating tumor DNA, EGFR epidermal growth factor receptor, ARMS amplification refractory mutation system, ddPCR droplet digital PCR

Fig. 2

EGFR mutations in ctDNA samples from patients with TKI resistance. a EGFR mutation profiles determined by ARMS. b EGFR mutation profiles in T790M+ and T790M− groups assessed by ARMS. c T790M mutation determined by ddPCR. d Scatter plot of the T790M abundance in the groups according to the T790M status by ARMS (top) and the number of patients with different abundance of T790M (bottom). TKI tyrosine kinase inhibitor, ctDNA circulating tumor DNA, EGFR epidermal growth factor receptor, ARMS amplification refractory mutation system, ddPCR droplet digital PCR

Fig. 3

Distribution of EGFR mutations between different failure sites. a The proportion of ARMS^T790M+ and ARMS^T790M− in different failure sites (left). The proportion of ARMS^19del+T790M, ARMS^L858R+T790M, and ARMS^T790M+ in different failure sites (up-right). The distribution of ARMS^wild-type, ARMS^19del, and ARMS^L858R in different failure sites (down-right). b The proportion of ddPCR^T790M+ and ddPCR^T790M− (left), as well as the abundance of T790M in patients with detectable T790M mutation (up-right) and in total patients (down-right). ARMS amplification refractory mutation system, ddPCR droplet digital PCR

Fig. 4

Survival curves of patients with different T790M mutations. a Survival curves after TKI failure in 307 patients. b OS curves for patients with different T790M status, as assessed by ARMS and ddPCR. MST median survival time, ARMS amplification refractory mutation system, ddPCR droplet digital PCR

Fig. 5

Survival curves of patients with different failure sites. a Survival curves categorized by failure site. b Survival curves of T790M+ and T790M− CF patients. c Survival curves of T790M+ and T790M− BF patients. d Survival curves of T790M+ and T790M− OF patients. CF, progressive disease limited to the chest in lung/pleural tissues and lymph nodes, with no evidence of progression beyond the chest; BF, progressive disease in a previously existing site or a new site of metastatic disease in the brain, with no evidence of extracranial progression; OF, progressive disease in other distant sites or multiple sites including the chest and intracranial region. T790M mutation was detected by ddPCR. MST median survival time, ARMS amplification refractory mutation system, ddPCR droplet digital PCR

Fig. 6

Survival curves of patients receiving different subsequent treatments. a Curve for T790M+ and T790M− CF patients. b Curve for T790M+ and T790M− BF patients. c Curve for T790M+ and T790M− OF patients. CF, progressive disease limited to the chest in lung/pleural tissues and lymph nodes, with no evidence of progression beyond the chest; BF, progressive disease in a previously existing site or a new site of metastatic disease in the brain, with no evidence of extracranial progression; OF, progressive disease in other distant sites or multiple sites including the chest and intracranial region. T790M mutation was detected by ddPCR