Dynamic monitoring of EGFR mutations in circulating cell-free DNA for EGFR-mutant metastatic patients with lung cancer: Early detection of drug resistance and prognostic significance

Abstract

Abstract. Detecting genetic mutations in circulating cell-free DNA (cfDNA) is a promising approach of liquid biopsy. Between June 2014 and May 2015, 168 plasma samples were collected monthly from 20 patients with metastatic lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation receiving gefitinib therapy. Clinically relevant EGFR mutations, including exon 19 deletion, L858R and T790M, were quantified using droplet digital polymerase chain reaction. In baseline samples, 19 (95.0%) patients had the same mutation with the matched tumors, and pretreatment T790M mutations were also detected in 3 (15.0%) patients. The dynamics of EGFR mutations were generally associated with treatment response for patients with or without measurable disease. For patients with immeasurable tumor deposits, monitoring disease evolution using cfDNA-based mutation quantification appeared to be more reliable compared with measuring the diameters of target tumor lesions. In addition, molecular progressive disease, defined as a ≥20% increase of EGFR mutation concentration compared with the lowest concentration recorded during treatment, was tracked up to 8 months prior to objective progression. In survival analysis, sex (P= 0.005), pretreatment T790M mutation status (P= 0.006), T790M mutation status at the disease progression (P= 0.043) and growth rate of EGFR mutations (P= 0.023), had a significant impact on median progression-free survival. In conclusion, dynamic monitoring of EGFR mutations in cfDNA is feasible and appears to be useful in early prediction of drug resistance for patients with lung cancer receiving EGFR tyrosine kinase inhibitors.

Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings

“…17,18 This approach allows for regular testing of patients at various stages of treatment, for efficacy monitoring and real-time identification of potential new mutations. 15,18,19 Liquid biopsies have been tested in the context of EGFR mutation-positive (EGFRmþ) NSCLC and can be used for detection of Del19 and L858R. 10,14,15,20,21 EGFR mutations detected in plasma and urine have been shown to be concordant with those identified by tumor biopsy, supporting the use of liquid biopsies as a screening tool.…”

“…15,18,19 Liquid biopsies have been tested in the context of EGFR mutation-positive (EGFRmþ) NSCLC and can be used for detection of Del19 and L858R. 10,14,15,20,21 EGFR mutations detected in plasma and urine have been shown to be concordant with those identified by tumor biopsy, supporting the use of liquid biopsies as a screening tool. 10,14,22 In addition, use of liquid biopsies from plasma to monitor tumor progression and identify EGFR mutations associated with resistance to therapy (e.g., acquired T790M) has been documented, with such biopsies showing 60-80% sensitivity and specificity approaching 100% in detecting specific resistance mutations.…”

“…[11][12][13] In addition, tissue biopsies, particularly re-biopsies at the point of progression on initial treatment, are invasive and costly, and therefore not always feasible. 10,11,[14][15][16] Given these drawbacks, the less invasive liquid biopsy may be preferred over traditional tumor biopsy, particularly in monitoring for resistance. 11 The use of liquid biopsies, which may be obtained from blood, saliva, or urine, provides a minimally invasive method for collecting cell-free circulating tumor DNA and circulating tumor cells.…”

“…10,14,22 In addition, use of liquid biopsies from plasma to monitor tumor progression and identify EGFR mutations associated with resistance to therapy (e.g., acquired T790M) has been documented, with such biopsies showing 60-80% sensitivity and specificity approaching 100% in detecting specific resistance mutations. 15,16,21,[23][24][25] EGFR tyrosine kinase inhibitors EGFR-driven tumors become dependent on EGFR signaling for growth and survival, a phenomenon known as oncogene addiction. 5,26 Oncogene addiction postulates that some tumors become dependent on a single oncogene for growth and survival, such that inhibition of this oncogene is sufficient to block tumor growth and induce tumor regression.…”

A case report of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR -tyrosine kinase inhibitors with T790M mutation and epithelial-to-mesenchymal transition

“…In terms of the acquired TKI resistant T790M mutation, it may be harbored in the original lesion but at levels below the threshold of detection, and then may expand selectively under Gefitinib treatment, leading to the failure of Gefitinib therapy. And this resistance mechanism that the selected amplification of minority cancer cells with preexistence gene mutation under the TKI therapeutic pressure have being evidenced in some in vitro and in vivo experiments of NSCLC [7] , [8] , [15] , [16] , [17] , [18] , which indicate that heterogeneous tumors inherently possess the potential to give rise to EGFR -TKI resistant cells with different resistance mechanisms depending on the treatment, and which has also been concerned and recognized for a long time [19] , [20] . It happens that there are similar comparable reports about the tumor lesion heterogeneity, in which the main points are that a single biopsy from a tumor might not be sufficient to give a full picture of its genetic landscape [6] .…”