Circulating cell-free plasma tumour DNA shows a higher incidence of EGFR mutations in patients with extrathoracic disease progression

Background Non-invasive monitoring of epidermal growth factor receptor (EGFR) mutations conferring sensitivity and resistance to tyrosine kinase inhibitors (TKIs) is vital for efficient therapy of lung adenocarcinoma (LADC). Although plasma circulating cell-free tumour DNA (ctDNA) is detectable at an early stage, the size of the tumour does not strongly correlate with concentration of whole cell-free DNA (cfDNA), including normal leucocyte DNA. We sought to examine the clinical features of patients with LADC whose cfDNA examination held clues for analysis of cancer genomics. Methods Forty-four plasma samples from 37 patients with LADC receiving EGFR-TKI therapy, including 20 who developed resistance, were prospectively subjected to droplet digital PCR-cfDNA analysis to detect EGFR mutations and analysed according to clinical features. Results cfDNA samples from 28 (64%) of the 44 samples were positive for TKI-sensitive mutations. Samples from 19 (95%) of the 20 EGFR-TKI-resistant patients were positive for TKI-sensitive mutations. In 24 patients without TKI resistance, 7 (54%) of 13 patients with regional lymph node metastases, 4 (67%) of 6 patients with advanced T stage (T3 or T4) and 8 (57%) of 14 patients with extrathoracic disease progression were also positive for TKI-sensitive mutations. cfDNA analysis from patients with acquired TKI-resistance disease or extrathoracic disease progression correlated with a high detection rate of TKIsensitive mutations (acquired resistance: risk ratio=2.53, 95% CI 1.50 to 4.29; extrathoracic disease progression: risk ratio=5.71, 95% CI 0.84 to 36.74). Conclusions cfDNA in patients with EGFR-TKI-resistance or extrathoracic disease progression may be useful for analysis of cancer genomics. Trial registration number UMIN 000017581.