Changes in the concentration of EGFR-mutated plasma DNA in the first hours of targeted therapy allow the prediction of tumor response in patients with EGFR-driven lung cancer.

PURPOSE: This study aimed to analyze changes in the plasma concentration of EGFR-mutated circulating tumor DNA (ctDNA) occurring immediately after the start of therapy with EGFR tyrosine kinase inhibitors (TKIs). METHODS: Serial plasma samples were collected from 30 patients with EGFR-driven non-small cell lung cancer before intake of the first tablet and at 0.5, 1, 2, 3, 6, 12, 24, 36 and 48 h after the start of the therapy. The content of EGFR alleles (exon 19 deletions or L858R) in ctDNA was measured by ddPCR. RESULTS: ctDNA was detected at base-line in 25/30 (83%) subjects. Twelve (50%) out of 24 informative patients showed > 25% reduction of the ctDNA content at 48 h time point; all these patients demonstrated disease control after 4 and 8-12 weeks of therapy. The remaining 12 individuals showed either stable content of EGFR-mutated ctDNA (n = 5) or the elevation of ctDNA concentration (n = 7). 10 of 12 patients with elevated or stable ctDNA level achieved an objective response at 4 weeks, but only 5 of 10 evaluable patients still demonstrated disease control at 8-12 weeks (p = 0.032, when compared to the group with ctDNA decrease). The decline of the amount of circulating EGFR mutant copies at 48 h also correlated with longer progression-free survival (14.7 months vs. 8.5 months, p = 0.013). CONCLUSION: Comparison of concentration of EGFR-mutated ctDNA at base-line and at 48 h after the start of therapy is predictive for the duration of TKI efficacy.

Tumor irradiation may facilitate the detection of tumor-specific mutations in plasma.

BACKGROUND: The mutation-based analysis of circulating tumor DNA (ctDNA) is a promising diagnostic tool for clinical oncology. However, it has low success rate because many cancer patients do not have detectable ctDNA in the bloodstream. AIM: To evaluate whether preoperative tumor irradiation results in a transient increase of plasma ctDNA concentration due to the induction of apoptosis in radiation-exposed cells. METHODS: This study focused on patients with locally advanced rectal cancer, because preoperative tumor irradiation is a part of their standard treatment plan. Nine subjects, whose tumors contained KRAS, NRAS or BRAF mutations, donated serial blood samples 1 h prior to the first fraction of irradiation (at baseline), immediately after the first fraction (time 0), and 1, 3, 6, 12, 24, 36, 48, 72 and 96 h after the first fraction. The amount of mutated gene copies was measured by droplet digital PCR. RESULTS: Five out of nine patients were mutation-negative by ctDNA test at baseline; two of these subjects demonstrated an emergence of the mutated DNA copies in the bloodstream within the follow-up period. There were 4 patients, who had detectable ctDNA in the plasma at the start of the experiment; three of them showed an evident treatment-induced increase of the content of mutated RAS/RAF alleles. CONCLUSION: Local tumor irradiation may facilitate the detection of tumor-specific DNA in the bloodstream. These data justify further assessment of the clinical feasibility of irradiation-assisted liquid biopsy.