Fragment size and dynamics of EGFR-mutated tumor-derived DNA provide prognostic information regarding EGFR-TKI efficacy in patients with EGFR-mutated NSCLC

Abstract

Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) is a complementary and alternative test to tissue-based NGS. We performed NGS analysis of ctDNA samples collected from patients with EGFR-mutated non-small cell lung cancer (NSCLC) who received osimertinib; the samples were collected after second-line treatment, before osimertinib treatment, one week and one month after osimertinib treatment, and at the time of resistance formation. We examinedthe correlation with osimertinib efficacy. From January to December 2018, 34 patients with EGFR-mutated NSCLC harboring EGFR T790M mutations were enrolled, and a total of 132 peripheral blood samples were collected. The fragment sizes of EGFR-mutated ctDNAs were significantly shorter than that of their corresponding normal fragments. Osimertinib treatment of patients with shorter EGFR-mutated ctDNA fragments resulted in shorter progression-free survival (PFS). The disappearance time of EGFR-mutated fragment fractions and clonal evolution patterns (new driver mutation group, additional mutation group vs. attenuation group) were each associated with the PFS achieved with osimertinib treatment; however,multivariate analysis revealed that only shorter EGFR-mutated ctDNA fragments were associated with the PFS resulting from osimertinib treatment. EGFR-mutated ctDNA fragment size, time of disappearance of these fragments, and clonal evolution pattern were related to the effects of osimertinib. In particular, short EGFR-mutated ctDNA fragmentation may be closely related to osimertinib efficacy prediction.

Genetic mutation profiling reveals biomarkers for targeted therapy efficacy and prognosis in non-small cell lung cancer

“…Tumor clonal changes can predict the efficacy of EGFR-TKIs and whether patients will develop drug resistance [ [29] , [30] , [31] ]. These genetic clonal changes may include EGFR mutations, mutations in other signaling pathway genes, alterations in cell cycle regulatory genes, and so on.…”

Prognostic Value of Circulating Tumor DNA (ctDNA) in Oncogene-Driven NSCLC: Current Knowledge and Future Perspectives

“…It has been reported that insufficient tumor biopsy samples that yield inconclusive molecular results occur in 8-26% of patients [38]. To this significant problem, EGFR evaluation using ctDNA represents a clinically useful alternative [39]. The diagnostic accuracy of ctDNA analysis in detecting EGFR mutations in NSCLC patients' plasma has been confirmed in several studies, where a high level of concordance compared to traditional tissue genotyping has been observed [40].…”

Endovascular image-guided sampling of tumor-draining veins provides an enriched source of oncological biomarkers

“…This 'liquid biopsy' can characterize a tumor in a manner comparable to a tissue biopsy and holds significant promise for orchestrating approaches for early detection, diagnosis, assessment of minimal residual disease, genotyping tumors, and tracking therapeutic response and resistance (4)(5)(6)(7)(8). Several actionable mutations in genes with diagnostic and prognostic significance, such as EGFR for lung cancer, and KRAS and BRAF for colorectal cancer have been well-studied from ctDNA extracted from peripheral blood samples (9)(10)(11)(12). However, many limitations hold liquid biopsy back from its full potential, and tissue biopsy remains the standard of care in current clinical oncology practice (2, 3, 7, 8).…”