Longitudinal monitoring of somatic genetic alterations in circulating cell‐free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors

Abstract

Background The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment. Methods Plasma samples were prospectively collected from non–small cell lung cancer patients with EGFR‐activating mutations during EGFR‐TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next‐generation sequencing. Results One hundred patients, including 87 who were EGFR‐TKI naïve, were enrolled. Median progression‐free survival was significantly shorter for EGFR‐TKI–naïve patients with EGFR‐activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P < .001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR‐activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07‐10.79; P < .001) for EGFR‐TKI–naïve patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04). Conclusion Liquid biopsy shows potential for prediction of EGFR‐TKI efficacy and elucidation of clonal tumor evolution during targeted therapy.

Liquid biopsy as a follow‐up tool: Comment on longitudinal monitoring of somatic genetic alterations in circulating cell‐free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors

“…Bone and adrenal glands metastases were more frequent among patients with detectable EGFR ‐activating mutations in cfDNA at baseline than among those without (bone, 56.5% vs 21.6%, P = .001; adrenal glands, 13.0% 6.0 vs 0.0%, P = .02) . These results are in line with a recent pooled analysis of 10 studies suggesting that metastatic site location influences the diagnostic accuracy of circulating tumor DNA (ctDNA) EGFR mutation testing in NSCLC with a higher sensitivity in patients with extrathoracic disease (M1b) versus pulmonary contralateral metastases or pleural/pericardial effusion (M1a) (odds ratio, 5.09; 95% CI, 2.93‐8.84) …”

“…In addition, a crucial point was represented by the detection of EGFR exon 20 p.T790M. The authors confirmed a high efficacy of osimertinib in patients with an elevated basal expression of this mutation (>20 copies/mL) than first‐ or second‐generation TKIs . To overcome the limited reference range of ddPCR, with the aim to identify other resistance mechanisms than the traditional one ( EGFR exon 20 p.T790M) in the NSCLC patients population considered in the study by Iwama et al, the authors performed an NGS‐based analysis of collected ctDNA samples, showing that the number of mutations identified in ctDNA was significantly higher in patients experienced a disease progression than at baseline ( P = .04) …”

“…Another relevant point raised by the authors was the high rate of progression in patients with an increase of EGFR mutation detection during TKI treatment (PFS, 9.1 months vs 19.0 months; hazard ratio, 4.72) . In addition, a crucial point was represented by the detection of EGFR exon 20 p.T790M.…”

“…Recently, the therapeutic landscape of EGFR ‐mutated NSCLCs has been revolutionized by the advent of the third‐generation EGFR‐TKI osimertinib in a first‐line setting, replacing first‐ and second‐generation inhibitors and changing the scenario of mechanisms of acquired resistance, including druggable alterations such as MET amplification, EGFR C797S mutation, PIK3CA mutation, BRAF mutation, and HER2 amplification/mutation, among others . In this issue of Cancer , Iwama et al evaluated the role of a longitudinal monitoring of somatic genetic alterations in cell‐free DNA (cfDNA) of EGFR ‐mutated NSCLC patients throughout EGFR‐TKI treatment. Using digital droplet polymerase chain reaction (ddPCR) and NGS, the authors evaluated the presence of somatic mutations and alterations at baseline and every 12 weeks until progression in 100 NSCLC patients who harbored sensitive EGFR mutations.…”

“…Interestingly, median progression‐free survival (PFS) was significantly longer in patients with undetectable EGFR mutations at baseline (19.0 months vs 7.9 months), suggesting a prognostic role for cfDNA quantity . Other investigators have evaluated the role of cfDNA quantity as a prognostic factor, in addition to the detected mutation variants .…”