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<jats:p> 11528 </jats:p><jats:p> Background: Currently, response assessment of patients with non-small cell lung cancer (NSCLC) primarily relies on imaging scans, which do not reflect biological processes at the molecular level. We utilized circulating tumor DNA (ctDNA) coupled with capture-based ultra deep next generation sequencing to conduct dynamic monitoring of treatment response, thus evaluating the ability of ctDNA as a tumor clonal response biomarker. Methods: We performed capture-based sequencing on longitudinal plasma samples, including baseline and a minimum of 2 evaluation points, obtained from 88 patients with advanced NSCLC using a ctDNA panel, spanning 160KB of human genome and consisting of critical exons and introns from 168 genes. This real world study comprises a highly heterogeneous cohort with a mixture of prior treatment exposure. Results: At baseline, treatment-naïve patients often harbor solo driver mutation; in contrast, patients with prior treatments are more likely to harbor concurrent driver mutations. Patients who received molecular targeted therapy according to the baseline sequencing results have a longer progression-free survival (PFS) (p = 0.0001), demonstrating the value of ctDNA in directing treatment. During subsequent evaluations, we observed 74% concordance rate between molecular and radiographic responses. Furthermore, our data revealed that during follow-up, patients with at least one time of undetectable ctDNA are associated with a longer PFS (p = 5.52e<jats:sup>-6</jats:sup>), regardless the type of treatment commenced. Among 44 patients who had at least one time of undetectable ctDNA, 39 achieved partial response or stable disease as their best response. Collectively, this phenomenon reflects clonal response, thus demonstrating the biological nature underlying the clinical response assessed by imaging modalities. Conclusions: This real world study demonstrates that patients with at least one time of ctDNA clearance during subsequent evaluation are associated with a longer PFS. Our study warrants further investigations to explore the value of ctDNA clearance as a surrogate endpoint of efficacy and as a risk stratification factor. </jats:p>
