Plasma-based longitudinal mutation monitoring as a potential predictor of disease progression in subjects with adenocarcinoma in advanced non-small cell lung cancer

Abstract

Background Identifying and tracking somatic mutations in cell-free DNA (cfDNA) by next-generation sequencing (NGS) has the potential to transform the clinical management of subjects with advanced non-small cell lung cancer (NSCLC). Methods Baseline tumor tissue (n = 47) and longitudinal plasma (n = 445) were collected from 71 NSCLC subjects treated with chemotherapy. cfDNA was enriched using a targeted-capture NGS kit containing 197 genes. Clinical responses to treatment were determined using RECIST v1.1 and correlations between changes in plasma somatic variant allele frequencies and disease progression were assessed. Results Somatic variants were detected in 89.4% (42/47) of tissue and 91.5% (407/445) of plasma samples. The most commonly mutated genes in tissue were TP53 (42.6%), KRAS (25.5%), and KEAP1 (19.1%). In some subjects, the allele frequencies of mutations detected in plasma increased 3–5 months prior to disease progression. In other cases, the allele frequencies of detected mutations declined or decreased to undetectable levels, indicating clinical response. Subjects with circulating tumor DNA (ctDNA) levels above background had significantly shorter progression-free survival (median: 5.6 vs 8.9 months, respectively; log-rank p = 0.0183). Conclusion Longitudinal monitoring of mutational changes in plasma has the potential to predict disease progression early. The presence of ctDNA mutations during first-line treatment is a risk factor for earlier disease progression in advanced NSCLC.

Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors

“…Targeting multiple mutations simultaneously also elevates the sensitivity of detecting ctDNA [12,46]. Indeed, the number of ctDNA negative patients when using NGS approaches is substantially lower (4-8%) than was observed with our single variant assay [14,47]. Studies that used an NGS approach to monitor ctDNA in response to ICI therapy demonstrate a correlation between ctDNA dynamics and response similar to our findings [12,13,48].…”

Kinase drug discovery 20 years after imatinib: progress and future directions

“…More effective targeting of DTP populations may be a new strategy to delay or prevent acquired resistance from occurring 201 . Early intervention may also be facilitated by monitoring molecular tumour progression routinely and non-invasively using ctDNA from patient plasma samples, enabling earlier and more informed changes in treatment management to be deployed on the basis of molecular signals before clinical progression 202 , 203 . Opportunities in this area will expand significantly, as non-invasive technologies for detecting biomarkers become more sensitive and more widely available.…”

KRAS Gene Copy Number as a Negative Predictive Biomarker for the Treatment of Metastatic Rectal Cancer With Cetuximab: A Case Report

“…For example, the detection of ctDNA in peripheral blood has shown great potential in the clinic, particularly for those patients who cannot undergo biopsy ( 52 – 54 ). Recent research found that in patients with advanced non-small cell lung cancer, elevation of ctDNA preceded an abnormal radiographic finding and the frequency of mutated alleles in ctDNA increased consecutively for 3-5 months before clinical evidence of disease progression ( 55 ). Moreover, as for melanoma patients, an undetectable ctDNA at baseline or during treatment tended to correlate with a better objective response to therapy ( 56 ).…”