Ultrasensitive Circulating Tumor DNA Improves NSCLC Detection

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Ultrasensitive circulating tumor DNA (ctDNA) detection appears to improve the clinical sensitivity of minimal residual disease (MRD) at key landmarks in early stage non-small cell lung cancer (NSCLC), researchers reported at the 2024 ASCO Annual Meeting.

“PhasED-Seq detected MRD at levels below one ppm and was associated with significantly better outcomes, revealing potential benefits of adjuvant therapy in patients with MRD+. This suggests that ultrasensitive MRD detection is promising for use in risk-adapted trials in early stage NSCLC,” James M. Isbell, MD, MSCI, and colleagues wrote in the abstract of their poster presentation.

“Translation of ctDNA MRD in NSCLC has been hampered by suboptimal sensitivity of 1st-generation assays. Here, we explore how improvements in analytical sensitivity can drive improved clinical sensitivity for MRD after surgery in NSCLC,” the researchers added.

To investigate MRD kinetics, Dr. Isbell and his colleagues analyzed longitudinal ctDNA in early stage NSCLC using data from the TRACERx study. The researchers generated patient-specific mathematical models to predict MRD levels at the postsurgical landmark and estimate the impact of an assay’s 95% detection limit (LOD95) on clinical sensitivity.

Dr. Isbell and his colleagues performed tumor-informed ctDNA testing using a single nucleotide variation (SNV) -based assay, Cancer Personalized Profiling by deep Sequencing (CAPP-Seq), and a phased variant-based assay, Phased variant Enrichment and Detection by Sequencing (PhasED-Seq), Foresight Diagnostics, on 269 samples from 46 patients. The researchers also evaluated how well MRD predicted patient outcomes at the landmark time point and the effect of adjuvant treatment.

The researchers assessed ctDNA MRD dynamics in 23 patients with three or more consecutive samples with detectable ctDNA without intervening therapy. MRD kinetics correlated strongly with exponential growth, with a median ctDNA doubling time of 51 days. Extrapolating MRD levels to the postsurgical landmark predicted that improving MRD assay LOD95 from 100 ppm (0.01%) to one ppm could more than double clinical sensitivity.

Dr. Isbell and his colleagues then used two essays to evaluate 46 NSCLC cases. The median LOD95 was one ppm for PhasED-Seq and 84 ppm for CAPP-Seq. Twelve cases were MRD+ by PhasED-Seq, and all of them recurred (100%), with MRD levels as low as 0.19 ppm. By contrast, six cases were MRD+ by the SNV-based approach, and five (83%) recurred. PhasED-Seq had a higher clinical sensitivity than the SNV-based method (12/18, 67% versus 5/18, 28%; P=0.022).

Kaplan Meier analysis for freedom from recurrence showed significantly poorer outcomes for patients with detectable MRD regardless of the method used, but outcomes were better stratified using PhasED-Seq (HR, 3.1 versus 11.4).

Patients with MRD- after surgery, according to both assays, had similar outcomes regardless of adjuvant therapy (chemotherapy, radiotherapy, or both). However, patients with MRD+ by PhasED-Seq who received adjuvant therapy had significantly better outcomes than those who did not (HR 8.2; P=0.00035). No similar benefit for adjuvant therapy was found with the SNV-based assay. Using PhasED-Seq, 80% (4/5) of patients with MRD+ who received adjuvant therapy cleared their MRD, compared to 0% (0/3) who did not have adjuvant treatment.