The TRACERx study investigated phylogenetic tracking and minimal residual disease (MRD) detection using circulating tumor DNA (ctDNA) profiling following resection in patients with stage I to III non–small cell lung cancer (NSCLC). Investigators found that ctDNA is an adjuvant biomarker capable of both detecting MRD following surgery and defining the clonality of relapsing disease. Abbosh et al will present the data at the American Association for Cancer Research (AACR) Virtual Annual Meeting (Abstract CT023).
MRD detection in solid tumors describes the isolation of ctDNA molecules in the blood following cancer treatment. The detection of MRD following surgical removal of a tumor categorizes patients as being at high risk for disease recurrence. Establishing an MRD approach to treating early-stage NSCLC will facilitate the escalation of standard-of-care treatment in patients whose disease will relapse and overcome challenges associated with conventional adjuvant drug-trial design.
The researchers generated patient-specific anchored-multiplex polymerase chain reaction (AMP) enrichment panels for 78 patients with stage I to III NSCLC who had undergone surgery and analyzed 608 plasma samples. Extensive patient-specific circulating-free DNA (cfDNA) enrichment panels targeted a median of 196 (range = 72–482) clonal and subclonal variants detected in primary tumor tissue by multiregion exome sequencing.
Analytic validation experiments benchmarked assay performance.
The researchers’ analytic validation of a 50-variant AMP-MRD assay demonstrated a sensitivity of 89% for mutant DNA at a mutant allele frequency of 0.008% (with 25 ng of DNA input into the assay). Specificity was 100% experimentally and 99.9% (95% confidence interval = 99.67%–99.99%) modelled in silico.
The researchers found that 45 patients had a relapse of their primary NSCLC; ctDNA was detected at or before clinical relapse in 37 of these patients. In these 37 patients, the median ctDNA lead-time (time from ctDNA detection to clinical relapse) was 151 days (range = 0–984 days), and the median time to relapse from surgery was 413 days (range = 41–1,242 days).
In 10 of 10 patients who developed second primary cancers during follow-up, no ctDNA was detected, reflecting specificity of the MRD assay toward the primary tumor. In 23 patients who remained relapse-free during a median of 1,184 days of study follow-up, ctDNA was detected in 1 of 199 time points analyzed.
Analysis of standard-of-care adjuvant surveillance imaging with computed tomography (CT), positron-emission tomography/CT, or magnetic resonance imaging for 220 encounters revealed examples of MRD-positive patients where standard-of-care radiologic surveillance was negative for impending relapse. Through the application of large cfDNA enrichment panels targeting up to 483 variants per patient, the researchers observed dynamic changes in clonal composition and copy-number status prior to NSCLC relapse, categorized relapse as monoclonal or polyclonal, and identified distinct subclonal dynamics during systemic intervention for disease recurrence.
The study authors concluded, “ctDNA is an adjuvant biomarker capable of both detecting MRD following surgery and defining the clonality of relapsing disease. These data pave the way for clinical trials predicated on escalation of adjuvant standard of care in [patients with] non–small cell lung cancer who exhibit MRD-positive status following surgery.”
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