Circulating Tumor DNA for Early Risk Stratification of Oligometastatic Lung Cancer

Abstract

Some patients with oligometastatic disease experience prolonged progression-free survival when treated with local consolidative radiotherapy (RT). Precisely identifying these patients remains challenging, however. We hypothesized that pre-RT liquid biopsy circulating tumor DNA (ctDNA) analysis could risk-stratify oligometastatic non-small-cell lung cancer (NSCLC) patients and enable earlier personalized selection for consolidative RT. A real-world multi-institutional cohort of 1,487 patients who were diagnosed with oligometastatic NSCLC was analyzed. Each patient underwent liquid biopsy ctDNA analysis using the Tempus xF assay (v2) at least once, for a total of 1,880 ctDNA assays. 20% of the cohort (n = 309) underwent RT after liquid biopsy was obtained and oligometastatic NSCLC was diagnosed by the treating physician. Each patient in the sub-cohort of 309 patients had oligometastatic disease, defined as metastatic disease present in 1-5 organ systems. Outcomes for overall survival (OS) and progression-free survival (PFS) were defined with respect to the initiation time of RT to minimize the risk of guarantee-time bias. ctDNA results were analyzed for variants using VarDict and characterized as pathogenic or likely pathogenic following ACMG/AMP guidelines for variant classification, as determined by SnpEff. Variants considered benign, likely benign, or having conflicting evidence were excluded from consideration. Overall survival was significantly worse in oligometastatic NSCLC patients with detectable ctDNA pre-RT, as compared to those without detectable ctDNA pre-RT, with a median OS of 16.8 months versus 25 months (p = 0.030, HR = 1.65, CI = 1.05-2.61). Similar findings were also observed for PFS, which was worse in patents with detectable ctDNA pre-RT, with a median PFS of 5.4 months versus 8.8 months (p = 0.004, HR = 1.57, CI = 1.15-2.13). ctDNA variant allele frequency (VAF) levels demonstrated significant risk correlations, with the maximum pre-RT ctDNA VAF associated with increased risk of both disease progression (p = 0.0084) and death (p = 0.0073). These findings were corroborated by multivariate Cox proportional hazards modeling for PFS (p = 0.02, PFS HR = 4.69, CI = 1.42-13.30) and OS (p = 0.004, HR = 5.66, CI = 1.64-16.85). Notably, multivariate Cox modeling did not show significant impacts of other clinical parameters, including gender, age at diagnosis, smoking status, and squamous histology. Additionally, the ctDNA mutational burden (the number of detectable pathogenic or likely pathogenic variants) was significantly associated with risk for both PFS (p = 0.003, HR = 1.16, CI = 1.06-1.26) and OS (p = 0.003, HR = 1.15, CI = 1.04-1.25) in a multivariate Cox regression model. These data suggest that liquid biopsy ctDNA detection represents a powerful pre-RT biomarker to risk-stratify oligometastatic NSCLC patients and potentially enable personalized decision-making for local consolidative RT.