Cell-Free Circulating Tumor DNA for NonInvasive Molecular Profiling Among Patients Undergoing Definitive Chemoradiation for Locally Advanced Lung Cancer

Abstract

Purpose: We prospectively explored the utility of liquid biopsy for cell-free circulating tumor DNA (ctDNA) as a prognostic and predictive biomarker in patients with non-small cell lung cancer (NSCLC) treated with definitive chemoradiation therapy.

Methods and materials: This prospective clinical cohort consisted of patients with unresectable, locally advanced NSCLC who had liquid biopsy testing before initiation of cancer therapy. Liquid biopsy testing was performed using an institutional assay that included 129 genes and paired white blood cell sequencing. Variant allele frequency was defined as the proportion of mutant alleles at a particular genetic locus. A US Food and Drug Administration-recognized database (OncoKB) was used to classify alterations. We evaluated progression-free survival from the start of radiation therapy using the log-rank test.

Results: Among 25 patients with prospective testing of ctDNA levels before therapy initiation, 18 patients had adenocarcinoma (72%), 7 patients had squamous cell carcinoma (28%), and 23 (92%) were former or current smokers. Twelve patients (48%) received adjuvant durvalumab. The median radiation dose was 60 Gy in 30 fractions (range, 55-66 Gy in 20-33 fractions). Seventy-six percent of patients (n = 18) had one or more alterations detected (median, 3 alterations, range, 1-8), including genomic markers of radiation response in 3 patients. The most common driver alteration detected was KRAS mutation in 24% of the cohort (n = 6). The detection of ctDNA levels was significantly associated with pretreatment 18F-fluorodeoxyglucose positron emission tomography standardized uptake value metrics, and the association was strengthened by integrating the number of mutations (compared with variant allele frequency) as the outcome variable. Among patients with baseline detectable ctDNA levels, the median progression-free survival was 21.3 months and was not reached among patients without baseline ctDNA level detection (hazard ratio, 4.54, P = .04).

Conclusions: Prospective liquid biopsy testing among patients treated with definitive chemoradiation therapy identifies driver alterations and markers of radiation response with direct implications for therapy personalization.

Figure 1

Oncoprint of most common alterations detected in circulating tumor DNA. Abbreviation: LR = local recurrence.

Figure 2

(A) Cumulative incidence of distant failure with complete risk of death using cell-free circulating tumor DNA (ctDNA) level detection. (B) Cumulative incidence of local failure with complete risk of death using ctDNA detection.

Figure 2

(A) Cumulative incidence of distant failure with complete risk of death using cell-free circulating tumor DNA (ctDNA) level detection. (B) Cumulative incidence of local failure with complete risk of death using ctDNA detection.

Figure 3

The linear regression curves for the association between detected cell-free circulating tumor DNA (ctDNA), (Max VAF) and SUV_Kurtosis (A) and between ctDNA (number of mutations) and SUV_Max (B). The linear regression equation is inserted above the regression line and the coefficient of determination (P-value) is inserted below the corresponding regression line. Abbreviations: SUV = standardized uptake value; VAF = variant allele frequency.