Prospective, Cell-Free Circulating Tumor DNA (ctDNA) Profiling in Locally Advanced Lung Cancer Treated with Chemoradiation

Abstract

Liquid biopsy for cell-free circulating tumor DNA (ctDNA) allows for non-invasive, comprehensive genomic profiling. We explored the utility prospective liquid biopsy for (ctDNA) in among non-small cell lung cancer (NSCLC) patients treated with definitive chemoradiation. This prospective clinical cohort consists of unresectable, locally advanced NSCLC patients who had liquid biopsy testing prior to initiation of cancer therapy. Liquid biopsy testing was performed using a next-generation sequencing assay (MSK-ACCESS) which includes 129 genes and paired white blood cell sequencing. An FDA-recognized database (OncoKB) was utilized to classify alterations associated with radiation resistance (including KEAP1, NFE2L2, STK11, and PIK3CA) and radiation sensitivity (including ATM, ATR, BRCA1/2, ARID1A, MLH1 and other DNA Damage Repair Pathway alterations). We evaluated progression-free survival (PFS) from the completion of chemoradiation using the Log-rank test. Among 25 patients with prospective ctDNA testing prior to therapy initiation, 17 patients had stage III disease (68%), 8 patients had stage II disease (32%), 18 patients had adenocarcinoma (72%), 7 patients had squamous cell carcinoma (28%), and 23 (92%) were former or current smokers. The median radiation dose was 60 Gy in 30 fractions (range: 55 to 66 Gy in 20 to 33 fractions). 76% of patients (n = 18) had one or more alterations detected (median: 3 alterations, range: 1 - 8) including genomic markers of radiation response in 2 patients in BRCA1/2 (n = 2) and radiation resistance in 1 patient in KEAP1. The most common driver alteration detected was KRAS in 24% of the cohort (n = 6). Among patients with baseline detectable ctDNA, the median PFS was 21.3 months and was not reached among patients without baseline ctDNA detection (HR 4.54, p = 0.04). Using an institutional assay, the presence of baseline cell-free ctDNA appeared prognostic in patients with unresectable, locally advanced NSCLC treated with definitive chemoradiation. We also detected driver alterations and potential markers of radiation resistance and response using ctDNA testing. Prospective cell-free ctDNA profiling may offer pathways to therapy personalization among patients with locally advanced unresectable lung cancer.