Real-world tissue-based circulating tumor dna (ctdna) minimal residual disease (mrd) assay predicts outcome in lung cancer patients who had curative treatments

BackgroundAs highly sensitive liquid biopsy assays have been developed, minimal residual disease (MRD) has emerged as a novel tool to predict the prognosis of cancer patients.1 Monitoring MRD during post-curative-intent treatment can help detect relapse of disease many months earlier compared to radiological imaging evaluation.1,2,5 Recurrence remains a challenge among early-stage non-small cell lung cancer (NSCLC) patients who are treated with curative intent.3 Some patients with seemingly successful treatment of early-stage cancer can have occult micrometastases or MRD that persists after the initial therapy which can be a potential source of subsequent metastatic relapse at distant sites.4 This study compares longitudinal changes in tissue-based ctDNA levels of thirty NSCLC patients.MethodsThirty patients included in this study were treated with concurrent chemoradiotherapy or surgery and/or neoadjuvant or adjuvant chemotherapy for stage I-IV lung cancer. The patients underwent a multiplex polymerase chain reaction (mPCR) assay for detection of ctDNA in plasma, where 16 individual-specific mutation signatures were identified by upfront tissue sampling. These were matched to normal whole-exome sequencing to identify progression or relapse of disease (SignateraTM, Natera, Austin, Texas). Patients who were MRD-positive at any time point after curative treatment were defined as ‘MRD positive (MP)’. Among patients who were monitored for two or more times, patients whose MRD was persistently detected in blood were classified as ‘MRD persistently positive (MPP)’. Results ctDNA was evaluated one time in fifteen patients (42.9%) and two or more times in twenty patients (57.1%). MRD was detectable among nine patients (25.7%) after curative treatment at a median of 4 months (range 0–41 months). Among nine MP patients, six experienced progressions. In twenty-nine patients with NSCLC who did not relapse after surgery, the assay confirmed MRD negativity at 71 of 73-time points. Three patients were MPP, ctDNA was continuously detectable in three out of twenty patients, and all of them showed progression, including one patient who died (figure 1). MRD positive patients had marginally worse overall survival (OS) and progression-free survival (PFS) (p=0.092 and p=0.04, respectively). However, persistent MRD positivity showed a stronger correlation with poor OS and PFS (p=0.037 and p < 0.001, respectively) (figure 2).ConclusionsThis is the first report of real-world data on tissue-based ctDNA MRD assay among NSCLC patients treated curatively. The results indicate that post-curative-intent treatment ctDNA MRD monitoring can be predictive of clinical prognosis including OS or PFS.ReferencesZviran A, Schulman RC, Shah M, Hill STK, Deochand S, Khamnei CC, et al. Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat Med. 2020 Jul;26(7):1114–24. Phallen J, Sausen M, Adleff V, Leal A, Hruban C, White J, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017 Aug 16;9(403):eaan2415. Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD, et al. Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling. Cancer Discov. 2017 Dec;7(12):1394–403. Abbosh C, Frankell A, Garnett A, Harrison T, Weichert M, Licon A, et al. Abstract CT023: Phylogenetic tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung TRACERx study. Cancer Res. 2020 Aug 15;80(16_Supplement):CT023. Rolfo C, Mack PC, Scagliotti GV, Baas P, Barlesi F, Bivona TG, et al. Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC. J Thorac Oncol. 2018 Sep 1;13(9):1248–68.Ethics ApprovalThe study was approved by Northwestern University’s Institutional Review Board, study number STU00207117.