Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling

Aadel A Chaudhuri, Jacob J Chabon, Alexander F Lovejoy, Aaron M Newman, Henning Stehr, Tej D Azad, Michael S Khodadoust, Mohammad Shahrokh Esfahani, Chih Long Liu, Li Zhou, Florian Scherer, David M Kurtz, Carmen Say, Justin N Carter, David J Merriott, Jonathan C Dudley, Michael S Binkley, Leslie Modlin, Sukhmani K Padda, Michael F Gensheimer, Robert B West, Joseph B Shrager, Joel W Neal, Heather A Wakelee, Billy W Loo, Ash A Alizadeh, Maximilian Diehn

Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.