Paolo Manca, Chin‐Tung Chen, Farheen Shah, Christina Y. Lee, Dylan Domenico, Dana M. Omer, Santiago González, Ino de Bruijn, Samuel Terkper Ahuno, Walid K. Chatila, Madison Darmofal, Iman Tavassoly, Adam J. Widman, Michael F. Berger, Brian Houck‐Loomis, Elli Papaemmanuil, Rona Yaeger, Asaf Zviran, Julio García‐Aguilar, Francisco Sánchez-Vega
Optimal selection of patients with locally advanced rectal cancer for watch and wait (WW) and optimal management during follow-up remain challenging. We employed a primary-tumor-informed whole genome sequencing (WGS) assay to detect circulating tumor DNA (ctDNA) and estimate tumor fraction (TF) before, during and after neoadjuvant therapy. ctDNA was detected in 95% of baseline samples, and TF was a significant baseline predictor of sustained clinical complete response (scCR). High TF during or after neoadjuvant therapy was associated with lower likelihood of scCR and higher risk of relapse. Very low TF during surveillance was detected in a large proportion of patients who did not experience a recurrence, suggesting the existence of persisting low amounts of ctDNA. WGS-based ctDNA assessment thus provides high sensitivity, which is crucial for treatment de-escalation, but additional research is needed to also ensure good specificity (the trial is registered in ClinicalTrials.gov with the identifier NCT02008656).