In the absence of sequencing quality issues (for which there was no evidence) or major non-neoplastic clone(s) present in this sample (which is an intriguing possibility that remains hypothetical), the loss of SMAD4—which is the only EAC driver reported as mutated in carcinomas but not in precursors such as Barrett's oesophagus38—raises the possibility that the remaining post-treatment cancer in patient #8 represents an earlier stage of EAC development, such as an early cancer or even severe dysplasia. Here, SMAD4 is linked to cancer.