It is noteworthy that a minority of TMB-high (≥20 Mut/Mb) cases occur also in MSS and POLE/POLD wild-type gastrointestinal cancers, mainly associated with mutations in other DNA damage response genes [100], although the effective response to immunotherapy for these tumours is yet to be prospectively evaluated and has shown inconsistent results across different retrospective analyses [101]. This evidence concerns the gene POLE and neoplasm.