Correlations between genetic alterations and response/immedi- ate progression to first-line cis/carboplatin and etoposide were frequent, but rarely affected PFS. In MVA, TP53 mutation was a significant predictor for inferior RR to cis/carboplatin for NEC. Except for a longer survival for TP53 mutated SC-NEC after platinum/etoposide, none of the investigated genetic alterations in our study was associated with a significant impact on OS in NEC. When separating NEC according to cell-type, several genetic alterations were correlated to efficacy indicating that the classification of digestive NEC into large cell and small cell is molecularly and clinically relevant. ATM alterations and BRCA mutations could be potential targets for novel therapeutic approaches. Several NET G3 genetic alterations were associated with PFS, however NET G3 cases were limited. When searching for novel prognostic molecular markers, still including the known traditional clinical markers seems important. The reason for the lack of substantial correlations between genetic alterations and OS is not obvious but could be due to the extreme aggressiveness of the disease with a very short PFS and OS. In future search for markers predicting treatment success, a multi-omics approach might be a way to better uncover the molecular mechanism behind the poor treatment outcome for digestive NEC.