Treatment outcome according to genetic tumour alterations and clinical characteristics in digestive high-grade neuroendocrine neoplasms

Background Chemotherapy has limited efficacy in advanced digestive high-grade neuroendocrine neoplasms (HG-NEN) and prognosis is dismal. Predictive markers for palliative chemotherapy are lacking, and prognostic markers are limited. Methods Digestive HG-NEN patients ( n = 229) were prospectively included 2013–2017. Pathological re-assessment revealed 188 neuroendocrine carcinomas (NEC) and 41 neuroendocrine tumours (NET G3). Tumour-DNA was sequenced across 360 cancer-related genes, assessing mutations (mut) and copy number alterations. We linked sequencing results to clinical information and explored potential markers for first-line chemotherapy efficacy and survival. Results In NEC given cis/carboplatin and etoposide (PE), TP53 mut predicted inferior response rate in multivariate analyses ( p = 0.009) and no BRAFmut NEC showed response. In overall assessment of PE-treated NEC, no genetic alterations were prognostic for OS. For small-cell NEC, TP53 mut were associated with longer OS ( p = 0.011) and RB1 deletions predicted lack of immediate-progression ( p = 0.003). In non-small cell NEC, APC mut were associated with immediate-progression and shorter PFS ( p = 0.008/ p = 0.004). For NET G3, ATRX mut, ARID1A - and ERS1 deletions were associated with shorter PFS. Conclusion Correlations between genetic alterations and response/immediate-progression to PE were frequent in NEC but affected PFS or OS only when subdividing for cell-type. The classification of digestive NEC into large- and small-cell seems therefore molecularly and clinically relevant.