Elvebakken, HegeHegeElvebakkenVenizelos, AndreasAndreasVenizelosPerren, AurelAurelPerren0000-0002-6819-6092Couvelard, AnneAnneCouvelardLothe, Inger Marie BInger Marie BLotheHjortland, Geir OGeir OHjortlandMyklebust, Tor ÅTor ÅMyklebustSvensson, JohannaJohannaSvenssonGarresori, HerishHerishGarresoriKersten, ChristianChristianKerstenHofsli, EvaEvaHofsliDetlefsen, SönkeSönkeDetlefsenVestermark, Lene WLene WVestermarkKnappskog, StianStianKnappskogSorbye, HalfdanHalfdanSorbye2024-10-262024-10-262024-09https://boris-portal.unibe.ch/handle/20.500.12422/178349BACKGROUND 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), TP53mut 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, TP53mut 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, ATRXmut, 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.en500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healtharticle10.48350/1980453890913710.1038/s41416-024-02773-w