High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare and have poor outcome. Molecular data for HG GEP-NEN is limited and the WHO classification based on morphology and proliferation, while treatment strategies are extrapolated from small-cell lung cancer (SCLC). We aimed to characterize molecular features and relate these to classification, primary site and potential new treatments.
After pathological re-evaluation, we analysed 360 cancer genes in tumours and matched blood from 172 HG GEP-NEN patients; 147 neuroendocrine carcinomas (NEC) and 25 neuroendocrine tumours (NET G3).
For NEC, frequently mutated genes were TP53 (65%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 48%. Other frequent losses were ARID1A (48%), ESR1 (41%) and ATM (45%). Frequent amplifications were found in MYC (50%) and KDM5A (46%). While these molecular features had limited similarities with SCLC, we found potentially targetable mutations in 72% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). 9/147 (6%) NEC were MSI. Alterations affecting TP53 and RB1 signalling were associated with improved prognosis. NET G3 had frequent mutations in ATRX (16%), MEN1, MYO5B, SF3B1, SMAD2 and TP53 (each 12%).
We performed a comprehensive assessment of the molecular tumour alterations in a large series of gastroenteropancreatic high-grade neuroendocrine neoplasms. We found few RB1 mutations and a marked difference in the molecular profile compared to prior results in SCLC and LCLC, challenging the use of SCLC as a paradigm for GEP-NEC. We found a quite similar profile comparing large-cell and small-cell GEP-NEC, but a profile variation according to primary tumour site and suggest a possible molecular strategy to separate NEC from NET G3. Our study shows a very high fraction of GEP-NEC with targetable mutations, pointing to novel important therapeutic strategies.
Clinical trial identification
Legal entity responsible for the study
Novartis and Ipsen.
All authors have declared no conflicts of interest.