1100MO - Molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms

Background

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.

Methods

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).

Results

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%).

Conclusions

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

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Novartis and Ipsen.

Disclosure

All authors have declared no conflicts of interest.