1174P RESUNET (GETNE-2016-01): A phase II study to evaluate the efficacy and safety of the rechallenge with sunitinib in G1/G2 pancreatic neuroendocrine tumours (pNET). A Spanish Task Force Group in neuroendocrine and endocrine tumours (GETNE) study

Abstract

Background: Neuroendocrine tumours (NETs) are clinical heterogeneous. To date, no studies have focused on the genetic characteristics of NETs at different anatomical sites. We aim to explore the genetic similarities or differences between NETs at different sites. Methods:The patients were from a clinical study STEM (from a single institute, NCT03204032, NCT03204019). This cohort included 47 patients, including 14 Pancreatic NETs (pNETs), 11 Rectal NETs, 14 Thoracic NETs, and 8 Others. Whole exome sequencing (WES) was performed. The WES data of pancreatic cancer (PCa), rectal cancer (RC) and lung cancer (LC) from TCGA were used to compare the genetic characteristics with NETs.Results: Somatic mutational analysis showed that there were no differences in tumor mutation burden, intra-tumoral heterogeneity or mutation spectrum between different NETs. We found several specific driver mutations for pNETs (MEN1 et.al), Rectal NETs (APC et.al) and Thoracic NETs (CACNA1A). Compared with cancers, few significantly mutated genes were shared by pNET and PCa; mutations in APC mostly occurred in both Rectal NET and RC; and some common mutations were observed in Thoracic NET and LC. Copy number analysis showed that copy number loss frequently occurred in all NETs. Deletions of chromosomal regions 14q11. 2, 19p13.2, 19q13.31 and 1p36.21 were observed in all NETs. Moreover, we found several specific alterations of chromosomal regions for different NETs. Compared with NETs, counterpart cancers harbored copy number gain as well as copy number loss. Some altered chromosomal regions were shared by Thoracic NET and LC, while none were shared by NET and cancer at pancreas or rectum. Furthermore, we investigated the main altered pathways previously reported in pNETs or small intestine NETs. All NETs had frequent alterations in WNT pathway, PI3K/mTOR pathway, DNA repair pathway, chromatin remodeling pathway and cell cycle pathway. However, several differences in pathway alterations were observed between different NETs, indicating that pathway alterations may be achieved through different genetic routes.Conclusions: NETs at different sites had different genetic characteristics, which have the potential to distinguish the primary site of NETs.Legal entity responsible for the study: The authors.

Drug Development in Neuroendocrine Tumors: What Is on the Horizon?

“…Rechallenge showed activity with median PFS of 7.2 months and a 9.1% ORR, suggesting that resistance to MKIs may be transient. Among the most common recurrent toxicities, asthenia (54% and no G3-5), neutropenia (27%, including 18% G3-5), and palmoplantar erythrodysesthesia (18%, including 9% G3-5) where the most relevant [54]. The PAZONET phase II trial included 15 patients previously treated with MKI.…”