Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study

Abstract

Background:The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical.Methods:Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ⩽20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ⩽20%).Results:A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67 <2%/n=9) did not harbour any mutations. Prevalence of mutations correlated with higher risk of progression within the previous year (32% (low risk) vs 11% (high risk), P=0.01) and TP53 mutation correlated with worse survival (2-year survival 66% vs 97%, P=0.003).Conclusions:Poorly differentiated NECs have a high mutation burden with potentially targetable mutations. The TP53 mutations are associated with poor survival in neuroendocrine malignancies. These findings have clinical trial implications for choice of therapy and prognostic stratification and warrant confirmation.

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…Two studies using nextgeneration sequencing (NGS) revealed alterations; among those, MEN1 and ATRX/DAXX alterations were the most frequent ones ( (Tang et al 2016). Two additional studies (Kimura et al 2016, Vijayvergia et al 2016) confirmed mutations in KRAS and TP53. PHLDA3, a pleckstrin homology-like protein, which is a potent inhibitor of AKT activation (Kawase et al 2009), is inactivated in 72% of pNET patients due to PHLDA3 gene loss of heterozygosity (Ohki et al 2014).…”

“…Three publications reported low-frequency KRAS mutations (10-20%) also in pNET (Yuan et al 2014, Vijayvergia et al 2016, Kimura et al 2016. Although targeting RAS directly is a mission impossible (Cox et al 2014), new options arouse from targeting RAS downstream effectors and cell cycle checkpoint control.…”

Gastroenteropancreatic Neuroendocrine Tumors

“…Loss of retinoblastoma (Rb) and mutations of Kirsten rat sarcoma viral oncogene homolog ( KRAS ) have been recently reported in 55% and 49% of patients with pNECs, in whom such molecular alterations seem to predict response to platinum‐based chemotherapy . Overall, the frequency of mutations is substantially higher in NECs than in NETs …”

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

“…In addition, mutations may increase tumor antigenicity, and the mutational load may predict response of tumors to immunotherapy [34,35,36]. In contrast to carcinoid tumors [34], NECs show a higher mutational frequency [37,38], suggesting that high-grade NENs may be a preferred target of immunotherapy.…”