title: Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study.
abstract: The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical.
  
  
  
  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%).
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA.
authors.forename: Namrata
authors.initials: N
authors.lastname: Vijayvergia
authors.affiliation: Department of Medical Oncology, Roswell Park Cancer Center, Buffalo, NY, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Boland
authors.affiliation: Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Handorf
authors.affiliation: Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Gustafson
authors.affiliation: Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
authors.forename: Harry S
authors.initials: HS
authors.lastname: Cooper
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA.
authors.forename: Fathima
authors.initials: F
authors.lastname: Sheriff
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Astsaturov
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Cohen
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Engstrom
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000473:pathology*; D010865:Pilot Projects; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor