Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study
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 sequenci...
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Published in | British journal of cancer Vol. 115; no. 5; pp. 564 - 570 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
23.08.2016
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0007-0920 1532-1827 |
DOI: | 10.1038/bjc.2016.229 |