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Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer
Namrata Vijayvergia1, Patrick M Boland2, Elizabeth Handorf3
1Department of Medical Oncology, Fox Chase Cancer Center, 333, Cottman Avenue, Suite C307, Philadelphia, PA 19111, USA.
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.
Insights
Neuroendocrine tumors, especially poorly differentiated types, show a high mutation rate. TP53 mutations are linked to worse survival, impacting treatment strategies for these rare cancers.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Neuroendocrine malignancies are rare, hindering the development of targeted therapies.
- A deeper understanding of their underlying biology is crucial for advancing treatment options.
Purpose of the Study:
- To investigate the somatic mutation landscape in various neuroendocrine malignancies.
- To correlate mutation status with clinicopathologic features and patient outcomes.
Main Methods:
- Prospective study involving next-generation sequencing of 50 cancer-related genes in 63 patients with neuroendocrine malignancies.
- Clinicopathologic correlation was performed for poorly differentiated neuroendocrine carcinomas (NECs), pancreatic neuroendocrine tumors (PanNETs), and non-pancreatic neuroendocrine tumors (NP-NETs).
Main Results:
- High incidence of somatic mutations (SMs) observed: 83% in poorly differentiated NECs, 45% in PanNETs, and 14% in NP-NETs.
- TP53 was the most common mutation in NECs (57%). Other mutations included KRAS, PIK3CA/PTEN, and BRAF.
- Mutation prevalence correlated with increased risk of progression and TP53 mutations were associated with significantly worse survival.
Conclusions:
- Poorly differentiated NECs exhibit a substantial mutation burden, including potentially targetable mutations.
- TP53 mutations are a significant negative prognostic factor in neuroendocrine malignancies.
- Findings support the use of mutation profiling for prognostic stratification and guiding clinical trial therapies.
