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Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.ORCID iD: 0000-0001-9881-769X
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.ORCID iD: 0000-0003-4001-0572
Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
Inst Gustave Roussy, Villejuif, France.
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187667Article in journal (Refereed) Published
Abstract [en]

Background Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC. Materials and methods Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS). Results All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses. Conclusion In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.

Place, publisher, year, edition, pages
2017. Vol. 12, no 11, article id e0187667
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-341933DOI: 10.1371/journal.pone.0187667ISI: 000414572100031PubMedID: 29112960OAI: oai:DiVA.org:uu-341933DiVA, id: diva2:1183370
Funder
Swedish Cancer Society, CAN558/2014Available from: 2018-02-16 Created: 2018-02-16 Last updated: 2019-04-21Bibliographically approved
In thesis
1. Gastroenteropancreatic Neuroendocrine Neoplasms Grade 3: Biological and Clinical Aspects
Open this publication in new window or tab >>Gastroenteropancreatic Neuroendocrine Neoplasms Grade 3: Biological and Clinical Aspects
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis was to investigate biological and clinical aspects of G3 gastroenteropancreatic neuroendocrine neoplasms (G3 GEP-NENs).

In our first study, the expression of the tumor suppressor p53 was investigated. In a cohort of G3 GEP-NENs we found the expression of p53 protein to be present in 39% of 124 cases. Expression of p53 correlated to poorer progression-free survival (PFS) and overall survival (OS) for patients with G3 GEP-NENs originating from colon or rectum. In the next study, we aimed to demonstrate the prevalence of PD-L1 expression in G3 GEP-NENs and its possible clinical importance. Ten per cent of 136 tumor specimens were immunoreactive for PD-L1 in either tumor cells or immune cells. In contrast to p53 expression that could be correlated to PFS and OS in a subgroup of patients the expression of PD-L1 did not correlate to any clinicopathological variables and conclusively, PD-L1 may not have a vital role for the pathogenesis of G3 GEP-NENs. In a further study, we sought to identify new potential biomarkers and a panel of immuno-oncological proteins were measured in serum collected from pancreatic G3 NENs and healthy controls. Out of 87 proteins, 62% were significantly lower in serum concentration in healthy controls compared to patients. One protein, FasL, was present in significantly higher levels in healthy controls compared to patients. FasL may have a protective role in its ability to activate T cells in the immune system. Other proteins of interest were chemokine (c-c motif) ligand and interleukin 8 that both correlated to poorer prognosis in G3 pancreatic NEN patients. More studies are needed for further understanding of the roles and clinical relevance of immuno-oncological proteins in G3 pancreatic NENs.

Finally, we evaluated whether intravenous or oral administration of etoposide differed with regards to PFS and OS in patients with G3 GEP-NENs. There was no significant difference in PFS nor OS between patients receiving oral compared to intravenous etoposide; demonstrating that an oral option of etoposide is not inferior in its efficacy as compared to the more used intravenous formulation. These results suggest that considering oral options of etoposide is important since they are more often preferred by patients, increase the quality of life for the patients and reduce hospital costs.

This thesis has contributed to an understanding of the distribution and clinical relevance of p53 and PD-L1 in GEP-NENs. A potential role of FasL, chemokine and interleukin 8 as prognostic and/or diagnostic factors in pancreatic G3 NENs has been identified and should be further investigated. The thesis also gave some insight into the role of oral etoposide as an alternative option to intravenous formulation with regards to efficacy. Oral formulations are preferred by many patients and improve quality of life while decreasing hospital-related costs. Further studies are needed to compare the tolerability of oral formulation compared to the intravenous formulation. 

 

 

 

Place, publisher, year, edition, pages
Uppsala University: Acta Universitatis Upsaliensis, 2019. p. 51
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1576
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-382061 (URN)978-91-513-0663-6 (ISBN)
Public defence
2019-06-13, Enghoffsalen, Ingång 50, Akademiska sjukhuset, Uppsala, 13:00 (English)
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Supervisors
Available from: 2019-05-20 Created: 2019-04-21 Last updated: 2019-06-17

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Ali, Abir SalwaGrönberg, MalinWelin, StaffanGrimelius, LarsTiensuu Janson, Eva

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