Multicentric morphological and molecular appraisal of GEP-NEN G3 with clinical correlations

Project title: "Multicentric morphological and molecular appraisal of GEP-NEN G3 with clinical correlations"

Digestive NEN of high grade of malignancy, also called grade 3 (NEN G3) are aggressive, highly proliferative malignancies. Their pathological diagnosis is difficult and their treatment is challenging. The use of new immunohistochemical markers may help the pathological diagnosis, but their interpretation is still not well defined.

The aim of this project is to evaluate the patho-molecular profile of a large series of GEP-NEN G3 with clinical correlation, to better define diagnostic work-up and to better predict survival and response to treatments. A multicenter ENETS-driven consortium (Bichat/Beaujon Hospitals-University Paris-Cité, University Bergen, IEO/Milan, IRCCS-INT/Milan, University Bern, IGR/University Paris-Saclay Erasmus-University Rotterdam) will allow to optimize NEN G3 collection with high quality pathological and clinical records. We will set up a cohort of 200 patients with available clinical data and mandatory slides available retrospectively (2010-2020). We will standardize pathology assessment of both HE stain, including parameters of tumour cells and stroma and mandatory markers including Ki-67, Rb and p53. To this end, we will use a pathology platform to upload digital slides in each center to allow expert pathologists to view all slides blinded to clinical follow-up and interpretation of other pathologists, and the new ENETS database to share clinical data. The analysis of both pathological markers and clinical characteristics with treatment data (response, PFS OS) will hopefully improve the diagnosis of these rare cancers and better treatment selection for these patients.

Specific aims: to define patho-molecular profiles, including evaluation of specific biomarkers, that could predict survival and response to treatments of GEP-NEN G3:

- Set up a large European multicentric fully annotated cohort of digestive NENG3 cases with high quality clinical data and mandatory pathological slides

- Gather clinical data including patients’ characteristics, response to chemotherapy and survival in the ENETS database as a proof-of-concept study for further ENETS database-centered studies within ENETS

- Assess characteristics of HE stain and immunohistochemical markers by comparing the analyses of expert pathologists from all participating European centers.
i. centralize the digital slides on a telepathology platform accessible to all centers
ii. compare the pathological analyses using a voting form included in the platform
iii. decipher the importance of morphology vs proliferation vs markers in the diagnostic of GEP-NEN G3: define the inter-observer agreement for NET vs NEC using HE alone, or using HE+Ki-67, or using HE+Ki-67+markers; analyze ambiguous cases where no consensus is reached, define their aspects and frequency; find a set of new diagnostic criteria to help classify difficult cases, to be implemented in further guidelines

- Establish clinico-pathological correlations between all these pathological characteristics and prognosis, survival and response to treatments.

Principle investigator: University of Bergen, Halfdan Sorbye

This project is supported through an ENETS CoE Synergy Grant