Metastases and primaries in neuroendocrine tumors

CarciNor is the Norwegian patient advocacy association for neuroendocrine (NET) and carcinoid cancer. CarciNor is working to raise the awareness for NET cancer, and we support and promote NET cancer research through CarciNor Research Fund. In cooperation with the professional community, we aim to encourage more and better research projects related to NET cancer, to ensure better methods of diagnosis and treatment for those affected by NET cancer.

CarciNor Research Award 2015 goes to Espen Thiis-Evensen MD PhD, National Centre for Neuroendocrine Tumours, Rikshospitalet, Oslo University Hospital, Norway. For our international followers, we bring you the English protocol of the research project.

– CarciNor

Espen Thiis-Evensen MD PhD, National Centre for Neuroendocrine Tumours, Rikshospitalet, Oslo University Hospital, Norway
Espen Thiis-Evensen MD PhD, National Centre for Neuroendocrine Tumours, Rikshospitalet, Oslo University Hospital, Norway. Photo: Mari Sandvold

Why do liver metastases from neuroendocrine small intestinal tumors grow so much faster than the primary tumor?

Metastases and primaries in neuroendocrine tumors (The MePriNET-study).

Gaining new insight into mechanisms regulating tumor growth in neuroendocrine tumors originating from the small bowel.

Background:

In patients with small intestinal neuroendocrine tumors one often finds that the metastases, especially livermetastases, can be multiple and large, while the primary tumor is small, often less than 1 cm in diameter.

We know that malignant tumors harbor different sub-clones with different malignant potential and different ability to give rise to metastases.  It remains unknown how the distribution of different clones is in the primary NET compared to the distribution in metastases and why the malignant cells in the primary tumor shows less tendency to proliferate than those in especially metastases in the liver.

The environment in the liver might stimulates the malignant cells to proliferate, probably by growth factors that are not to the same extent present in the small intestine where the primary tumor is located. These growth factors most likely activate signaling pathways in the malignant cell inducing cell proliferation and thereby tumor growth.

Molecular studies of samples from both the primary tumor and metastases collected at the same time in the same patient will provide extensive knowledge about the genomic and transcriptomic profiles during tumor development.

CT pictures from patient with a small intestinal neuroendocrine tumor with multiple liver metastases. OUS, Rikshospitalet
CT pictures from patient with a small intestinal neuroendocrine tumor with multiple liver metastases. OUS, Rikshospitalet

All malignant tumors shed detectable genetic material into the circulation. For several malignant diseases identification of this material specific for the tumor type in question are detected in the blood and may be found to be associated with disease recurrence after treatment and detected earlier than by other conventional methods, including radiology and pathology.

Within our hospital we have the close patient contact, quality controlled clinical data and skilled molecular biologists and bioinformaticians to perform advanced sequencing analyses.

Aim with the study:

Primary objective: By analyzing the exome (all coding sequences in the genome) and the transcriptome (all mRNAs and non-coding RNAs) in tissue specimen from the primary tumor with tissue from liver- and other metastases in the same patient we will identify gene alterations and expression pattern affecting cellular pathways that may be activated in the metastases and not in the primary tumor. Identifying such molecular changes would give new insight into the biological behavior of neuroendocrine tumors, and could pinpoint possible targets for new therapeutics. This study could be followed by targeted sequencing in a larger retrospective series for validation.

Secondary objective: We will try to find genetic markers specific for neuroendocrine tumors that could be detected in blood samples. This could be used for early diagnosis and to monitor disease recurrence, or disease progression.

Methods

Tissue samples collected at routine surgery will be investigated through genome-wide analyses (exome and RNA sequencing). Mutations will be explored among primary and metastatic lesions with emphasis on alterations along tumorigenesis of the individual patient. Gene expression patterns in the metastases compared to the primary tumor will be identified and investigated further. Blood samples will be collected at diagnosis and at clinically indicated follow-ups of the patients. Results from the genomic studies will provide candidates for individual monitoring markers for early detection of relapse.

Study population

20 patients with known neuroendocrine small bowel tumors, WHO grade G1 and G2, with metastatic disease scheduled for surgery as a part of treatment of their malignant disease.

Facilities:

Patient recruitment: 1. At the Center for neuroendocrine tumors, a European Center of Excellence, Section for gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, 2. Department of Oncology, Haukeland University Hospital, Bergen, Norway (Professor Halfdan Sørbye).

Tissue sampling: Tissue samples from primary tumors and metastases will be collected during surgery and immediately frozen to -80 degrees Celsius and stored in local Biobanks in Section for gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, and Department of Oncology, Haukeland University Hospital, Bergen.

Blood sampling: At the Center for neuroendocrine tumors, Section for gastroenterology and Department of Oncology, Haukeland University Hospital, Bergen.

Genomic analyses: Sequencing and analyses of primary and metastatic NET tissue using blood as normal controls will be done at Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet (Professor Ragnhild A. Lothe).

Project group

  • Espen Thiis-Evensen, MD, Ph.D, Center for neuroendocrine tumors, Section for gastroenterology, Oslo University Hospital, Rikshospitalet
  • Professor Ivar P. Gladhaug, Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet
  • Sven-Petter Haugvik, cand. med., Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet
  • Professor Ragnhild A. Lothe, Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet
  • Professor Tor J. Eide, Departement of Pathology, Oslo University Hospital, Rikshospitalet
  • Dag T. Berntzen, cand. med., Clinic for Image and Intervention, Oslo University Hospital, Rikshospitalet

Project plan

Formalities: Approval from the Regional ethics committee and to the University’s research council, approval for storage and handling of human tissue samples.

Inclusion of patients: Starting April 2014, ending April 2016. Repeated gene mutation and differential expression patterns found in livermetastases compared to the primary tumor will need validation to prove clinical significance, and thus a retrospective larger study may be performed in parallel with continued prospective sampling of new patients.

Financial needs:

The project is made possible by an unrestricted grand from the pharmaceutical company Novartis.

 

 

Text: Espen Thiis-Evensen, MD, Ph.D, Leader of the Center for neuroendocrine tumors, Oslo University Hospital, Rikshospitalet

Photo: OUS Rikshospitalet og Mari Sandvold

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