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It has been showed that alkylating chemotherapy, particularly the widely used agent temozolomide, may cause high tumor mutational burden (TMB) in certain tumors by causing inactivating mutations in the DNA mismatch repair (MMR) system. This can cause therapy resistance and tumor progression but may also predict response for immunotherapy. Hypermutation is very uncommon in neuroendocrine tumors. However, small studies indicate that around 30% of pancreatic tumors develop high TMB after alkylating chemotherapy. The aim of this study is therefore to study the occurrence and frequency of DNA hypermutation after alkylating chemotherapy in endocrine neoplasms and to investigate non-invasive methods that may capture the development of hypermutation (imaging, ctDNA etc.).
This is a prospective multicenter study. 94 patients from Swedish endocrine cancer centers in Uppsala, Stockholm, Göteborg and Lund will be included and divided into two groups. Group A will include patients that are about to start treatment with alkylating chemotherapy. Blood samples for liquid biopsy will be collected at baseline and at follow-up and if the tumor progresses, tissue biopsy will be obtained from two different lesions and analyzed with GMS560. Group B will include patients experiencing tumor progression after having received alkylating chemotherapy at any point in their disease course before. At inclusion, both liquid and tissue biopsy will be obtained and analyzed as described above.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with endocrine neoplasms who have or will receive treatment with alkylating chemotherapy. | Group A (about to start alkylating chemotherapy) Group B (at progression, previous alkylating chemotherapy) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Core needle biopsy | Procedure | Core needle biopsy of metastatic lesions |
|
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of pancreatic neuroendocrine tumor patients with hypermutation and/or mismatch repair deficiency after treatment with alkylating chemotherapy | Proportion of pancreatic neuroendocrine tumor patients with hypermutation (tumour mutation burden >30) and/or mismatch repair deficiency (by DNA sequencing or immunohistochemistry) in tissue or liquid biopsy at any timepoint after treatment with alkylating chemotherapy. | Through study completion, an average of 2 years. |
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| Measure | Description | Time Frame |
|---|---|---|
| Proportion of non-pancreatic endocrine neoplasms that develop hypermutation and/or mismatch repair deficiency after treatment with alkylating chemotherapy | Do non-pancreatic endocrine neoplasms (adrenocortical carcinoma, pheochromocytoma and paraganglioma, lung carcinoids and intestinal neuroendocrine tumors) develop hypermutation (tumor mutation burden >30) and/or mismatch repair deficiency (by DNA sequencing or immunohistochemistry) in tissue or liquid biopsy at any timepoint after treatment with alkylating chemotherapy? |
Inclusion Criteria:
Exclusion Criteria:
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Patients with endocrine neoplasms who have or will receive treatment with alkylating chemotherapy
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Lovisa Falkman, MD | Contact | +46186110000 | lovisa.falkman@uu.se |
| Name | Affiliation | Role |
|---|---|---|
| Joakim Crona, MD PhD | Uppsala University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Akademiska Sjukhuset | Recruiting | Uppsala | Sweden |
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| ID | Term |
|---|---|
| D009369 | Neoplasms |
| D004701 | Endocrine Gland Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D062005 | Biopsy, Large-Core Needle |
| D018962 | Phlebotomy |
| ID | Term |
|---|---|
| D001707 | Biopsy, Needle |
| D001706 | Biopsy |
| D003581 | Cytodiagnosis |
| D003584 | Cytological Techniques |
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| Phlebotomy | Procedure | Phlebotomy of peripheral vein |
|
| Through study completion, an average of 2 years. |
| D019411 |
| Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D013048 | Specimen Handling |
| D003949 | Diagnostic Techniques, Surgical |
| D013514 | Surgical Procedures, Operative |
| D011677 | Punctures |
| D008919 | Investigative Techniques |
| D001800 | Blood Specimen Collection |
| D013812 | Therapeutics |