Study of Acquired Resistance to Alkylator Chemotherapy in Endocrine Neoplasms

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.