Epidemiological and experimental studies on sarcoma with focus on gastrointestinal stromal tumors

Sarcoma is the common denominator for malignant tumors of mesenchymal origin. Sarcomas encompass almost 100 diagnoses with different histology, molecular features and natural history, and may present in any part of the body. The most common sarcoma in the abdomen is the gastrointestinal stromal tumor (GIST). GIST is most frequent in the stomach followed by the small intestine, yet can occur throughout the gastrointestinal tract. The first line of treatment for GIST is complete surgical resection, if feasible. Since the discovery of targeted small-molecule therapy with imatinib in 1998 and the successful treatment of the first GIST patient two years later, this therapy has attracted much attention and GIST has become a model system for modern oncological treatment. This thesis is based on translational research in the field of sarcoma with the main focus on GIST.

In paper I, a proof-ofconcept study of intracellular imatinib measurements is presented. Cell-cultures of imatinib-sensitive and resistant cells were exposed to imatinib in different concentrations. The analysis was performed with liquid chromatography mass spectrometry and time-of-flight detection (LC/MS-TOF). The imatinib-resistant cellline had significantly lower imatinib concentrations. Clinical samples from three patients were analyzed using the same protocol and showed imatinib accumulation in tissue and a large variability between patients.

In paper II, the importance of surgical technique and surgical margins was studied. Resecting GIST with a wide margin of >2 cm normal tissue and intact covering peritoneum, lead to improved recurrence-free survival. The impact of the margin was independent when adjusting for other known risk factors such as size, site and mitotic index.

Paper III analyzed an expanded cohort of imatinib treated and resected GIST using an improved, updated protocol for mass spectrometry and drug transporter expression analysis. The previous finding of large intra- and interpatient variability of imatinib concentrations was confirmed. Plasma and tissue concentrations were not correlated to the response. Low expression of drug transport proteins was correlated to the improved histological response.

Finally, paper IV is a nested case-control study and describes trends in breast sarcoma incidence in Sweden during the period of 1993- 2003, showing a 4-fold increase of angiosarcoma. The angiosarcoma patients were overrepresented as carrying a history of breast cancer with the highest risk 5-10 years after their breast cancer diagnosis (OR 167, CI 95% 35.1-791; p<0.001). This points to the possibility that the increased use of radiotherapy could be a reason for a rise in incidence of angiosarcoma.

List of scientific papers

I. Berglund E, Ubhayasekera SJ, Karlsson F, Akcakaya P, Aluthgedara W, Åhlen J, Fröbom R, Nilsson IL, Lui WO, Larsson C, Zedenius J, Bergquist J, Bränström R. Intracellular concentration of the tyrosine kinase inhibitor imatinib in gastrointestinal stromal tumor cells. Anticancer Drugs. 2014; 25(4):415-422.
https://doi.org/10.1097/CAD.0000000000000069

II. Åhlen, J, Karlsson F, Wejde J, Nilsson IL, Larsson C, Bränstrom R. Wide Surgical Margin Improves the Outcome for Patients with Gastrointestinal Stromal Tumors (GISTs). World J Surg. 2018;42(8): 2512-2521.
https://doi.org/10.1007/s00268-018-4498-9

III. Karlsson F, Ubhayasekera SJ, Haglund F, Fröbom R, Åhlén J, Nilsson IL, Zedenius J, Bergquist J, Bränström R. Intracellular concentration of imatinib and drug transporter expression in gastrointestinal stromal cell tumors (GIST). [Submitted]

IV. Karlsson F, Granath F, Smedby KE, Zedenius J, Bränström R, Nilsson IL. Sarcoma of the breast: breast cancer history as etiologic and prognostic factor-A population-based case-control study. Breast Cancer Res Treat. 2020;183(3):669-675.
https://doi.org/10.1007/s10549-020-05802-3