ABSTRACT
Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. Inactivating mutations or epigenetic deregulation of succinate dehydrogenase complex (SDH) genes are considered defining features of a subset of GIST occurring in the stomach. Based on comprehensive molecular profiling and biochemical analysis within a precision oncology program, we identified hallmarks of SDH deficiency (germline SDHB-inactivating mutation accompanied by somatic loss of heterozygosity, lack of SDHB expression, global DNA hypermethylation, and elevated succinate/fumarate ratio) in a 40-year-old woman with undifferentiated gastric spindle cell sarcoma that did not meet the diagnostic criteria for other mesenchymal tumors of the stomach, including GIST. These data reveal that the loss of SDH function can be involved in the pathogenesis of non-GIST sarcoma of the gastrointestinal tract.
Subject(s)
Germ-Line Mutation , Sarcoma/genetics , Stomach Neoplasms/genetics , Succinate Dehydrogenase/genetics , Adult , DNA Methylation , Female , Humans , Loss of Function Mutation , Loss of Heterozygosity , Sarcoma/pathology , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: Prognosis and survival for patients with metastatic soft tissue sarcoma (STS) are dismal. Standard first-line systemic chemotherapy is anthracycline-based. Gemcitabine/docetaxel (GD) is a therapeutic option in the second-line setting. Here we present the data of our single center retrospective analysis, using GD in locally advanced or metastatic disease. PATIENTS AND METHODS: Between 2005 and 2012, a total of 34 patients were identified. The majority of tumors were located in the extremities (19/34, 56%) and abdomen/retroperitoneum (10/34, 29%). Most frequent histologies included leiomyosarcoma (13/34, 38%), liposarcoma (7/34, 21%), and pleomorphic sarcoma (6/34, 18%). RESULTS: Objective response to treatment by RECIST criteria after 3 cycles was low with 6% partial responses (PR, 2/34), 65% stable disease (SD, 22/34), and 29% progressive disease (PD, 10/34). Progression-free survival at 3 and 6 months was 77 and 62%, respectively. Patients with a clinical benefit (defined as PR or SD after the 3rd treatment cycle) had a significantly prolonged median progression-free and overall survival with 8.6 months (p < 0.0001; hazard ratio (HR) 33.1) and 22.4 months (p < 0.0001; HR 12.9), respectively. Most common toxicities included hand-foot syndrome, edema, pancytopenia, febrile neutropenia, and mucositis. CONCLUSION: Overall, we conclude that GD is an active second-line regimen in metastatic STS, with manageable side effects.