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Advances in GIST Management

(P 27) A MULTICENTER RETROSPECTIVE STUDY ON THE CLINICAL BEHAVIOR OF SDH-DEFICIENT GIST

Location: The Liffey, Level 1
Objective: Three percent of gastrointestinal stromal tumors (GIST) show succinate dehydrogenase (SDH) deficiency on immunohistochemistry (IHC) which is caused either by a germline mutation in one of the SDH genes, or by SDHC promotor hypermethylation. Little is known about SDH-deficient GIST but some studies suggest that the clinical presentation of SDH-deficient GIST is different from KIT/PDGFRA mutated GIST. The aim of this study is to investigate the patient characteristics and clinical behavior of SDH-deficient GIST.

Methods: In this international, multicenter, retrospective study patients with IHC proven SDH-deficient GIST with or without SDH germline mutations were included. Patient and tumor characteristics, treatment and SDH-related variables were collected. Follow-up time was defined as the interval between GIST diagnosis and the moment of data collection or death.

Results: We included 104 patients treated in 16 institutions worldwide. Of the 79 (76%) patients with germline mutations 39 (49%) were in SDHA, 25 (32%) in SDHB, 13 (16%) in SDHC and two (3%) were in the SDHD gene. In the remaining patients: no SDH germline mutation was identified (n=6), germline mutation testing was not performed (n=11), SDHC promotor hypermethylation was found (n=2), results were pending (n=2) or missing (n=1), or a variant of unknown significance (n=3) was found. The majority of patients were female (65/104, 63%) and the median age at diagnosis was 35 (range 9-77) years. Of the 94 patients (90%) with a gastric GIST, 23 patients (25%) had multifocal gastric GIST. The stage at diagnosis was localized, metastatic or unknown in 54 (52%), 40 (38%) and 10 patients (10%) respectively. The most common metastatic locations were liver (43/104, 41%) and peritoneum (23/104, 22%). Carney-Stratakis syndrome and Carney triad were reported in 18 (17%) and 6 (6%) patients, respectively. In most patients treatment consisted of surgery alone (46/104, 44%) or surgery combined with systemic treatment (40/104, 38%). The most commonly used systemic therapies were imatinib (44/104, 42%), sunitinib (32/104, 31%) and regorafenib (21/104, 20%). During the median follow-up time of 11 years, (range < 1-40 years), 19 patients treated for localized disease (19/54, 35%) developed a recurrence (median time to recurrence 4, range < 1-23 years). Six patients (6/54, 11%) developed a recurrence ≥10 years after diagnosis. GIST was reported as the cause of death in 9 patients and for 5 patients the cause of death was not reported.

Conclusion: The clinical behavior of SDH-deficient GIST is different from KIT/PDGFRA mutated GIST. While GISTs normally present later in life, SDH-deficient GISTs occur in much younger patients and show a strong gastric predilection. We observed a high frequency of metastatic disease and a high recurrence rate, including late recurrences. Despite the ineffectiveness of imatinib in SDH-deficient GIST, almost half of patients received imatinib. However, imatinib might have been started before IHC and mutation analysis were performed and the duration of treatment was not reported. These results show that SDH-deficient GISTs require a different diagnostic and treatment approach.