(P 28) RETROSPECTIVE ANALYSIS OF SUCCINATE DEHYDROGENASE (SDH)-DEFICIENT GASTROINTESTINAL STROMAL TUMOR (GIST) OUTCOMES: AN INTERNATIONAL STUDY OF 256 PATIENTS

Objective: About 5-10% of GIST are caused by germline mutations in the SDH genes or epigenetic silencing of the SDHC promoter. Both mechanisms lead to loss of a functional SDH complex and therefore SDH-deficiency. Limited data on these tumors from case reports/series often describe SDH-deficient (SDH-def) GIST as "indolent," pediatric, insensitive to tyrosine kinase inhibitors, and recalcitrant to serial or more extensive surgical resections. Yet, we are seeing SDH-def GIST patients dying from this cancer with limited understanding of why their disease is more aggressive. Therefore, we sought to combine data from an SDH-def GIST referral center (UCSD), the NIH GIST Clinic and the Life Raft Group (international patient advocacy group with a patient-reported database) to examine this understudied population.

Methods: Patients with pathologically diagnosed SDH-def GIST before April 30, 2021 were identified. Duplicate patients were counted once. We then examined demographic, clinicopathologic, and mutation profiles, as well as clinical management, and prognostic factors of overall survival (OS). We used Kaplan-Meier analyses and a multivariable Cox Proportional Hazard model to identify important clinical factors. The final model was determined via backwards selection and was stratified based on covariates that violated the proportional hazards ratio.

Results: Overall, 256 SDH-def GIST patients were included. The median age at diagnosis was 29 years (range: 5-79) with 68% females. Of these patients, 55.5% presented with localized disease vs. regionally advanced (11.7%) or metastatic (32.8%) disease. The most common mutations were SDHA (18.4%) and SDHB (17.6%), though many patients had unknown SDH mutations (49.6%), likely reflecting lack of access to mutational testing. For all patients, the median OS was 39 years after diagnosis (Fig. A) with an 88.8% and 77.4% OS rate at 5- and 10-years, respectively. We then performed univariate OS analyses (Fig. B-F). Patients who were age ≥29 years at diagnosis [HR 2.36, 95% CI 1.32-4.21 p=0.004], male [HR 2.51, 95% CI 1.43-4.42, p=0.001], or had regionally advanced or metastatic disease at diagnosis [HR 1.81, 95% CI 1.04-3.16, p=0.034 compared to localized] had worsened OS rates. Furthermore, patients treated with sunitinib [HR 7.25, 95% CI 3.26-16.10, p< 0.001], regorafenib [HR 3.27, 95% CI 1.79-5.97, p< 0.001], or temozolomide [HR 3.58, 95% CI 1.40-9.16, p=0.008] had worsened OS. These likely represent surrogates for more aggressive biology or extensive disease. In fact, receipt of >2 drug therapies was associated with worse prognosis [HR 8.77, CI 3.13-24.60, p< 0.001] compared to those with only 1 drug therapy. But, contrary to an earlier study, surgical resection was associated with a decreased hazard of death and improved OS [HR 0.279, 95% CI 0.11-0.72, p=0.008]. On multivariable analysis, backwards selection resulted in age, sex, sunitinib, number of lines of therapy, and number of surgeries as significant covariates. Due to differences in underlying hazards, the models were stratified based on sunitinib use and number of surgeries. In the final model, older age at diagnosis, male sex, and number of therapies were all associated with worsened OS (Table).

Conclusion: To our knowledge, this represents the largest SDH-def GIST analysis to date. Despite being believed to be mostly confined to the pediatric and adolescent population, and still often mislabeled as Pediatric GIST, SDH-def GIST occurs across the age spectrum, and a diagnosis later in life portends a worse prognosis. Moreover, male sex is a poor prognostic factor, raising questions as to the underlying biological differences to explain this finding. For the first time, we also show that surgical resection is associated with improved survival in this patient population. Finally, in contrast to other GIST subtypes, advanced stage at diagnosis does not independently correlate with OS, suggesting that further studies are needed to develop prognostic models.