Sex differences in localized gastrointestinal stromal tumor.

Abstract

e23511 Background: Sex plays an important role in the incidence and prognosis of several cancer types. Male patients with gastrointestinal stromal tumors (GISTs) have inferior outcomes compared to women, but the reasons behind the sex differences are not well understood. This study aimed to investigate whether sex was a prognostic factor in localized GIST and to explore the relationship between sex and established clinical, molecular and histopathological characteristics. Methods: The study cohort is population-based and consisted of patients who underwent surgical resection of primary, non-metastatic GIST at Oslo University Hospital, Norway between January 2000 and September 2017. Recurrence-free survival (RFS) was the primary endpoint. Mutation analysis was performed by Sanger sequencing or by the AmpliSeq for Illumina Cancer Hotspot Panel version 2. Results: The study cohort comprised 409 patients, 202 women and 207 men. There were 275 gastric tumors (67.2%) and 134 non-gastric tumors (32.8%). Disease recurrence was recorded in 87 patients (21%) after a median follow-up of 64 months. Men with gastric tumors had inferior RFS compared to women (HR 2.18; 95% CI 1.07-4.45; P= 0.029), while there was no difference for non-gastric tumors (HR 0.77; 95% CI 0.44-1.33; P= 0.341). There was a substantial sex variation in the type of primary KIT mutation related to tumor location. Men with gastric tumors had a deletion or insertion-deletion that involved codons 557 and 558 (del557/558) more than twice as frequently as women (34% versus 16%; P= 0.008). Men also had slightly larger tumors (mean 6.6 cm versus 5.5 cm; P= 0.035) and more often tumors located in the upper third of the stomach, but there was no difference in mitotic count (23% versus 22% with > 5 mitoses per 5 mm2). There was no difference in adjuvant imatinib treatment between men and women. No sex differences in primary mutation, tumor size or mitotic count were observed for non-gastric tumors. When KIT del557/558 mutation was included in the Cox regression analysis for gastric tumors, sex was not significantly associated with RFS (HR 1.49; 95% CI 0.70-3.18; P= 0.303), while del557/558 mutation was a strong prognostic factor (HR 6.40; 95% CI 3.17-12.94; P< 0.001). Del557/558 mutation was not associated with RFS in non-gastric tumors (HR 0.67; 95% CI 0.33-1.35; P= 0.262). Conclusions: Women with localized, gastric GISTs had a lower risk of recurrence compared to men. There was no sex difference in outcome or baseline characteristics for non-gastric tumors. Men with gastric tumors more often had KIT del557/558 primary mutations, which may explain their inferior outcome. The observed sex difference in primary mutations in GISTs is unexplained and should be further explored.