(P 23) GENOMIC COMPLEXITY AS A BIOMARKER FOR ADJUVANT IMATINIB TREATMENT IN HIGH-RISK GASTROINTESTINAL STROMAL TUMOR

Objective: Gastrointestinal stromal tumors (GISTs) are characterized by oncogenic KIT or platelet-derived growth factor alpha (PDGFRA) mutations, whereas malignant progression occurs through stepwise accumulation of additional chromosomal aberrations. Adjuvant imatinib treatment for three years is recommended for patients with localized GIST at high risk of recurrence. Nearly half of high-risk patients are cured by surgery alone and 30-40% relapse after stopping adjuvant therapy, indicating that the currently used risk classification does not precisely predict patient outcome after standard treatment. The aim of this study was to investigate if genomic tumor complexity could be used as a prognostic biomarker and to characterize in detail the genomic and transcriptomic landscape of high-risk GIST.

Methods: Patients who underwent resection of primary GIST at Oslo University Hospital between 1998 and 2020 were included. Karyotypes were categorized as simple if they had ≤ 5 chromosomal changes and complex if there were > 5 chromosomal aberrations. Somatic mutations, DNA copy number changes, and expression of mRNA and miRNA genes and pathways were investigated using whole exome sequencing, RNA sequencing, and miRNA expression analysis.

Results: Chromosomal aberrations were detected in 206 tumors, of which 76 had a complex karyotype. The most frequently observed changes were losses at 14q, 22q, 1p, and 15q. High-risk patients with a simple tumor karyotype had an estimated 5-year recurrence-free survival (RFS) of 94%, whereas patients with a complex karyotype had an estimated 5-year RFS of 51%. A complex karyotype was associated with poor RFS in multivariable analysis adjusted for the established prognostic factors tumor site, size, mitotic count, and rupture. The prognostic impact of genomic complexity was confirmed in an independent validation cohort. Using genomic and transcriptomic profiling in a subset of samples, we confirmed that chromosomal instability was the most pronounced genomic feature and associated with disease relapse. The tumor mutational burden was low; no recurrent actionable somatic mutations were identified except for mutations in KIT and PDGFRA. Gene expression analysis showed that mRNA and miRNA genes involved in cell cycle signaling and the kinetochore complex were associated with genomic complexity and differentially expressed between metastatic and non-metastatic tumors.

Conclusion: Genomic tumor complexity is an independent prognostic biomarker in localized, high-risk GIST and is associated with cell cycle deregulation and dysfunctional control of the kinetochore machinery. Recurrences were infrequent for tumors with simple karyotypes; hence, de-escalation of adjuvant imatinib treatment should be explored in patients with genomically simple GISTs. Conversely, tumors with complex genomes frequently relapsed after adjuvant therapy. Patients with genomically complex tumors may benefit from continued imatinib treatment.