The clinical impact of performing routine next generation sequencing (NGS) in gastrointestinal stromal tumors (GIST).

Abstract

11010 Background: The majority of GISTs harbor activating mutations in KIT or PDGFRα but the clinical relevance of other genomic alterations is unknown. We sought to determine the clinical impact of performing routine NGS and to describe the molecular landscape in GIST. Methods: From April 2014 to August 2016, 177 patients (pts) consented to an IRB-approved protocol. Tumor and matched normal samples were prospectively analyzed in a CLIA-compliant laboratory, with MSK-IMPACT, a NGS assay of up to 468 cancer-associated genes. Results: 191 samples were analyzed. NGS was most often performed in the setting of advanced disease (n = 108 (57%)). The primary tumor was most commonly tested (n = 120 (63%)). NGS guided clinical management in 79% (n = 150) of cases [matched therapy (MT) offered, n = 120/150 (80%); MT not offered, n = 24/150 (16%)]. In 25/41 cases (61%) where NGS did not influence management, treatment was not indicated because the GISTs were low risk. Most samples had ≤ 3 mutations (muts) (range: 0-17). Actionable muts were identified in 155/191 samples (81%). These included muts in KIT, PDGFRα and BRAF [oncoKB stratification: level 1 (84%), 2A (13%), 2B (2%), 3A(1%)]. 33/177 pts did not have a KIT/ PDGFRα mut [SDH deficiency, n = 15 (45%), NF1, n = 10 (30%), BRAF, n = 1(3%), NF1&BRAF, n = 1 (3%)]. 5pts had quadruple wild type GIST. Most GISTs had at least one genetic alteration in a non-driver allele (74%, n = 141/191)[frequently mutated genes in KIT exon 11 driven i) primary tumors include TP53, MAX, MLL2, SETD2, PIK3CA, TSC1; and ii) metastatic tumors include RB1, SETD2, PTEN, ANKRD11, TP53, TSC1]. CDKN2A deletion was the most common copy number alteration identified in KIT driven GIST and occurred most often in metastatic samples (with and without co-occurring, secondary KIT muts) and those with high mitotic rate. Conclusions: NGS of GIST informs clinical management in the majority of pts through the identification of muts in canonical driver genes. NGS also identifies a high prevalence of tumor-specific genetic alterations in non-canonical driver genes. These genes function in multiple pathways including intracellular signaling, chromatin remodeling, proteasomal degradation and cell cycle regulation.