Molecularly-guided therapeutic options beyond tyrosine kinase inhibitors (TKIs) for gastrointestinal stromal tumors (GIST).

Abstract

58 Background: GISTs are characterized by KIT/PDGFRA mutations. A range of multi-targeted tyrosine kinase inhibitors (TKIs) are available for treatment, however, resistance mechanisms inevitably emerge. Recent data (Boichuk, et al 2014) suggests the potential efficacy of various cytotoxic therapies that were identified as being able to effectively kill TKI-responsive and -resistant GIST cells. We sought to investigate the theranostic markers associated with non-TKI therapy options for their potential role in treatment of GIST. Methods: 147 GIST cases were evaluated. A multiplatform approach of biomarker testing was used and included a combination of sequencing (NGS, Sanger), protein expression (IHC) and gene amplification (ISH). Results: Multidrug resistance phenotype was found in 52-68% (PGP, MRP1). Tubulin-binding agents (taxanes, vinca alkaloids) may be of potential use due to the high frequency of low TUBB3 expression (72% or 39/54). Anthracyclines and topoisomerase inhibitors may be of potential benefit in 1/3 of patients based on expression of TOPO2A (32% or 32/99) and TOPO1 (34% or 37/110). Cytotoxic agents used in non-GIST solid tumors, may also be considered, based on high frequency of low expressin of MGMT (47% or 57/122), TS (70% or 76/109) and RRM1 (79% or 88/111). PTEN was intact (positive expression) in the majority of GIST (87%). Nine patients were examined for PD1/PDL1: 56% exhibited positive tumor infiltrating lymphocytes and 33% exhibited PDL1 tumor expression. Only one amplification event was observed: cMET (0/53), HER2 (0/69), EGFR (0/16), PIK3CA (0/1) and TOP2A (1/11). Mutational screening using a hot spot cancer panel (and Sanger sequencing for some genes) resulted in the detection of variants in only 10 genes, excluding KIT (97/132) and PDGFRA (5/55). Variants were detected in the following genes, in decreasing order of frequency: RB1, APC and JAK3 (2/55; 2/55; 2/57), PIK3CA (2/69) and ABL1, cMET, EGFR, KDR, VHL and BRAF (1/55, 1/57, 1/57, 1/57, 1/52, 1/78). Conclusions: A multi-platform approach of theranostic biomarkers identified therapies beyond TKIs for GIST. Various cytotoxics and non-KIT/PDGFRA targeted therapies were identified based on protein expression or gene variations.