Precision Oncology in Gastrointestinal Stromal Tumors

Abstract

GIST (gastrointestinal stromal tumors) represent 20% of sarcomatous tumors and 1–2% of primary gastrointestinal cancers. They have an excellent prognosis when localized and resectable, though their prognosis is poor in the metastatic setting, with limited options after the second line until recently. Four lines are now standard in KIT-mutated GIST and one in PDGFRA-mutated GIST. An exponential growth of new treatments is expected in this era of molecular diagnostic techniques and systematic sequencing. Currently, the main challenge remains the emergence of resistance linked to secondary mutations caused by selective pressure induced by TKIs. Repeating biopsies to tailor treatments might be a step in the right direction, and liquid biopsies at progression may offer a non-invasive alternative. New molecules with wider KIT inhibition are under investigation and could change the catalog and the sequence of existing treatments. Combination therapies may also be an approach to overcome current resistance mechanisms. Here, we review the current epidemiology and biology of GIST and discuss future management options, with an emphasis on genome-oriented therapies.

Large-scale, prospective observational study of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors in a real-world clinical setting

“…Unlike colorectal cancer, where molecular profiling is helping to develop agents targeting specific pathways/biological sites associated with tumors ( 14 , 15 ), the development of drugs for the treatment of GIST has not progressed to the same extent ( 4 , 16 ). This is an unmet need in this patient population and until a wider range of alternative treatment options becomes available, it is important to make the best use of therapies available to us.…”

“…Oncogenic gain-of-function mutations of the genes encoding KIT and platelet-derived growth factor receptor A (PDGFRA) are the driver events for most GISTs, with activating KIT mutations present in approximately 80% of GISTs and PDGFRA mutations in 5–10% ( 3 , 4 ). Tyrosine kinase inhibitors (TKIs) are the mainstay of the treatment of advanced GISTs.…”

Combination of Genomic Landsscape and 3D Culture Functional Assays Bridges Sarcoma Phenotype to Target and Immunotherapy

“…Drug rediscovery protocol (DRUP) indicated that rare tumours, such as sarcomas, benefit from genomics-guided treatment [4]. This approach has indeed delivered some successes, such as in lung tumours harbouring neurotrophic receptor tyrosine kinase (NTRK) fusion treated with its inhibitor [5]; in non-small-cell lung cancers (NSCLCs) treated with molecules targeting BRAFV600E mutations [6]; and in gastrointestinal stromal tumours (GISTs) treated with c-Kit inhibitors [7]. However, precision oncology approaches to cancer treatment have indicated that, in many patients, genomic profiling is not sufficient to match each patient to an effective therapy [4,8,9].…”

A giant gastric stromal tumor with dizziness as the main complaint: A case report and literature review

“…GISTs are often asymptomatic and discovered incidentally on imaging. [ 3 ] However, the clinical presentations of GIST are highly variable depending on their location and size. Small tumors are usually incidental findings on operation, endoscopy or imaging studies for other reasons.…”