Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications

Abstract

Gastrointestinal stromal tumors (GISTs) are composed of various molecular subtypes, with differing prognostic and predictive relevance. Previously, tumors lacking mutations in the KIT and PDGFRA genes have been designated as 'wild-type' GISTs; however, they represent a heterogeneous group currently undergoing further subclassification. Primary and secondary resistance to imatinib poses a significant clinical challenge, therefore ongoing research is trying to evaluate mechanisms to overcome resistance. Thorough understanding of the prognostic and predictive relevance of different genetic subtypes of GIST can guide clinical decision-making both in the adjuvant and the metastatic setting. Further work is required to identify tailored therapies for specific subgroups of GISTs wild-type for KIT and PDGFRA mutations and to identify predictive factors of resistance to currently approved systemic therapies.

Molecular Profile of Gastrointestinal Stromal Tumors in Sixty-Eight Patients from a Single Swiss Institution

“…The slightly higher frequency of KIT mutation may be explained by the fact that our cohort consists mainly of patients at an advanced disease stage who were amenable to tyrosine kinase receptor inhibitor therapy. It is well-known that KIT -mutated GIST generally have worse clinical outcomes compared to PDGFRA -mutated GIST [17]. Therefore, KIT -mutated GIST may be overrepresented in our study.…”

Clinical trends and effects on quality metrics for surgical gastroesophageal cancer care

“…While some of the changes or trends observed may well represent special practice referral patterns that are not entirely reflective of general trends, some changes nevertheless are sensible given the evolution of GC care in the past two decades: there is a significant shift away from distal GC to more GEJ cancers, and there are currently more noninvasive palliation options not requiring operative intervention any longer (14); additionally, there is a shift towards preoperative chemotherapy or chemoradiation for mid-stage gastric and GEJ cancers that qualify for curative intent treatment (16). Finally, there are changes in GIST resections consistent with an increasing recognition of GISTs representing a spectrum of neoplasms with unique biologic behavior and treatment response for which resective indications have become more refined (3,17). Under these circumstances, it appears to be a worthwhile exercise to analyze how possible quality metrics for oncologic and surgical care have fared, and whether any specific trends over time can be elucidated.…”

Early outcomes of exon 11 mutants in GIST treated with standard dose Imatinib

“…The shorter PFS/EFS associated with mutation 557-558 groups has been explained by the Trp 557 being identified as having inhibitory roles in the control of receptor kinase activity as well substitution of proline for Lys 558 leading to a high degree of constitutive receptor phosphorylation (23). While IM only has inhibitory effect in a non-phosphorylated KIT receptor and thus resistance in the mutation 557-558 can be explained, whether non-KIT related mechanisms of resistance to IM also have a role to play needs further evaluation (24). In vitro studies evaluating the IC50 of IM in the mutation 557-558 cohort are required to identify the appropriate doses and benefit of IM in this cohort.…”