Publication:
Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib.

No Thumbnail Available

Date

2018-08-20

Authors

Serrano, César
García-Del-Muro, Xavier
Valverde, Claudia
Sebio, Ana
Durán, José
Manzano, Aránzazu
Pajares, Isabel
Hindi, Nadia
Landolfi, Stefania
Jiménez, Laura

Advisors

Journal Title

Journal ISSN

Volume Title

Publisher

Metrics
Google Scholar
Export

Research Projects

Organizational Units

Journal Issue

Abstract

Oncogenic KIT/PDGFRA signaling inhibition with imatinib achieves disease control in most patients with advanced/metastatic gastrointestinal stromal tumor (GIST), but resistance eventually develops after 20-24 months. Notably, a small subset of these patients obtain durable benefit from imatinib therapy. We analyzed clinical, pathological, and molecular characteristics and long-term outcomes in patients with metastatic GIST treated with continuous daily dosing of frontline imatinib in a cohort of patients benefiting for ≥5 years. A control group was obtained from the national Spanish Group for Sarcoma Research database and used as comparator. Sixty-four imatinib long-term responders (LTRs) and 70 control cases were identified. Compared with controls, LTRs at baseline had better performance status (PS) 0-1 (100% vs. 81%), lower mitotic count (median, 8 vs. 15), and tumor burden (number of metastases, 3 vs. 7). KIT exon 11 was the only region found mutated in LTRs. LTRs achieved 34% complete responses and a median progression-free survival of 11 years, compared with 4% and 2 years, respectively, in the control cohort. Prognostic factors that independently predicted long-term benefit with imatinib were PS, number of metastases prior to imatinib, and response to imatinib. Fifteen LTR patients developed new side effects attributable to imatinib after ≥5 years of continuous treatment. No resistance mutations were found in metastatic samples from three patients progressing on imatinib. GISTs in LTRs are a distinctive entity with less aggressive behavior and marked sensitivity to KIT inhibition. Patients reaching 5 or more years on imatinib have a higher chance of remaining progression free over time. This work demonstrates that clinical and inherent tumor characteristics define a subset of patients with gastrointestinal stromal tumor (GIST) with increased likelihood to achieve durable response to first-line imatinib therapy. Patients reaching ≥5 years on imatinib have a greater chance of remaining progression free over time, although the disease is unlikely to be cured. Imatinib is well tolerated for >5 years, and emergent toxicities are overall manageable. Resistance to imatinib emerging in patients with GISTs after long-term imatinib treatment does not involve polyclonal expansion of KIT secondary mutations.

Description

MeSH Terms

Adult
Antineoplastic Agents
Case-Control Studies
Disease Progression
Drug Resistance, Neoplasm
Female
Gastrointestinal Neoplasms
Gastrointestinal Stromal Tumors
Humans
Imatinib Mesylate
Male
Middle Aged
Prognosis
Progression-Free Survival
Sarcoma
Time Factors

DeCS Terms

CIE Terms

Keywords

Gastrointestinal stromal tumor, Imatinib mesylate, Long‐term, c‐KIT

Citation