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

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Serrano, C
  • Garcia-del-Muro, X
  • Valverde, C
  • Sebio, A
  • Duran, J
  • Manzano, A
  • Pajares, I
  • Hindi, N
  • Landolfi, S
  • Jimenez, L
  • Rubio-Casadevall, J
  • Estival, A
  • Lavernia, J
  • Safont, MJ
  • Pericay, C
  • Martinez-Marin, V
  • Vicente-Baz, D
  • Vivancos, A
  • Hernandez-Losa, J
  • Arribas, J
  • Carles, J

Grupos

Abstract

Background 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. Methods 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. Results 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. Conclusion 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. Implications for Practice 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.

Datos de la publicación

ISSN/ISSNe:
1083-7159, 1549-490X

ONCOLOGIST  OXFORD UNIV PRESS

Tipo:
Article
Páginas:
680-687
PubMed:
30126859
Factor de Impacto:
2,613 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 10

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Keywords

  • c-KIT; Gastrointestinal stromal tumor; Imatinib mesylate; Long-term

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