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Tumor Size, Location, and Mitotic Rate, but Not Genotype, Associated With Recurrence-Free Survival in Trial of Adjuvant Imatinib vs Placebo in GIST

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Key Points

  • Tumor size, location, and mitotic rate, but not genotype, were significantly associated with recurrence-free survival in both the placebo and imatinib groups.
  • Compared with the placebo group, recurrence-free survival was significantly prolonged in imatinib patients with a KIT exon 11 deletion of any type but not in those with KIT exon 11 insertions or point mutations, KIT exon 9 mutations, PDGFRA mutations, or wild-type tumors

The ACOSOG Z9001 (Alliance) study showed that 1 year of adjuvant imatinib (Gleevec) prolonged recurrence-free survival after resection of primary gastrointestinal stromal tumors (GIST). As reported by Corless et al in the Journal of Clinical Oncology, a study evaluating correlation of pathologic and molecular features with long-term outcome in the trial showed that tumor size, location, and mitotic rate, but not tumor genotype, were associated with recurrence-free survival.

Study Details

In the trial, 645 patients with GIST were randomly assigned to imatinib (n = 317) or placebo (n = 328). A total of 645 tumor specimens were available for analysis of mitotic rate and mutation status. Median follow-up for the current analysis was 74 months. Recurrence-free survival remained superior in the imatinib group (hazard ratio [HR] = 0.6, P < .001) in the long-term analysis. There was no significant difference in overall survival (P = .19).

Effect of Tumor Size, Location, and Mitotic Rate

On multivariable analysis of patients in the placebo group, tumor size > 10 cm (HR = 3.25, P < .001 for trend), small bowel location (HR = 1.97, P = .023 for trend), and high mitotic rate (≥ 10/11.87 mm2; HR = 7.81, P < .001 for trend) were significantly associated with lower recurrence-free survival, with no significant associations observed for recurrence-free survival and KIT exon 9 mutation, KIT exon 11 deletion or no deletion, or PDGFRA mutation vs wild type.

On multivariable analysis of patients in the imatinib group, tumor size > 10 cm (HR = 6.51, P < .001 for trend), small bowel location (HR = 2.03) or other location besides stomach and rectum (HR = 4.01; P = .045 for trend), and high mitotic rate (HR = 4.97, P < .001 for trend), but not tumor genotype, were associated with lower recurrence-free survival.

Comparison of outcomes in the two treatment arms by tumor genotype showed that recurrence-free survival was significantly prolonged with imatinib treatment in patients with a KIT exon 11 deletion of any type (P < .001), but not in those with KIT exon 11 insertions or point mutations, KIT exon 9 mutations, PDGFRA mutations, or wild-type tumors, although the lack of associations may have reflected limited power to detect differences in small patient groups. Among patients with KIT exon 11 mutations, imatinib therapy appeared to be associated with increased recurrence-free survival in those with deletions covering codons 557 or 558 (P = .0027) and in those with deletions not involving these codons (P = .0036).

The investigators concluded, “Our findings show that tumor size, location, and mitotic rate, but not tumor genotype, are associated with the natural history of GIST. Patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer recurrence-free survival.”

Christopher Corless, MD, PhD, of Oregon Health & Science University, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by grants from the Alliance for Clinical Trials in Oncology, Alliance Statistics and Data Center, American College of Surgeons Oncology Group, and National Cancer, an award from the Society of Surgical Oncology, and by a contract between Novartis and the National Cancer Institute under a cooperative research and development agreement. For full disclosures of the study authors, visit jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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