Format:
8
ISSN:
2374-2445
Content:
〈h3〉Importance〈/h3〉〈p〉Little is known about whether the duration of adjuvant imatinib influences the prognostic significance of KIT proto-oncogene receptor tyrosine kinase (〈i〉KIT〈/i〉) and platelet-derived growth factor receptor α (〈i〉PDGFRA〈/i〉) mutations.〈/p〉〈h3〉Objective〈/h3〉〈p〉To investigate the effect of〈i〉KIT〈/i〉and〈i〉PDGFRA〈/i〉mutations on recurrence-free survival (RFS) in patients with gastrointestinal stromal tumors (GISTs) treated with surgery and adjuvant imatinib.〈/p〉〈h3〉Design, Setting, and Participants〈/h3〉〈p〉This exploratory study is based on the Scandinavian Sarcoma Group VIII/Arbeitsgemeinschaft Internistische Onkologie (SSGXVIII/AIO) multicenter clinical trial. Between February 4, 2004, and September 29, 2008, 400 patients who had undergone surgery for GISTs with a high risk of recurrence were randomized to receive adjuvant imatinib for 1 or 3 years. Of the 397 patients who provided consent, 341 (85.9%) had centrally confirmed, localized GISTs with mutation analysis for〈i〉KIT〈/i〉and〈i〉PDGFRA〈/i〉performed centrally using conventional sequencing. During a median follow-up of 88 months (completed December 31, 2013), 142 patients had GIST recurrence. Data of the evaluable population were analyzed February 4, 2004, through December 31, 2013.〈/p〉〈h3〉Main Outcomes and Measures〈/h3〉〈p〉The main outcome was RFS. Mutations were grouped by the gene and exon.〈i〉KIT〈/i〉exon 11 mutations were further grouped as deletion or insertion-deletion mutations, substitution mutations, insertion or duplication mutations, and mutations that involved codons 557 and/or 558.〈/p〉〈h3〉Results〈/h3〉〈p〉Of the 341 patients (175 men and 166 women; median age at study entry, 62 years) in the 1-year group and 60 years in the 3-year group), 274 (80.4%) had GISTs with a〈i〉KIT〈/i〉mutation, 43 (12.6%) had GISTs that harbored a〈i〉PDGFRA〈/i〉mutation, and 24 (7.0%) had GISTs that were wild type for these genes.〈i〉PDGFRA〈/i〉mutations and〈i〉KIT〈/i〉exon 11 insertion or duplication mutations were associated with favorable RFS, whereas〈i〉KIT〈/i〉exon 9 mutations were associated with unfavorable outcome. Patients with〈i〉KIT〈/i〉exon 11 deletion or insertion-deletion mutation had better RFS when allocated to the 3-year group compared with the 1-year group (5-year RFS, 71.0% vs 41.3%;〈i〉P〈/i〉 〈 .001), whereas no significant benefit from the 3-year treatment was found in the other mutational subgroups examined.〈i〉KIT〈/i〉exon 11 deletion mutations, deletions that involved codons 557 and/or 558, and deletions that led to pTrp557_Lys558del were associated with poor RFS in the 1-year group but not in the 3-year group. Similarly, in the subset with〈i〉KIT〈/i〉exon 11 deletion mutations, higher-than-the-median mitotic counts were associated with unfavorable RFS in the 1-year group but not in the 3-year group.〈/p〉〈h3〉Conclusions and Relevance〈/h3〉〈p〉Patients with〈i〉KIT〈/i〉exon 11 deletion mutations benefit most from the longer duration of adjuvant imatinib. The duration of adjuvant imatinib modifies the risk of GIST recurrence associated with some〈i〉KIT〈/i〉mutations, including deletions that affect exon 11 codons 557 and/or 558.〈/p〉〈h3〉Trial Registration〈/h3〉〈p〉clinicaltrials.gov Identifier:NCT00116935〈/p〉
Note:
Published online March 23, 2017
,
Gesehen am 30.08.2018
In:
JAMA oncology, Chicago, Ill. : American Medical Association, 2015, 3(2017), 5, Seite 602-609, 2374-2445
In:
volume:3
In:
year:2017
In:
number:5
In:
pages:602-609
In:
extent:8
Language:
English
DOI:
10.1001/jamaoncol.2016.5751
