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Clinical Trial
. 2017 May 1;3(5):602-609.
doi: 10.1001/jamaoncol.2016.5751.

Effect of KIT and PDGFRA Mutations on Survival in Patients With Gastrointestinal Stromal Tumors Treated With Adjuvant Imatinib: An Exploratory Analysis of a Randomized Clinical Trial

Heikki Joensuu  1 , Eva Wardelmann  2 , Harri Sihto  3 , Mikael Eriksson  4 , Kirsten Sundby Hall  5 , Annette Reichardt  6 , Jörg T Hartmann  7 , Daniel Pink  8 , Silke Cameron  9 , Peter Hohenberger  10 , Salah-Eddin Al-Batran  11 , Marcus Schlemmer  12 , Sebastian Bauer  13 , Bengt Nilsson  14 , Raija Kallio  15 , Jouni Junnila  16 , Aki Vehtari  17 , Peter Reichardt  6
Affiliations
Clinical Trial

Effect of KIT and PDGFRA Mutations on Survival in Patients With Gastrointestinal Stromal Tumors Treated With Adjuvant Imatinib: An Exploratory Analysis of a Randomized Clinical Trial

Heikki Joensuu et al. JAMA Oncol. .

Abstract

Importance: Little is known about whether the duration of adjuvant imatinib influences the prognostic significance of KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor α (PDGFRA) mutations.

Objective: To investigate the effect of KIT and PDGFRA mutations on recurrence-free survival (RFS) in patients with gastrointestinal stromal tumors (GISTs) treated with surgery and adjuvant imatinib.

Design, setting, and participants: 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 KIT and PDGFRA 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.

Main outcomes and measures: The main outcome was RFS. Mutations were grouped by the gene and exon. KIT 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.

Results: 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 KIT mutation, 43 (12.6%) had GISTs that harbored a PDGFRA mutation, and 24 (7.0%) had GISTs that were wild type for these genes. PDGFRA mutations and KIT exon 11 insertion or duplication mutations were associated with favorable RFS, whereas KIT exon 9 mutations were associated with unfavorable outcome. Patients with KIT 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%; P < .001), whereas no significant benefit from the 3-year treatment was found in the other mutational subgroups examined. KIT 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 KIT 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.

Conclusions and relevance: Patients with KIT 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 KIT mutations, including deletions that affect exon 11 codons 557 and/or 558.

Trial registration: clinicaltrials.gov Identifier: NCT00116935.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Joensuu reported receiving honoraria from consultation from Orion Pharma, BluePrint Medicines, and Ariad Pharmaceuticals. Dr Joensuu reported owing stock in Orion Pharma, Faron Pharmaceuticals, and Sartar Therapeutics. Dr P. Reichardt reported receiving honoraria from Novartis, Pfizer, Bayer, PharmaMar, Amgen GSK, and Lilly and serving on advisory boards for Novartis, Pfizer, Bayer, PharmaMar, Ariad, Amgen, GSK, AstraZeneca, Clinigen, and Lilly. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Profile of the Study
GISTs indicate gastrointestinal stromal tumors.
Figure 2.
Figure 2.. Associations of KIT Proto-oncogene Receptor Tyrosine Kinase (KIT) and Platelet-Derived Growth Factor Receptor α (PDGFRA) Mutation Types With Recurrence-Free Survival
A, Different types of KIT and PDGFRA mutations. B, KIT exon 11 deletion or insertion-deletion (indel) mutations. C, KIT exon 11 substitution mutations. D, KIT exon 9 mutations.
Figure 3.
Figure 3.. Associations of KIT Proto-oncogene Receptor Tyrosine Kinase (KIT) Exon 11 Deletion Mutations With Recurrence-Free Survival
A and B, Deletion and insertion-deletion (indel) mutations. C and D, KIT exon 11 mutations that do or do not involve codons 557 and/or 558.
Figure 4.
Figure 4.. Associations of Gastrointestinal Stromal Tumor Mitotic Count With Recurrence-Free Survival in Patients With KIT Proto-oncogene Receptor Tyrosine Kinase (KIT) Exon 11 Deletion Mutation
A and B, KIT exon 11 deletion and insertion-deletion (indel) mutations. C and D, KIT exon 11 mutations that involve codons 557 and/or 558. HPFs indicates high-power fields.
See this image and copyright information in PMC

Comment in

References

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