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 triala
<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.&...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 23, 2017
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| In: |
JAMA oncology
Year: 2017, Volume: 3, Issue: 5, Pages: 602-609 |
| ISSN: | 2374-2445 |
| DOI: | 10.1001/jamaoncol.2016.5751 |
| Online Access: | Verlag, Volltext: https://jamanetwork.com/journals/jamaoncology/fullarticle/2612802 Verlag, Volltext: http://dx.doi.org/10.1001/jamaoncol.2016.5751 
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| Author Notes: | Heikki Joensuu, MD; Eva Wardelmann, MD; Harri Sihto, PhD; Mikael Eriksson, MD; Kirsten Sundby Hall, MD; Annette Reichardt, MD; Jörg T. Hartmann, MD; Daniel Pink, MD; Silke Cameron, MD; Peter Hohenberger, MD; Salah-Eddin Al-Batran, MD; Marcus Schlemmer, MD; Sebastian Bauer, MD; Bengt Nilsson, MD; Raija Kallio, MD; Jouni Junnila, MSc; Aki Vehtari, PhD; Peter Reichardt, MD |
| Summary: | <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> |
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| Item Description: | Published online March 23, 2017 Gesehen am 30.08.2018 |
| Physical Description: | Online Resource |
| ISSN: | 2374-2445 |
| DOI: | 10.1001/jamaoncol.2016.5751 |