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.
OBJECTIVE
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.


METHODS
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.


METHODS
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
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00116935.
Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Heikki
H
Joensuu
Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany.
Eva
E
Wardelmann
Laboratory of Molecular Oncology and Translational Cancer Biology Program, Biomedicum, University of Helsinki, Helsinki, Finland.
Harri
H
Sihto
Department of Oncology, Skåne University Hospital and Lund University, Lund, Sweden.
Mikael
M
Eriksson
Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Kirsten
K
Sundby Hall
Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch, Berlin, Germany.
Annette
A
Reichardt
Department of Hematology, Oncology, Immunology, Franziskus Hospital, Catholic Hospital Consortium Ostwestfalen, Bielefeld, Germany.
Jörg T
JT
Hartmann
Department of Hematology, Oncology and Palliative Care, HELIOS Klinikum Bad Saarow, Germany.
Daniel
D
Pink
Department of Gastroenterology/Endocrinology, University of Göttingen, Göttingen, Germany.
Silke
S
Cameron
Division of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, Mannheim, Germany.
Peter
P
Hohenberger
Clinical Cancer Research, Krankenhaus Nordwest, Universitäres Centrum für Tumorerkrankungen University Cancer Center Frankfurt, Frankfurt, Germany.
Salah-Eddin
SE
Al-Batran
Department of Internal Medicine III, University Hospital-Großhadern, Ludwig Maximilians University, Munich, Germany.
Marcus
M
Schlemmer
Sarcoma Center, West German Cancer Center, University of Duisburg-Essen, Essen, Germany.
Sebastian
S
Bauer
Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
Bengt
B
Nilsson
Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland.
Raija
R
Kallio
Pharma Ltd, Turku, Finland.
Jouni
J
Junnila
Helsinki Institute for Information Technology, Department of Computer Science, Aalto University, Espoo, Finland.
Aki
A
Vehtari
Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Berlin-Buch, Berlin, Germany.
Peter
P
Reichardt
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D004334:Drug Administration Schedule; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage* / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha