KIT mutations linked to imatinib response in GIST

Last Updated: 2017-03-31

By Will Boggs MD

NEW YORK (Reuters Health) - Different KIT mutations have various associations with the response of gastrointestinal stromal tumors (GISTs) to adjuvant imatinib, according to results from a Scandinavian Sarcoma Group multicenter trial.

"Patients with KIT deletion mutations derive the most benefit from adjuvant imatinib,” Dr. Heikki Joensuu from Helsinki University Hospital and the University of Helsinki, in Finland, told Reuters Health by email. “The present findings support the strategy of treating patients with KIT exon 11 deletion mutation with long durations of adjuvant imatinib.”

High-risk patients with GISTs commonly receive at least three years of imatinib, but little is known about the link between duration of adjuvant imatinib and the prognostic significance of KIT and PDGFRA mutations.

Dr. Joensuu and colleagues investigated the relationship between various KIT and PDGFRA mutations and recurrence-free survival in 341 patients with GISTs treated with surgery and adjuvant imatinib.

Patients with a KIT exon 11 deletion or indel mutation treated with three years of adjuvant imatinib had much better five-year recurrence-free survival than did similar patients treated with one year of imatinib (71.0% vs. 41.3%, p<0.001), the researchers report in JAMA Oncology, online March 23.

These mutations in KIT exon 11 involving codons 557 and/or 558 were associated with unfavorable recurrence-free survival compared with the rest of the patients in the subgroup of patients assigned to one year of imatinib treatment, but no such associations were present among patients who were assigned to three years of imatinib treatment.

Tumor mitotic count was also significantly associated with recurrence-free survival in the subset of patients who had KIT deletion or indel mutations and were assigned to one year of treatment, but this association was not present among patients assigned to three years of treatment.

There were no significant differences in recurrence-free survival according to treatment duration in patients with other KIT or PDGFRA mutations.

“Although the presence of KIT exon deletion mutation, deletion of the critical codons 557/558 in exon 11, and a high tumor mitotic count are established prognostic factors in patient populations treated with surgery only for localized GIST, they are not prognostic when the patients are treated with surgery and adjuvant imatinib for 3 years,” Dr. Joensuu said.

“Yet, mutation analysis of the KIT and PDGFRA genes is important to carry out when planning the management of GIST patients who have undergone surgery for a localized GIST, since some GISTs harbor mutations that are not sensitive to imatinib,” he said.

“The ongoing randomized trials that compare longer than 3-year durations of adjuvant imatinib to the current standard of 3 years are important, since we need to find out whether still longer adjuvant treatments provide further efficacy benefits,” Dr. Joensuu added.

“In our opinion, physicians who are considering a recommendation of adjuvant therapy for resected primary GIST should first determine the genotype of the patient’s tumor,” write Dr. Michael C. Heinrich from Oregon Health and Science University in Portland and colleagues in a related editorial. “Patients with PDGFRA D842V-mutant GIST or whose tumor lacks any KIT/PDGFRA mutations should not be treated with adjuvant imatinib.”

“Over the past 16 years, KIT selective kinase inhibitors such as imatinib have revolutionized the treatment of advanced GIST,” they conclude. “It is clear that adjuvant therapy with imatinib can improve the recurrence-free survival and overall survival of molecularly selected patients with GIST. For these patients, an ounce of prevention may be just what the doctor ordered; for the rest, a pound of research is still recommended.”

The analysis did not have commercial funding. The trial was supported by Novartis Oncology; one of Dr. Joenssu’s coauthors reported financial ties to the company, which markets imatinib as Gleevec.

SOURCE: http://bit.ly/2nmf3Ue and http://bit.ly/2ogcqrR

JAMA Oncol 2017.