Adjuvant Imatinib Duration Impacts GIST Prognostic Mutations

For gastrointestinal stromal tumours, the prognostic impact of tumour mutations may differ in patients given 1 year of imatinib versus those given a 3-year course

medwireNews: Exploratory analysis suggests that the duration of adjuvant imatinib in gastrointestinal stromal tumour (GIST) patients may influence the relationship between recurrence-free survival (RFS) and tumour risk factors, such as mutations and mitotic count.

Heikki Joensuu, from Helsinki University Hospital in Finland, and co-workers examined the impact of imatinib duration in participants of the Scandinavian Sarcoma Group VIII/Arbeitsgemeinschaft Internistische Onkologie (SSGXVIII/AIO) study who had undergone surgery and were at high risk of GIST recurrence.

In all, 174 patients were randomly assigned to receive 1 year of imatinib 400 mg/day while 167 patients were assigned to receive the same dose for 3 years, the team explains in JAMA Oncology.

Of these participants, 80.4% had a KIT mutation, including exon 11 deletions or insertion–deletion (indel) mutations in 54.4%, while 12.6% had a PDGFRA mutation and 7.0% had neither of these aberrations.

In patients with a KIT exon 11 deletion or indel mutation, RFS was “substantially better” in those assigned to the 3-year regimen than the 1-year course, with a significant difference found between the 5-year values of 71.0% versus 41.3%.

But no such relationship was identified between imatinib duration and 5-year RFS in other mutation subgroups, the authors say.

Further analysis revealed that for patients assigned to 1 year of imatinib, RFS was significantly altered by the presence or absence of a KIT exon 11 deletion or indel mutation and whether these mutations included codons 557 and/or 558, or if either of these two codons were deleted.
However, RFS did not significantly differ in these subgroups when patients were assigned to receive 3 years of imatinib, the researchers say.

Among patients with KIT exon 11 deletion or indel mutations, the rate of 5-year RFS was lower among those with a mitotic count higher than the median value than for those with median counts or below, but only if they had been assigned to receive 1 year of imatinib (54.5 vs 28.4%); RFS was not significantly linked to mitotic count in patients given 3 years of treatment.

Similarly, for patients with a KIT mutation involving codons 557 and/or 558, the rate of 5-year RFS was significantly lower among those with a mitotic count above versus at or below the median in the 1-year imatinib treatment group (55.2 vs 30.8%) but not the 3-year treatment group.

“To our knowledge, the observation that the duration of adjuvant imatinib treatment influences the clinical significance of important prognostic factors, such as tumor mitotic count and tumor genotype, is novel”, say Heikki Joensuu et al.

They hypothesise that adjuvant imatinib may “influence profoundly the molecular biology of some GISTs” and that “longer adjuvant imatinib treatment eradicates more efficiently GIST cells that harbor imatinib-sensitive KIT mutations and have a high cell proliferation rate than the shorter treatment.”

Moreover, the authors suggest the current findings may explain why this trial’s original findings showed an overall survival benefit in the 3-year imatinib arm that was not found in earlier studies with shorter durations of imatinib therapy.

“The present findings further suggest that patients with GISTs treated with long durations of adjuvant imatinib may need to be followed up longer for tumor recurrence because some of the recurrent tumors may surface late despite the presence of high-risk features at the time of the diagnosis”, they write.

“More important, studies that evaluate the prognostic factors of localized GISTs now not only need to consider whether adjuvant imatinib was administered but also need to take into account the duration of adjuvant imatinib.”

And the investigators add: “Two ongoing randomized trials are currently comparing 5 vs 3 years and 6 vs 3 years of adjuvant imatinib treatment to evaluate whether still longer adjuvant treatments will provide further benefits.”

Reference

Joensuu H, Wardelmann E, Sihto H, et al. 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. JAMA Oncol; Advance online publication 23 March 2017. doi:10.1001/jamaoncol.2016.5751

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