Average life expectancy had been no better than 18 months for people diagnosed with advanced gastrointestinal stromal tumors, or GISTs.
The outlook changed dramatically in 2001 with the arrival of the targeted therapy drug imatinib (Gleevec). “Now we’ve learned that some might live a decade or longer. And we’ve come to understand which class of patients benefit the most,” said Michael Heinrich, M.D., first author of a new report on the long-term outcomes of women and men who enrolled in the pivotal clinical trial organized in 2000 by SWOG, the research consortium headquartered at the OHSU Knight Cancer Institute.
Imatinib was ushered from lab bench to clinical success as a treatment for chronic myeloid leukemia by Brian Druker, M.D., director of the OHSU Knight Cancer Institute. It is a tyrosine kinase inhibitor that targets a mutant protein, BCR-ABL1, that is a driver of malignant transformation in CML. Imatinib also inhibits two tyrosine kinase receptors, KIT and PDGFRA, which are often mutated in GIST to drive cancer cell growth and division.
The SWOG randomized Phase III clinical trial enrolled patients with GIST that was not surgically curable. Heinrich and colleagues collected survival data on 695 patients ten years after initiation of accrual on this study. They used next-generation gene sequencing to re-analyze DNA from formalin-fixed, paraffin-embedded tumors from 20 cases originally classified as not having KIT or PDGFRA mutations.
“…we’ve learned that some might live a decade or longer. And we’ve come to understand which class of patients benefit the most.”
Overall 10-year survival was 23 percent, the researchers estimated. Imatinib was the sole therapy administered to nearly half (48.6 percent) of the 142 long-term survivors.
Resequencing identified a likely causative mutation in 17 of the 20 cases that had no cancer-causing mutation found in the original analysis. Three cases had KIT mutations that were missed in the original analysis. Twelve had mutations in a subunit of the succinate dehydrogenase complex. Loss of the neurofibromin 1 gene was the presumed driver mutation in two cases.
DNA sequencing also showed that survival rates were significantly higher for patients with a KIT exon-11 mutant GIST in comparison with patients whose tumor had a KIT exon-9 mutation, no KIT mutations, or mutations in PDGFRA.
The study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, the authors concluded. The next challenge is to define the optimal management of the other GIST subtypes.
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Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033 by Michael Heinrich, Cathryn Rankin, Charles D. Blanke, George D. Demetri, Ernest C. Borden, Christopher W. Ryan, Margaret von Mehren, Martin E. Blackstein, Dennis A. Priebat, William D. Tap, Robert G. Maki, Christopher L. Corless, Jonathan A. Fletcher, Kouros Owzar, John J. Crowley, Robert S. Benjamin, and Laurence H. Baker. JAMA Oncology (February 2017)
Down-the-Line Dividends from Smart Cancer Research by Charles D. Blanke (Februay 2017)
Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era: A population-based study in Western Sweden by Bengt Nilsson, Per Bümming, Jeanne M. Meis-Kindblom, Anders Odén, Aydin Dortok, Bengt Gustavsson, Katarzyna Sablinska, Lars-Gunnar Kindblom. Cancer (February 2005)