July 2017 Case

GISTs apparently originating outside of the gastrointestinal tract are often referred to as EGISTs. These are histologically and immunophenotypically similar to their gastrointestinal tract counterparts, however the clinical course is more aggressive. This case has high recurrence risk features including location, necrosis, mitotic rate, and tumor at margin.

Activating mutations of the c-KIT gene (KIT or CD117) are found in about 85% of GISTs (https://www.mycancergenome.org/content/disease/gist/kit/, Maki, R., V. Keedy. 2014. KIT in GIST. My Cancer Genome). KIT p.V559A (valine to alanine substitution at codon 559, encoded by c.1676T>C thymine to cytosine substitution at mRNA nucleotide position 1676) is a recurrent variant in malignant melanoma and GIST (COSM1255 and COSM12453, COSMIC database accessed June 2017). As with oncogenic "gain-of-function" variants of other receptor tyrosine kinases, mutations of GIST tend to cluster in certain protein domains where they perturb the receptor into a constitutively active state. For GIST, relevant domains are encoded by exons 9 (extracellular dimerization), 11 (juxtamembrane), 13 (kinase 1) and 17 (kinase 2). Some mutational diversity comprising missense (amino acid substitution) and short in-frame amino acid insertions or deletions is observed. Common recurrent variants are associated with more preclinical and clinical information than rare or novel variants; however, those in each domain/exon are usually observed to have common properties with respect to therapy prediction. In particular, exon 11 variants like V559A, which are most common in GIST relative to variants in other exons, confer a better response (by RR, PFS, OS) to first-line imatinib (Gleevec) therapy, but a worse response to sunitinib, than GISTs with other exonic variants. Also like other receptor tyrosine kinases, targeted anti-KIT therapies may induce secondary resistance mutations; in GIST, these occur primarily in exons 13, 14, 17, and 18. Resistance to imatinib may be managed by changing to other second or third generation tyrosine kinase inhibitors (TKIs) such as regorafinib, sorafenib, ponitinib, or nilotinib, optimally via clinical trials.

The 15% of GISTs with wild-type KIT may instead have variants in PDGFRA, BRAF or SDH (succinate dehydrogenase), in decreasing order of frequency. Cases with mutations in BRAF or SDH will require other drug treatment strategies due to the lack of the correct molecular target for TKIs. In summary, the molecular finding of KIT V559A despite extensive necrosis is consistent with the IHC studies and the pathologic diagnosis of GIST, provides valuable prognostic and predictive information, and supports a therapeutic rationale for instituting adjuvant imatinib therapy for this patient, which is currently underway.

1. Heinrich MC et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-9.

2. Debiec-Rychter M et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2004 Mar;40(5):689-95.

3. Heinrich MC et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008 Nov 20;26(33):5360-7. doi: 10.1200/JCO.2008.17.4284. Epub 2008 Oct 27.

4. Rutkowski P et al. The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study. BMC Cancer. 2012 Mar 22;12:107. doi: 10.1186/1471-2407-12-107.

5. Blanke CD et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb 1;26(4):626-32. doi: 10.1200/JCO.2007.13.4452.

6. Demetri GD et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010 Apr;8 Suppl 2:S1-41; quiz S42-4.