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Pediatric and Wild-type GIST

Presented by Dr. Michael Heinrich, OHSU, at ASCO Annual Meeting, June 4-8, 2010

Adult GIST is rare, making PED GIST very, very rare. In adult GIST more than 80% of patient’s tumors have either a KIT or PDGFra mutation. Whereas in PED GIST the incidence of a KIT or PDGFra mutation is very unusual, less than 10%. There is a slight male predominance of GIST in Adult WT patients. However, in PED GIST it’s a very extreme difference with girls or young women being 8-9 times more common than boys or young males. In adult GIST there is usually a unifocal primary compared to PED GIST, which often has a multi-focal primary presentation. In the adult form spindle cell histology is most common whereas in PED GIST epithelioid is most common. The stomach is the most commonly involved site in the adult, about 70%. In the PED GIST population the stomach is the site of the primary tumor 90% of the time. And in most cases adult WT GIST metastatic acts very aggressively, whereas in most cases of PED GIST metastatic disease can behave indolently in that they may survive many decades with the help of a good surgeon in managing their metastatic disease.

Now, even within PED GIST there are discreet syndromes. There is Carney’s Triad, which is the complex of GIST, Paraganglioma (PGL), and Pulmonary Chondroma. There is also Carney-Stratakis Syndrome, which presents as the combination of GIST and PGLs. We have now recently learned that this particular type of GIST is associated with germline loss-of-function mutations of the Succinate-dehydrogenase (SDH) B, C, or D gene. There is also a sporadic Pediatric GIST that doesn’t fit into either of the above 2 categories, and there is NF-1 associated GIST. NF-1 GIST is rare with around 6-25% of neurofibromatosis patients developing one or more GIST during their lifetime.

In the case of Carney-Stratakis syndrome (GIST tumors and PGLs) the underlying biology involves the SDH composed of 4 members: SDHa, SDHb, SDHc, and SCHd which forms something called mitochondrial complex II. This complex links SDH activity in the KREBS cycle in the cytoplasm with the mitochondrial electron transport chain. When you disrupt this complex at SDHb, c, or d the SDH activity can remain normal but the electron transport chain is disrupted. Deficiency of this complex causes both reactive oxygen species generation and up-regularities of hypoxia-induction factor (HIF-1a). We are now beginning to see a curious overlap of the biology of PED GIST with renal cell carcinoma (RCC). In RCC a deficiency of the Von-Hippel Lindau (VHL) protein leads to up-regulation of HIF-1R and it’s downstream targets such as Glutamine (GLUT1) and VEGF. There are other familial RCCs that involve deficiencies in SDH or Fumerate. It is now clear that with PED WT GIST, some are caused by derangements of this pathway suggesting a common biology between PED GIST and RCC suggesting the possibility that maybe everything we’ve learned about RCC in terms of therapeutics might be applicable at least to SDH-deficient PED GIST.

If you take a group of PED GIST patients you can actually find that even though they apparently didn’t have Carney-Stratakis syndrome (because they didn’t present with PGLs), if you sequence their SDH b or d genes you actually find mutations in 11%. You can also do immunohistochemistry(IHC) for SDHb deficiency (PGL with SDHb deficiency stains differently in the PGL with VHL deficiency). Using their IHC analysis they found that the SDHb protein was absent in 100% of PED GIST patient despite the absence of mutation, again suggesting that defects in cellular respiration my be a central oncogenic mechanism in PED GIST.

What about adult WT GIST? Adult WT GIST, present in 15-20% of adult GISTs, likely represents a heterogeneous group of disease. We can find KIT activation at least biochemically in most cases, however, the underlying biology is not understood. There are identifiable subsets in adult WT GIST. There are BRAF mutant GISTS which are rare, RAS mutant GISTS which are very, very rare, and SDHB deficient GIST which are not being identified immunohistochemically. We’re not sure why they lack the SDHb protein because they may not have SDH mutations, but this is an important lead for us. And there is also NF-1 associated GIST. Again, 6-25% of patients with NF-1 will develop one or more GISTS during their lifetime. And then there are some Adult WT GISTS with none of the above, which means we really know what is going on.

In terms of WT KIT going back to kinase sensitivity, it’s sensitive to IM but requires a higher dose (1000 nMolars) than a KIT exon 11 mutation. In the Phase II clinical studies with the adult WT patients treated with 400 vs. 800 mg/day IM there was no difference in PFS or OS between the 2 dose arms. So, for Adult WT GIST as a group, not considering the subgroups that we can’t routinely clinically identify, the data suggest that IM 400 mg/day is the recommended starting dose.

What about BRAF V600E mutant GIST? In three reported series, overall 7% of WT GISTs were reported to have BRAF. BRAF mutations were not found in KIT or PDGFra mutant GIST. In our series of WT GIST we found 1 BRAF mutation out of 99 patients. Also there were 2 cases with RAS mutations. And so there may be a potential role for BRAF or MEK inhibitors for treatment. In GIST BRAF and RAS mutations are rare, whereas in melanoma exactly the opposite is true with BRAF and RAS mutations being common and KIT mutations being rare. How does this play out in terms of treatment? At least in the case of Pediatric GIST it’s interesting that the front line response to IM is not that great. It was noted in a study that the difference between time-to-progression (TTP) on SU vs. IM showed a trend toward longer TTP for 5 out of 7 patients using second-line SU than using first-line IM. It was speculated by Dr. Heinrich that possibly this goes back to SU being a better RCC treatment. Perhaps this can be attributed to the concept that PED GIST patients may be be more biologically similar to RCC than adult GIST.

Presented by Dr. Katie Janeway on behalf of the Consortium of Pediatric and Wildtype GIST Research (CPGR) during the 2010 ASCO meeting.

85% of GISTs in children are wildtype, lacking either KIT or PDGFRa mutations. A sub-group of these pediatric GIST patients are classified as having Carney-Stratakis Syndrome. Carney–Stratakis Syndrome infers an inherited predisposition to develop GIST tumors and paragangliomas (PGLs) caused by a germline mutation of the succinate dehydrogenase (SDH) gene subunits B, C or D. These germline mutations result in dysfunction of Complex II of the electron transport chain and defective cellular respiration.

In this study it was found that 16% of the pediatric wildtype patients without a family history of PGL had germline mutations of the SDH gene. Thirteen pediatric KIT- / PDGFRA- wildtype GISTs lacking somatic mutations or deletions in SDH were evaluated for SDHB expression by immunohistochemistry (IHC) and western blotting. Interestingly, despite the fact that these 13 did not harbor an SDH mutation, they nevertheless all demonstrated a complete loss of SDHB protein expression. In contrast to this, only 25% of KIT-mutant and 0% of NF1-mutant GIST demonstrated a complete loss of SDHB protein expression.

In addition, Complex II activity was measured in a subset of the pediatric KIT- / PDGFRA-wildtype GISTs and in KIT-mutant GISTs. Complex II activity was absent (comparable to levels seen in SDH mutant paragangliomas) in pediatric KIT- / PDGFRA- wildtype GISTs lacking somatic SDH mutations or deletions.

Conclusions: A germline mutation in SDHB, C or D can cause KIT- / PDGFRA- wildtype GIST without an associated family history of paraganglioma. In the absence of SDH mutations or deletions, pediatric KIT- / PDGFRA-wildtype GISTs have complete loss of SDHB protein expression and loss of complex II activity. These findings indicate that SDHB loss and defective cellular respiration may be central mediators of oncogenesis in GISTs lacking receptor tyrosine kinase mutations.