Dr. Lee HelmanThe 15th Pediatric and Wildtype GIST Clinic was recently held at the National Institute of Health in Bethesda, Maryland on July 5 – 7, 2017. The Clinic is a collaborative effort between clinicians and researchers to collect data supporting the investigation and development of treatment for Gastrointestinal Stromal Tumor (GIST) patients who do not have either c-KIT or PDGF mutations. Eleven new patients were seen at this Clinic, bringing the total tally of patients evaluated since the clinic’s inception to 163. Becky Owens attended the meeting as a representative of GIST Support International and has provided the following summary of the keynote address given by Dr. Lee Helman.

Dr. Helman’s Keynote Address

The incidence of Pediatric GIST is rare. As a result, no doctor would typically see a lot of cases. In response to this, we formed a consortium of researchers dedicated to the study of this disease which didn’t appear to be responding to typical treatments used for GIST. Though there are still many unanswered questions, we have learned a lot since the first Clinic in 2008. The first major breakthrough occurred in 2011 when it was learned that mutations in the Succinate Dehydrogenase (SDH) gene were frequently involved in the disease pathogenesis. We then began to learn that there were different molecular subtypes, each one with a slightly different clinical presentation. We engaged surgeons to better understand the best surgical management. Ultimately, we desire to identify effective drug management for patients in all of the subtypes, but we aren’t there yet.

Most of the Clinic patients (with the exception of one) have presented with primary tumors in the stomach. In contrast, the primary tumors of KIT-mutant GIST patients may originate in other locations in the gastrointestinal tract such as the small bowel. In both instances, the most common site of metastasis is the liver.

It has been identified that 85% of the general GIST population have either a KIT or PDGF mutation. These patients typically respond to Gleevec or Sutent, as these drugs target the mutation driving their tumor growth. A much smaller percentage (4%) of GISTs, do not have either of these mutations, and are SDH-deficient. These patients rarely achieve systemic disease control with medication.

SDH-Deficient GISTs

We break the SDH-deficient GISTs into two groups: those that have SDH mutations and those that don’t.

SDH mutations can occur in subunit a, b, c, or d. The vast majority are located in a, b, or c—we have only identified one patient with a subunit d mutation. Approximately 25% of SDH-deficient GISTs don’t have a subunit mutation, but are instead SDHC epimutant. Of those with an identifiable SDH mutation, the female:male incidence is about 60:40. However, in SDHC epimutant GIST, the incidence is overwhelming female. The epimutant patients are usually younger, with an average age at original diagnosis of 23 years.

SDH-deficiency is determined by applying immunohistochemical (IHC) stain to the tumor sample. If you apply this stain to a KIT-mutant GIST tumor, there is plenty of the SDH protein present. In SDH-mutant GIST, there is an absence of the SDHB protein. However, identifying that a patient is SDH-deficient does not necessarily indicate that a SDH gene mutation is present, only that there is a problem somewhere in the function of the SDH complex.

Statistically, the vast majority of the patients seen at the Clinic are SDH-deficient. Genomic analysis of SDH-deficient tumors reveals that there is a difference in the way they are methylated. Methylation is the regulatory process by which a gene can be turned on or off to generate protein. It was a remarkable discovery that all of the SDH-deficient tumors were hypermethylated. They looked completely different from the KIT-mutant GIST tumors which were not hypermethylated.

One of the most interesting things we’ve learned is that most of the SDH mutations occur in the germline—meaning that the mutation can also be found in the structure of every cell in the patient’s body. This does not mean that every cell in the body has the cancer, just the potential. So why do the primary tumors always form in the stomach? We do not have a definite answer for this. It appears that in the tumor, the second allele of the gene has somehow become compromised, damaged, or lost.

We believe epimutant SDH-deficient patients without a specific SDH mutation have a problem with the regulatory element of the SDHC gene that make it behave as mutant because it doesn’t shut off. This could be the case with Carney Triad. Although the DNA sequence is not changed in epimutant genes, they are unable to perform normally. Distinguishing between having a mutation or an epimutation has clinical implications for two reasons:

  1. For those with an SDH mutation, we need to know if it is a germline or a somatic mutation. If it is germline, you have probably inherited the mutation from one of your parents and genetic counseling is recommended. Your siblings and children have a 50% chance of having also inherited the mutation. Having an SDH mutation can predispose you to getting GIST tumors and paragangliomas, as is the case with Carney-Stratakis Dyad patients. Those with an SDH germline mutation should be monitored for both GIST and/or paragangliomas. In most patients, we seem to see the GIST first, so we can then monitor for paragangliomas. If paragangliomas develop, they can usually be surgically removed.We have identified a few Clinic participants who are Wildtype for KIT/PDGF but are not SDH-deficient. Within this group we have identified mutations in in ARID1-A, BRAF, or NF1. NF1-mutant GISTs are usually germline. It is recommended that they be seen in a neurofibromatosis clinic and also followed by GIST experts. NF-mutant GIST patients are also at increased risk for paragangliomas and possibly for kidney cancer.
  1. For those with an epimutant SDH problem such as with Carney Triad, the family does not have to be tested as this is not an inherited problem. Carney Triad patients are prone to getting GIST tumors, paragangliomas, and pulmonary chondromas; however, their family members are not at increased risk.When looking at the whole genome with comparative hybridization, most cancer tumors have lots of changes across all their chromosomes and are genetically unstable. In contrast, when looking at the chromosomes of SDH-deficient tumor cells, they look much more like normal cells. They don’t need to lose or gain chromosomes in order to survive it is done through altered methylation instead.

Why would they be methylated?

The mitochondria create energy in every cell by generating ATP. ATP is made through a series of enzymatic changes, moving from alpha-ketoglutarate to succinate to fumarate, with the SDH gene involved in this last step. Without proper function of the SDH gene, succinate is not converted to fumarate, resulting in an accumulation of succinate. The ratio between alpha-ketoglutarate and succinate affects the ability of the cells to demethylate. Too much succinate and not enough alpha-ketoglutarate globally poisons the DNA demethylation process interfering with the ability of the cells to actively demethylate. The presence of excess succinate also impacts the enzymatic process involved with angiogenesis involving HIF-1a. In this case, the cells falsely perceive that they aren’t getting enough oxygen, a condition known as pseudohypoxia. Pseudohypoxia stimulates increased vascularization and cell proliferation in the tumors.

What else have we learned?

What we do know is that we can’t cure this by surgery because this mutation is in every cell in your body. It is often multifocal. Therefore, we usually discourage surgical removal of the whole stomach, opting for a more minimized approach with less impact on the quality of life. Surgery can be helpful to control bleeding, for obstruction, for symptomatic control, or to get a diagnosis. It has become the emerging opinion of the surgeons involved with the Clinic that obtaining clear margins may not be of as vital importance as with other cancers. In an analysis of the first 70 SDH-deficient Clinic attendees, frequently patients had developed a new tumor by 2 1/2 years post-op even if the surgeon had resected everything. Unlike with other types of cancers where if you have a recurrent tumor you have a really bad prognosis, with SDH-deficient GIST the recurrent disease doesn’t portend a horrible outcome. For most of SDH-deficient patients, the median survival is rather long. Therefore, we don’t recommend aggressive surgery as there is no evidence that it will control the disease. The Clinic surgeons recommend only removing a tumor that is causing a problem. Just because a tumor is present doesn’t necessarily mean we will recommend trying to take it out.

We don’t believe that patients with SDH-deficiency respond to Gleevec. We still have patients that come to us on Gleevec, but this number is fewer than before. If the patient is doing well, not progressing, and they are tolerating Gleevec, we usually don’t recommend discontinuing it. However, most of the NIH Clinic Specialists feel that Gleevec is probably not doing much. On the other hand, we usually recommend discontinuance of Gleevec to patients that are experiencing problematic side effects as there does not seem to be objective evidence that it is effective. This is in marked contrast to the recommended treatment for KIT or PDGF-mutant GIST patients, where you almost always see some initial response. With respect to Sutent, we definitely see some response in about 25% of cases. This may be attributable to Sutent’s anti-angiogenic effect inhibiting blood vessel growth. We’ve also seen some definite responses to Stivarga. If a newly diagnosed patient needs to be on a drug, we would probably recommend Sutent first, because it is generally better tolerated than Stivarga.

Where are we headed in terms of treatment?

There is a class of drugs called DNA  demehtyltransferase inhibitors that could demethylate SDH-deficient tumors. These drugs have been used successfully in myelodysplastic syndromes such as pre-leukemia. They work by inhibiting the methylation of a huge number of genes. There is a newer methyltransferase inhibitor that lasts longer in the bloodstream called SGI-110, or Guadacitabine. We’ve opened a new study at the NIH to evaluate the efficacy of Guadacitabine in addressing the methylation problem in SDH-deficient GIST.

This drug has been given to hundreds of patients with other cancers and we now know the side effects. It mainly affects the blood count, but most patients tolerate it extremely well. It is our hope that not allowing the genome of SDH-deficient tumors to stay methylated will prove to be a good treatment option. Presently, the drug is only available subcutaneously, so you would have to be at NIH in Bethesda, Maryland for five days in a row, every four weeks to receive it. If the treatment shows successful activity over time, we are hopeful that the shots could eventually be self-administered.

When the Pediatric and Wildtype GIST Clinic began in 2008, we weren’t sure if we’d even get three patients, but we ended up with 12. Everyone who had this disease felt that they were the only patient with it in the world. Now they know that they are not alone. First, we have to understand it, and then we have to develop treatments. That’s what we’re working really hard to do and that is our hope. We’re very appreciative to see all of the Clinic patients, because the more we see you, the more we understand.

Patients interested in participating in the NIH Pediatric and WT GIST Clinic may contact: