Summary of discussions at the 4th Pediatric and WT Gist Clinic, January 20, 2010
Dr. Su Young Kim presented the results from the first 3 clinics to the participants of the Fourth Pediatric and WT Gist Clinic held at the National Institute of Health on January 20, 2010. What follows is Part I of III of my summary of the material presented. These summaries are paraphrased from my notes.
Question: How do you study are rare disease? Answer: You bring specialists in the study of the disease together with patients and their families. Pediatric Gist patients can then be compared against other people, determining what is similar and what is different in an effort to figure out what is relevant. This process includes study of the clinical history, response to prior treatment, radiologic, genetic, and histiopathic findings, and acquisition and analysis of genetic material and tumor samples. All of this can then be compared and contrasted to what is found in adult KIT/PDGFRa mutated Gist and adult WT Gist with the goal being to define new targets for biological treatments.
The scientific data obtained during the clinics can help to determine whether the following anecdotal premises regarding Pediatric Gist are true.
1) Pediatric Gist is much more prevalent in females than males. Adult mutated Gist patients nationally present as 46% male, 54% female. The Pediatric Gist patient population at NIH has been 14% male, 86% femaleÃ¢â≠¬â•ˇthis despite all male Pediatric Gist patients being given priority due to their uniqueness.
2) Pediatric Gist patients do not possess KIT or PDGFRa mutations. 0% of the Pediatric Gist patients had KIT or PDGFRa mutations, this despite the fact that all children and young adults with Gist were admitted to the Clinic without previous regard for mutation analysis. In contrast, 90% of the general adult Gist population possess a mutation of the either the KIT or PDGFRa gene.
3) Pediatric Gist cells are epitheloid (round) shaped as contrasted to the high predominance of spindle (elongated) shaped cells in the mutated Gist population.
4) Pediatric Gist is frequently multifocal (having more than one tumor present) at the time of diagnosis as contrasted to adult mutant Gist which is usually characterized by one tumor site at the time of diagnosis.
5) Pediatric Gists have a higher incidence of stomach as the location of the primary tumor (80%) vs. in the adult mutated Gist population (50%).
6) In Pediatric Gist there does seem to be a positive correlation between slower disease progression associated with younger age of diagnosis, with younger patients having less aggressive disease.
Of the patients in the Pediatric and WT Gist Clinic database, the percentage of those still NED following their first surgery are as follows:
(50) Children 50%
(50) Adolescents 50%
(18) Young adults 42%
(7) Adults (40 years or older) 14%
There is also a positive correlation between the age at diagnosis and the number of months still in remission following the first surgery. For children the avg. was 37.5 months (range 13-55), adults avg. 22 months (range 3-57). However, with the large overlap it is difficult to definitively analyze this data.
Tumor size and mitotic rates also appear to be smaller overall associated with younger age of diagnosis, but again, the range overlap is large). It is hoped that these areas will become better defined as more data is collected.
7) What is the role of surgery? It is the current belief that prophylactic performance of complete gastectomy upon initial diagnosis is to be avoided when possible.
8) The role of TKIs in the treatment of Pediatric Gist is still under evaluation, with continuing data from patient participants from former clinics being of utmost value. This is particularly true in regard to the evaluation of the efficacy of Nilotinib. In the next few months 6 former patients presently taking Nilotinib will be undergoing scans. These patients will have been taking Nilotinib for at least a year and the scan results will yield useful data. All former clinic patients are encouraged to send updated information regarding their status following each scan.
An unexpected finding of the Ped Gist Clinics relates to the high incidence of keloid formation of the surgical scars of Pediatric Gist patients. Although keloid formation is common for African-Americans , this is considered rare for the Caucasion and Asian populations. 60% of the previous Pediatric Gist patients presented with keloid formation. In another division of NIH studies on the specific genetic attributes associated with keloid formation is presently ongoing. Preliminary findings are expected to be available in approximately 2 to 3 years.
Patients in the Pediatric and WT Gist Clinic undergo 3D videography analyzing the phenotypes of the patients. Each patient's facial features analyzed from a composite of 8 different pictures. So far, they do not have enough faces for meaningful analysis, but hope to by the end of this 4th Clinic. Preliminary results indicate that, by and large, the patient participants are a good-looking group (but we already knew that!--with a high percentage of features such as angular faces, high cheekbones, and symmetry.
On a much more dry and clinical note: blood and tissue samples from Clinic patients provide research tools. The following areas are of interest to the investigators.
IGF-1R: It has been found that Pediatric and WT Gist patients frequently have an increased amount of IGF-1R (ligands that bind and tells a cell to turn on and off) on the surface of their cells. Clinical trials utilizing an IGF-1R inhibitor (R1507) has shown some promise in the treatment of other sarcomas tne there is rationale to believe that it would have some benefit in the treatment of Pediatric and WT Gist. Unfortunately, Roche has decided not to pursue further development of R1507 for business development reasons. NIH is working hard to push to obtain access to R1507 and to get a study open in the near future.
BRAF: It is suspected that BRAF mutations may be present in a subpopulation of the Clinic participants. Patients with this mutation may present with an increased number of spots on their skin (known as nevi). A family history of Melanoma may be an indicator to check for this mutation. BRAF could be a therapeutic target for the treatment of BRAF mutant Gists. There are BRAF inhibitors presently in clinical trial for other types of cancer.
MET: Medical students at NIH have been performing research to identify additional mutations present in Pediatric Sarcoma patients. This research included the application of dye to test for the presence of increased MET in the blood of patients in the 3rd Pediatric and WT Clinic. It was found that many of the patients had 2 to 10 times the level of MET. They are presently testing the tumors samples of these patients to determine if MET is overexpressed in the tumors, potentially making them targets for MET inhibitors.
EGFR: EGFR testing is being performed on tumor samples as 12/26 of previously tested patients have been found to have elevated EGFR levels in the blood.
SDH: 15% of previous Clinic patients have been found to have SDH mutations. Although there is not direct treatment for SDH mutations it has been found that HIP1a is upregulated downstream of SDH mutations and is a potential therapeutic target open for future investigation.
The Pediatric and WT Gist Clinic has now expanded, with the Drs. From 8 different hospitals contributing. Also, there is collaboration with Peter Mac Hospital in Australia.
A Vision for the Future:
Expand the website to include several layers:
1) The first layer would be informational to the general public, to increase awareness of the clinic for the general public.
Additional layers of the website could include:
2) Information on patient data with patients de-identified. This layer would be behind a security firewall accessible to researchers only.
3) Patient information with patient identifiers present, with patient consent. This layer would also be behind a security firewall. Things like radiology reports, etc. could be uploaded to this site.
NIH is working with IT specialists to figure out a good way to enter data so that it is not cumbersome and is useful, while maintaining security.
Another Vision for the Future for the Clinic is to establish a Tumor Board. The Board could convene every week, electronically. Local docs could use this as a way to have access to Pediatric and WT Gist Specialists.
Again, this is only my summary written from my notes, an actual podcast of the presentation should be available in the near future
This concludes my summary of the presentation. As in the previous clinics, the Pediatric Gist Consortium continues to provide enthusiastic and tireless support for the investigation and treatment of Pediatric and Wildtype Gist patients. We are extremely grateful for their work.