This is a brief summary of abstracts presented at the 2013 GI ASCO meeting. Please note that abstracts have not been through a complete peer review process and are considered to be preliminary.
1. Muguruma et al., Randomized phase II study of 6 versus 12 months of adjuvant imatinib for patients with intermediate- or high-risk GIST.
GIST Abstract No: 9
LRG Summary: The clinical trials spearheaded by Dr Joensuu in Finland have shown the effectiveness of adjuvant imatinib therapy in preventing recurrence and improving progression-free survival and overall survival in high- and medium-risk GIST patients after surgery for primary disease. This was shown first for one year of adjuvant imatinib therapy, and then extended to three years of imatinib. Results for even longer treatment periods are anticipated. The evidence has been that longer treatment periods are justified and give better outcomes. In this clinical trial in Japan, patients were randomized to either 6 months or one year of adjuvant imatinib. The results showed very clearly that one year is better than six months. This result does not come as any surprise, and serves to strengthen the case for extended periods of adjuvant imatinib therapy.
2. Mahadevan et al., Activity of AT13387, a novel, non-ansamycin inhibitor of heat shock protein 90, against gastrointestinal stromal tumors (GIST).
GIST Abstract No: 105
LRG Summary: This report, from Astex Pharmaceuticals, Arizona Cancer Center, and Dana-Farber Cancer Institute, describes a Phase 1 trial of a new drug, AT13387, which drug acts by inhibiting a protein called heat shock protein 90 (HSP90). HSP90 is a protein which helps to stabilize c-KIT protein. There has been a lot of interest in HSP90 as a possible target for GIST therapy. Phase 1 trials are intended primarily to test safety and tolerable dose, rather than to establish drug effectiveness. Seven GIST patients were subjects in the trial. AT13387 was administered intravenously. The RP2D (Recommended Phase II Dose) was determined to be 260 mg per square metre, once weekly. A partial response was observed in one patient and stable disease in two more. The authors conclude that this drug “is a promising agent in GIST, including TKI-resistant c-Kit positive GIST” and state that it is currently being evaluated in combination with imatinib in an ongoing phase I/II study.
3. Park et al., The role of surgical resection following imatinib treatment in patients with metastatic or recurrent GIST.
GIST Abstract No: 62
LRG Summary: The goal of this research was to test whether surgery to remove residual lesions is warranted in patients with metastatic or recurrent GIST (i.e., *not* localized disease) who are being treated successfully (i.e., partial response or stable disease) with imatinib. (Presumably, all of the patients had undergone surgery for their primary disease.) This study was a retrospective analysis – that is, it was an analysis of prior patient records, rather than a prospective randomized clinical trial. The authors represent many medical centers in South Korea. There were 42 patients in the SI (surgical intervention) group versus 92 in the group treated with imatinib alone.
In the SI group, surgery of residual disease was performed after 7-87 months of imatinib treatment; the median time period was 19 months (i.e., before 19 months in half of the cases, after 19 months in half.) The patients were followed up for 15-129 months (median, 59 months). The doctors found that both progression-free survival (PFS) and overall survival (OS) were significantly longer in the SI group than in the imatinib-alone group, and they concluded that “surgical resection of the residual lesions after disease control with imatinib may be beneficial in patients with metastatic or recurrent GIST.”
4. Ghimire et al., Analysis of second primary cancers in gastroinstestinal stromal tumor patients using SEER database.
GIST Abstract No: 327
LRG Summary: The researchers examined the US “SEER” Surveillance, Epidemiology, and End Results cancer registry database, looking for evidence on the question of whether GIST patients are at greater risk of developing a second primary cancer. There conclusion is that, indeed, the risk of a second primary malignancy is higher among GIST patients than among the general population. Although the risk was found to be higher among GIST patients, the actual number of second primary malignancies was only 163 out of 2,436 GIST patients (SEER database, 1992-2009), and we (LRG) do not feel that this observation warrants any particular action by GIST patients, other than the continued attention due to one’s general health.
5. Yasui et al., Patterns of recurrence after resection of rectal gastrointestinal stromal tumors and the effect of adjuvant therapy.
GIST Abstract No: 531
LRG Summary: This is a study from a large group of Japanese hospitals, examining the outcomes of GISTs occurring in the rectum, which represent a small proportion (10% or so) of all GISTs. Most recurrences occurred close to the primary site.
6. Jansa et al., Blood cell-derived nanovesicles as biomarkers of homeostasis in gastrointestinal cancer.
GIST Abstract No: 152
LRG Summary: This study, from a group in Slovenia, is preliminary basic research on membrane-derived blood biomarkers that might have some diagnostic value in GIST.
Abstract No: 212
LRG summary: p53 is a tumour suppressor gene; the P53 protein is a “guardian of the genome”, inducing apoptosis (cell death) in cells that have undergone severe DNA damage. The p53 gene is mutated and inactivated in many human cancers. Several groups have been studying the possible involvement of p53 in the development of GIST. This topic is discussed in the recent posting by Dr. Sebastian Bauer and Dr. Jonathan Fletcher, at the LRG web site, “Understanding How GISTs Develop Enables Discovery of New Therapies”. If p53 inactivation is found to be significant in GIST, then new therapies might be possible – for example, using drugs that stabilize functional p53.
Normal cells express p53 only at very low levels. However, mutations in the p53 gene can lead to altered P53 proteins that are resistant to degradation, and these can accumulate to high levels; so, immunohistochemistry to detect overexpression of p53 protein can indicate the presence of p53 mutations.
Several studies have been published, looking at the incidence of p53 alteration (mutation or overexpression) in GIST, and asking whether p53 status correlates with clinical outcome. The answers are not yet conclusively known. In the study reported in this abstract, p53 protein overexpression was observed (by immunohistochemistry) in one-third of patients with localized small intestine GISTs, and a correlation was seen between overexpression and poor clinical outcome. More research will be needed to determine whether P53 may be a useful target for GIST therapy.
7. Park et al., Prognostic significance of p53 protein overexpression in localized gastrointestinal stromal tumors of the small intestine.