Gastrointestinal Stromal Tumor Patients with Molecular Testing Exhibit Superior Survival Compared to Patients without Testing: Results from the Life Raft Group (LRG) Registry.

Mutational testing for Gastrointestinal Stromal Tumor (GIST) patients remains underutilized. In this retrospective analysis, the target population (n = 1556) reported: 904 had molecular testing ("Tested") vs. 652 without testing ("Untested"). Overall survival (OS) was 14.7 vs. 12.7 years (p < 0.00001), in metastatic patients 1st line OS was 8.9 vs. 5.9 years in the Tested vs. Untested group (n = 416 vs. n = 254), respectively. From 1st - 3rd-line, no difference has been (self-)reported for progression-free survival (PFS). Dropout to/for further lines of treatment was 15% for patients with a Tested mutation vs. 47% in Untested patients.

Barriers to mutational testing in patients with gastrointestinal stromal tumors (GIST) - a survey of life raft group members.

BACKGROUND: Due to the low mutational testing rate in patients with Gastrointestinal Stromal Tumors (GIST), The Life Raft Group (LRG), a non-profit organization that provides support, advocacy and conducts research for patients with GIST, analyzed various factors that may have an impact on patients' ability to receive mutational testing. METHODS: A survey about mutational testing for patients with GIST or their caregivers, was conducted in June 2020. The survey, sent to 1004 GIST patients and caregivers through email, was promoted through social media with instructions to contact the LRG to participate. The survey was designed by the LRG Patient Registry Department. Members of the LRG, regardless of Patient Registry status, were eligible to participate. RESULTS: A total of 295 patients/caregivers participated in this study (response rate: 29.4%). The percentage of patients who indicated they had received mutational testing was much higher in this survey (80%) than in the general GIST community (26.7%). Several reasons were cited for having a test, including: "My doctor ordered/suggested that I have it done" (54%); "The Life Raft Group advised/suggested I have it done" (25%); "I asked my doctor to have it done" (22%); "I had it done as part of a clinical trial" (5%); "I am not sure" (3%) and "Other" (14%). Mutational testing resulted in a treatment change in 25% of cases. Patients were able to select more than one option when completing this question resulting in a percentage greater than 100. CONCLUSIONS: The LRG membership is voluntary and proactive; patients who join are more likely to participate in surveys and mutational testing, as well as more likely to have a GIST specialist. Mutational testing can influence understanding of a patient's GIST and the treatment best suited to each case. These are extremely important findings, as it helps ensure that patients are on the proper treatment, which should lead to better outcomes.

Correction to: Survival in advanced GIST has improved over time and correlates with increased access to post-imatinib tyrosine kinase inhibitors: results from Life Raft Group Registry.

[This corrects the article DOI: 10.1186/s13569-019-0114-5.].

Survival in advanced GIST has improved over time and correlates with increased access to post-imatinib tyrosine kinase inhibitors: results from Life Raft Group Registry.

BACKGROUND: The use of imatinib, sunitinib, and regorafenib has transformed the treatment of advanced GIST. Sunitinib and regorafenib improve progression free-survival in the second (2L) and third (3L) line, respectively, compared with placebo. However, the impact of these agents on overall survival (OS) is unclear. METHODS: The Life Raft Group (LRG) patient registry contains records from 1716 GIST patients; 526 have advanced to at least 2L treatment. Patient-reported treatment and outcome data were examined to determine treatment patterns and their impact on OS. RESULTS: Median OS from start of 2L therapy was 32.4 months for sunitinib (n = 436) compared with 27.1 months for patients treated with any other 2L drug (n = 74, p = 0.023, HR 1.377) and 16.8 months for patients who never received sunitinib in any treatment line (n = 42, p = 0.028, HR 1.52). In patients reporting progression in 2L, the median OS in patients subsequently receiving 3L regorafenib (n = 53, 26.2 months) was longer than that of 3L patients who never received regorafenib in any line of therapy (n = 174, 14.3 months, p = 0.0002, HR 2.231), and was longer than that of patients who received any other 3L treatment (19.8 months, p = 0.044, HR 1.525). OS for advanced GIST patients in the LRG registry has improved over time (p = 0.0013), correlated with the increased use of TKIs in ≥ 2L settings. CONCLUSIONS: In our analysis, sunitinib and regorafenib significantly improved OS compared with patients who never received these agents. Our data also support the hypothesis that the use of KIT/PDGFRA inhibitors, including non-approved agents, has improved OS for patients with imatinib- and sunitinib-resistant GIST.

Mutational Testing in Gastrointestinal Stromal Tumor.

Targeted treatment has become a major modality in cancer management. Such cancer drugs are generally designed to treat tumors with certain genetic/genomic makeups. Mutational testing prior to prescribing targeted therapy is crucial in identifying who can receive clinical benefit from specific cancer drugs. Over the last two decades, gastrointestinal stromal tumors (GISTs) have evolved from histogenetically obscure to being identified as distinct gastrointestinal mesenchymal tumors with well-defined clinical and molecular characteristics, for which multiple lines of targeted therapies are available. Although the National Comprehensive Cancer Network (NCCN) strongly recommends mutational testing for optimal management of GIST, many GIST patients still have neither a mutation test performed or any mutation-guided cancer management. Here, we review the mutation-guided landscape of GIST, mutational testing methods, and the recent development of new therapies targeting GIST with specific mutations.

Genomic aberrations in cell cycle genes predict progression of KIT-mutant gastrointestinal stromal tumors (GISTs).

BACKGROUND: Activating mutations of the receptor tyrosine kinase KIT are early events in the development of most gastrointestinal stromal tumors (GISTs). Although GISTs generally remain dependent on oncogenic KIT during tumor progression, KIT mutations alone are insufficient to induce malignant behavior. This is evidenced by KIT-mutant micro-GISTs, which are present in up to one-third of normal individuals, but virtually never progress to malignancy. METHODS: We performed whole exome sequencing on 29 tumors obtained from 21 patients with high grade or metastatic KIT-mutant GIST (discovery set). We further validated the frequency and potential prognostic significance of aberrations in CDKN2A/B, RB1, and TP53 in an independent series of 71 patients with primary GIST (validation set). RESULTS: Using whole exome sequencing we found significant enrichment of genomic aberrations in cell cycle-associated genes (Fisher's Exact p = 0.001), most commonly affecting CDKN2A/B, RB1, and TP53 in our discovery set. We found a low mutational tumor burden in these 29 advanced GIST samples, a finding with significant implications for the development of immunotherapy for GIST. In addition, we found mutation of spliceosome genes in a minority of cases, implicating dysregulation of splicing as a potential cancer promoting mechanism in GIST. We next assessed the prognostic significance of CDKN2A, RB1 or TP53 mutation/copy loss in an independent cohort of 71 patients with primary GIST. Genetic events (mutation, deletion, and/or LOH) involving at least one of the three genes examined were found in 17% of the very low-risk, 36% of the low-risk, 42% of the intermediate risk, 67% of the high-risk/low mitotic-count, and in 86% of the high-risk/high mitotic-count group. The presence of cell cycle-related events was associated with a significantly shorter relapse-free survival (median 67 months versus not reached; p < 0.0001) and overall survival (Log Rank, p = 0.042). CONCLUSION: Our results demonstrate that genomic events targeting cell cycle-related genes are associated with GIST progression to malignant disease. Based on this data, we propose a model for molecular pathogenesis of malignant GIST.

Survival of gastrointestinal stromal tumor patients in the imatinib era: life raft group observational registry.

BACKGROUND: Gastrointestinal stromal tumors (GIST), one of the most common mesenchymal tumors of the gastrointestinal tract, prior to routine immunohistochemical staining and the introduction of tyrosine kinase inhibitors, were often mistaken for neoplasms of smooth muscle origin such as leiomyomas, leiomyosarcomas or leiomyoblastomas. Since the advent of imatinib, GIST has been further delineated into adult- (KIT or PDGFRα mutations) and pediatric- (typified by wild-type GIST/succinate dehydrogenase deficiencies) types. Using varying gender ratios at age of diagnosis we sought to elucidate prognostic factors for each sub-type and their impact on overall survival. METHODS: This is a long-term retrospective analysis of a large observational study of an international open cohort of patients from a GIST research and patient advocacy's lifetime registry. Demographic and disease-specific data were voluntarily supplied by its members from May 2000-October 2010; the primary outcome was overall survival. Associations between survival and prognostic factors were evaluated by univariate Cox proportional hazard analyses, with backward selection at P < 0.05 used to identify independent factors. RESULTS: Inflections in gender ratios by age at diagnosis in years delineated two distinct groups: above and below age 35 at diagnosis. Closer analysis confirmed the above 35 age group as previously reported for adult-type GIST, typified by mixed primary tumor sites and gender, KIT or PDGFRα mutations, and shorter survival times. The pediatric group (< age 18 at diagnosis) was also as previously reported with predominantly stomach tumors, females, wild-type GIST or SDH mutations, and extended survival. "Young adults" however formed a third group aged 18-35 at diagnosis, and were a clear mix of these two previously reported distinct sub-types. CONCLUSIONS: Pediatric- and adult-type GIST have been previously characterized in clinical settings and these observations confirm significant prognostic factors for each from a diverse real-world cohort. Additionally, these findings suggest that extra diligence be taken with "young adults" (aged 18-35 at diagnosis) as pediatric-type GIST may present well beyond adolescence, particularly as these distinct sub-types have different causes, and consequently respond differently to treatments.

Evaluation of self-reported progression and correlation of imatinib dose to survival in patients with metastatic gastrointestinal stromal tumors: an open cohort study.

OBJECTIVES: Self-reported progression was evaluated as a predictor of survival in patients with metastatic gastrointestinal stromal tumor (GIST). METHODS: This is a follow-up of an open cohort study of Life Raft Group (LRG) members with a diagnosis of KIT-positive metastatic GIST receiving imatinib from May 2000-December 2007 reporting their subjective response to therapy by completion of an internet-based questionnaire. Subjects received >or= 1 year of imatinib and reported an initial positive response. Members reporting stable disease or progression were excluded. Self-reported progression-free survival (srPFS) was compared with overall survival (OS) and analyzed by starting and last reported dose. RESULTS: One hundred sixty-nine subjects reported a mean starting dose of 527.8+/-177.9 mg/d at a mean age of 53.8+/-11.6 years at initial diagnosis. Of those reporting progression, 66% died versus 11% of those not reporting progression (P < 0.0001). When analyzed by last reported dose, a median srPFS benefit of 27.3 months was observed for the >400 mg/d group (P = 0.0017). Sixty-two percent of subjects who initiated therapy at >400 mg/d reported a dose reduction. When analyzed by last reported dose, a significant benefit in OS (P = 0.0229) and srPFS (P = 0.0069) was observed for subjects taking 600 over 400 mg/d. CONCLUSIONS: srPFS strongly correlated with OS. Significant advantages were observed when last reported dose was considered, as was higher daily dose. These observations suggest that careful escalation to intermediate daily doses should be investigated further for its potential to reduce the incidence and severity of adverse events, but also as a strategy against developing secondary resistance to imatinib.