Czesław Osuch

SUCCINATE DEHYDROGENASE DEFICIENT GISTS – A CLINICOPATHOLOGIC, IMMUNOHISTOCHEMICAL, AND MOLECULAR GENETIC STUDY OF 66 GASTRIC GISTS WITH PREDILECTION TO YOUNG AGE

Most gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA-activating mutations, but a small subset is associated with loss of function of the succinate dehydrogenase (SDH) complex of mitochondrial inner membrane proteins. This occurs by germline mutations of the SDH subunit genes and hitherto unknown mechanisms. SDH-deficient GISTs especially include pediatric GISTs and those associated with Carney triad (CT) or Carney-Stratakis syndromes (CSSs); the latter 2 also include paraganglioma as a component. SDH-deficient GISTs were identified in this study on the basis of immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals functional loss of the SDH complex. We found 66 SDH-deficient GISTs among 756 gastric GISTs, with an estimated frequency of 7.5% of unselected cases. Nearly, all gastric GISTs in patients <20 years, and a substantial percentage of those in patients <40 years, but only rare GISTs in older adults were SDH deficient. There was a female predominance of over 2:1. Two patients each had either pulmonary chondroma or paraganglioma (CT), but none of the examined cases had SDH germline mutations (CSS) or somatic KIT/PDGFRA or BRAF mutations. SDH-deficient GISTs were often multiple and typically showed plexiform muscularis propria involvement and epithelioid hypercellular morphology. They were consistently KIT-positive and DOG1/Ano 1-positive and almost always smooth muscle actin negative. Tumor size and mitotic activity varied, and the tumors were somewhat unpredictable with low mitotic rates developing metastases. Gastric recurrences occurred in 11 patients, and peritoneal and liver metastases occurred in 8 and 10 patients, respectively. Lymph node metastases were detected in 5 patients, but lymphovascular invasion was present in >50% of cases studied; these 2 were not related to adverse outcome. Seven patients died of disease, but many had long survivals, even with peritoneal or liver metastases. All 378 nongastric GISTs and 34 gastric non-GIST mesenchymal tumors were SDHB positive. SDH-deficient GISTs constitute a small subgroup of gastric GISTs; they usually occur in children and young adults, often have a chronic course similar to that of pediatric and CT GISTs, and have potential association with paraganglioma, necessitating long-term follow-up.

Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour - the impact of tumour rupture on patient outcomes.

BACKGROUND Approval of imatinib for adjuvant treatment of gastrointestinal stromal tumours (GIST) raised discussion about accuracy of prognostic factors in GIST and the clinical significance of the available risk stratification criteria. METHODS We studied the influence of a new modification of the NIH Consensus Criteria (the Joensuu risk criteria), NCCN-AFIP criteria, and several clinicopathological factors, including tumour rupture, on relapse-free survival (RFS) in a prospectively collected tumour registry series consisting of 640 consecutive patients with primary, resectable, CD117-immunopositive GIST. The median follow-up time after tumour resection was 39 months. None of the patients received adjuvant imatinib. RESULTS The median RFS time after surgery was 50 months. In univariable analyses, high Joensuu risk group, tumour mitotic count >5/50 HPF, size >5 cm, non-gastric location, tumour rupture (7% of cases; P = 0.0014) and male gender had adverse influence on RFS. In a multivariable analysis mitotic count >5/50HPF, tumour size >5 cm and non-gastric location were independent adverse prognostic factors. Forty, 151, 86 and 348 patients were assigned according to the Joensuu criteria to very low, low, intermediate and high risk groups and had 5-year RFS of 94%, 94%, 86% and 29%, respectively. CONCLUSION The Joensuu criteria, which include 4 prognostic factors (tumour size, site, mitotic count and rupture) and 3 categories for the mitotic count, were found to be a reliable tool for assessing prognosis of operable GIST. The Joensuu criteria identified particularly well high risk patients, who are likely the proper candidates for adjuvant therapy.

The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study

BackgroundGastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure.MethodsWe identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes.ResultsOne year progression-free survival (PFS; calculated from the start of SU) rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH vs. 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively).ConclusionsWe confirmed that many advanced GIST patients benefit from SU therapy with OS > 1.5 year. Primary tumor KIT/PDGFRA genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS.NoteThe preliminary data of this study were presented during Annual Meeting of American Society of Clinical Oncology, 4-8 June 2011 and Connective Tissue Oncology Society Meeting, 26-28 October 2011 in Chicago, IL.

The Outcome of Targeted Therapy in Advanced Gastrointestinal Stromal Tumors (Gist) with Non-Exon 11 Kit Mutations

UNLABELLED GIST is the most common mesenchymal tumour of gastrointestinal tract arising from mutation of KIT or PDGFRA gene. Surgery is the primary method of treatment, however a targeted therapy with imatinib is necessary due to recurrence. The aim of the study was to evaluate efficacy of the targeted chemotherapy in advanced gastrointestinal stromal tumours with non-exon 11 KIT mutations. MATERIAL AND METHODS Data from 279 patients with advanced GIST treated with imatinib between 2001 and 2011 were analysed in the study. Exon 11 KIT mutation was found in 192 patients (68.7%), non-exon 11 KIT mutation was found in 87 patients (31.3%): this group included lack of mutation - wild-type, exon 9 KIT mutations, exon 18 PDGFRA D842V mutations, non-D842V PDGFRA mutations as well as non-exon 9 and 11 KIT mutations. Analysis of progression-free survival and overall survival were done for the entire group of patients and for patients with particular mutations, and then effects on progression-free survival and overall survival of such factors as sex, age, imatinib dose were evaluated. RESULTS Occurrence of non-exon 11 KIT mutation increases the risk of disease progression by 20% in comparison to the presence of exon 11 KIT mutation, however it does not increase the risk of patients death. Percentage of 5-year progression-free survivals is the greatest in the case of PDGFRA mutation other than D842V mutation. Percentage of 5-year survivals in case of the presence of D842V PDGFRA mutation is more than twice worse than in the case of the other mutations. Lesion location in the gastrointestinal tract affected the risk of death, with the greatest percentage of 5-year survival for lesions located in the stomach. Such factors as sex, age at diagnosis (<50, ≥50 years) and imatinib dose did not affect the risk of disease progression and the risk of patients death. CONCLUSIONS The ratio of overall survival of patients with advanced GIST with a mutation other than exon 11 KIT mutation treated with imatinib is similar to the ratio of overall survival of patients with GIST with exon 11 KIT mutation. An exception is the group of patients with GIST in whom the presence of D842V PDGFRA mutation was found. In general, longer survival has been found in patients with GIST located in the stomach in comparison to the small intestine or other less frequent locations. Percentage of 5-year progression-free survivals is the greatest in the case of PDGFRA mutation other than D842V mutation.

Treatment outcomes in older patients with advanced gastrointestinal stromal tumor (GIST)

BACKGROUND The aim of the study was to analyze the treatment results of advanced GIST in the largest, homogenous series of older patients. METHODS Between 2001 and 2016, 686 patients with metastatic/unresectable GIST were treated initially with imatinib and 656 were included in the analysis. Subsequently 232 patients were treated with sunitinib after imatinib failure. We have analyzed the outcomes of patients who have been treated with the tyrosine kinase inhibitor at the age ≥ 70 years and compared to control group of patients younger than 70 years old. RESULTS In the group of patients treated with imatinib, 139 (21%) started therapy at the age of at least 70 years (median age of the entire cohort: 60). Median progression-free survival (PFS) on 1st line imatinib did not differ between patients ≥70 yo (years old) and < 70yo (38.5 vs 44.9 months), but median overall survival (OS) was significantly better for younger patients (81 months vs. 50; p = 0.0001; although disease-specific survival - DSS was similar). Distribution of primary tumor mutational status was generally similar in older and younger patients. Permanent dose reduction (300-100 mg/day) was required for 23 patients (16.9%) in the older group and was significantly more frequent as compared to younger patients (5%). Drug-related adverse events were mainly of grades 1/2, but grade 3/4 toxicity occurred more frequently in older (14.7%) than in younger patients (3.8%). Similarly in group of patients treated with second-line sunitinib median PFS and DSS were comparable in groups of patients ≥70 yo (n = 55) and < 70yo (9.7 months vs 10.3 months; p = 0.7, and 21.5 vs 22.9 months). >40% of patients in both groups required dose adjustments to 37.5-25 mg daily. CONCLUSIONS Our study confirms that current therapy of advanced GIST with tyrosine kinase inhibitors (both in 1st and 2nd line) in older patients enable to achieve the similar disease control rate and final outcomes as in younger patients, but it demands close cooperation of experienced oncologist with patients for dose modifications and side effects management. Limitation of our study is that the patients did not undergo a comprehensive geriatric assessment, what might be helpful for personalized management of patients. Nevertheless, we confirm that older patients with GIST should not receive less treatment irrespective of comorbidities.

9405 Spectrum of KIT and PDGFRA mutations in primary gastrointestinal stromal tumours: Polish clinical GIST registry experience

e21504 Background: KIT or PDGFRA gene mutations are found in 80-90% of gastrointestinal stromal tumors (GIST). The prognostic value of those mutations for the outcome in primary tumors is controversial. OBJECTIVE To assess the spectrum, frequency and prognostic significance of the KIT and PDGFRA gene mutations in Polish group of surgically treated primary GISTs. METHODS DNA isolated from paraffin blocks from 300 patients (pts) with histologically diagnosed primary GISTs included in clinical registry database, were analyzed using denaturing high performance liquid chromatography (DHPLC) and direct sequencing for KIT (exons 9, 11, 13, 17) and PDGFRA (exons 12, 14, 18) mutations. For primary GIST risk assessment the Miettinen stratification was used. RESULTS KIT/PDGFRA genes mutations were found in 82% tumors: KIT was mutated in 69% and PDGFRA in 13% of tumors. KIT exon 11 and 9 mutations were found in 61.5% and 7.5% respectively. Among KIT exon 11 mutants the most frequent were deletions (32.7%) followed by point mutations (15.3%), duplications (8.4%) and complex rearrangements (5.1%). KIT exon 11 mutations were found at the similar rates in tumors with gastric and non-gastric localization (53.9% vs. 46.1% respectively) while KIT exon 9 duplications were more often observed in non-gastric GISTs (86.4%, p=0.00036) and PDGFRA mutations were more frequently found in tumors originated from the stomach (86.8%; p=0.00017). In high risk tumors KIT exon 11 deletions were more frequently found than point mutations (p=0.017). On the other hand mutations in PDGFRA were more often observed in very low-/low- than high risk GISTs as compared to KIT exon 11 (p=0.0026). There was no statistically significant correlation between disease-free survival and the spectrum or frequency of mutations. CONCLUSIONS Spectrum and frequency of KIT and PDGFRA mutations in Polish GIST population are similar to the previously described groups. No significance of mutations for disease outcome after surgery of primary tumors was found. [Table: see text].