In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) ...patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study.
This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used.
Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, HR = 0.71, 95% CI (0.57; 0.89), P = 0.002; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years HR = 0.88, 95% CI (0.65; 1.21), P = 0.43. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively.
With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.
•Adjuvant imatinib for 2 years significantly improved RFS, with a trend towards a better imatinib failure free survival.
Abstract At present, there is not a commonly used and generally accepted standardized approach for the pathologic evaluation of pretreated soft tissue sarcomas. Also, it is still unclear whether the ...cut-off for prognostic relevance is similar in the many different histological subtypes of STS. This manuscript, produced by a European Organization for Research and Treatment of Cancer – Soft Tissue and Bone Sarcoma Group (EORTC–STBSG) endorsed task force, aims to propose standardization of the pathological examination process and the reporting of STS resection specimens after neoadjuvant radio- and/or chemotherapy.
Desmoid-type fibromatosis is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Currently, there is no ...established or evidence-based treatment approach available for this disease. Therefore, in 2015 the European Desmoid Working Group published a position paper giving recommendations on the treatment of this intriguing disease. Here, we present an update of this consensus approach based on professionals’ AND patients’ expertise following a round table meeting bringing together sarcoma experts from the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group with patients and patient advocates from Sarcoma PAtients EuroNet. In this paper, we focus on new findings regarding the prognostic value of mutational analysis in desmoid-type fibromatosis patients and new systemic treatment options.
Superficial fibromas are a group of mesenchymal spindle cell lesions with pathomorphological heterogeneity and diverse molecular backgrounds. In part, they may be indicators of an underlying ...syndrome. Among the best‐known entities of superficial fibromas is Gardner fibroma, a plaque‐like benign tumor, which is associated with APC germline mutations and occurs in patients with familial adenomatosis polyposis (Gardner syndrome). Affected patients also have an increased risk to develop desmoid fibromatosis (DTF), a locally aggressive neoplasm of the deep soft tissue highly prone to local recurrences. Although a minority of DTFs occur in the syndromic context and harbor APC germline mutations, most frequently their underlying molecular aberration is a sporadic mutation in Exon 3 of the CTNNB1 gene. Up to date, a non‐syndromic equivalent to Gardner fibroma carrying a CTNNB1 mutation has not been defined. Here, we present two cases of (sub‐)cutaneous tumors with a hypocellular and collagen‐rich Gardner fibroma‐like appearance and pathogenic, somatic CTNNB1 mutations. We aim to differentiate these tumors from other fibromas according to their histological appearance, immunohistochemical staining profile and underlying somatic CTNNB1 mutations. Furthermore, we distinguish them from locally aggressive desmoid fibromatosis regarding their biological behavior, prognosis and indicated therapeutic strategies. Consequently, we call them CTNNB1‐mutated superficial fibromas as a sporadic counterpart lesion to syndromic Gardner fibromas.
Abstract Background Angiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicin is the standard first-line chemotherapy for advanced STS. It is not known whether angiosarcoma response to ...anthracycline-based chemotherapy is different to other STS subtypes. Methods Pooled data were analysed from 11 prospective randomised and non-randomised European Organisation for Research and Treatment of Cancer (EORTC) clinical trials of first-line anthracycline-based chemotherapy for advanced STS. Baseline patient characteristics, chemotherapy response, progression free survival (PFS) and overall survival (OS) of angiosarcoma patients were compared with other STS patients. Analysis was performed to identify factors prognostic for angiosarcoma response to chemotherapy, PFS and OS. Results With a median follow-up of 4.2 years, data from 108 locally advanced and metastatic angiosarcoma patients and 2557 patients with other STS histologies were analysed. 25% of angiosarcoma patients had a complete or partial response to chemotherapy compared to 21% for other STS histotypes. The median PFS was 4.9 months and OS 9.9 months, which were not significantly different from other STS histotypes. In univariate analysis, bone metastases were an adverse prognostic factor for OS (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.03–2.67; p = 0.036). Tumour grade was as an adverse prognostic factor for PFS (HR 1.72, 95% CI 1.01–2.92; p = 0.044) and OS (HR 2.03; 95% CI 1.16–3.56; p = 0.011). Compared to single agent anthracyclines, doxorubicin + ifosfamide was associated with improved PFS (HR 0.53, 95% CI 0.33–0.86; p = 0.010) and OS (HR 0.53, 95% CI 0.32–0.90; p = 0.018). Conclusions Angiosarcoma response and survival following first-line anthracycline-based chemotherapy was similar to other STS histotypes. Our analysis provides a useful measure of angiosarcoma response to chemotherapy for comparison with future clinical trials.
Tumors of soft tissue and bone represent a heterogeneous group of neoplasias characterized by a wide variety of genetic aberrations. Albeit knowledge on tumorigenesis in mesenchymal tumors is ...continuously increasing, specific insights on altered signaling pathways as a basis for molecularly targeted therapeutic strategies are still sparse. The aim of this study was to determine the involvement of YAP1/TAZ-mediated signals in tumors of soft tissue and bone. Expression levels of YAP1 and TAZ were analyzed by immunohistochemistry in a large cohort of 486 tumor specimens, comprising angiosarcomas (AS), Ewing sarcomas, leiomyosarcomas, malignant peripheral nerve sheath tumors (MPNST), solitary fibrous tumors, synovial sarcomas (SySa), well-differentiated/dedifferentiated/pleomorphic and myxoid liposarcomas (MLS). Moderate to strong nuclear staining of YAP1 and TAZ was detected in 53% and 33%, respectively. YAP1 nuclear expression was most prevalent in MPNST, SySa and MLS, whereas nuclear TAZ was predominately detected in AS, MLS and MPNST. In a set of sarcoma cell lines, immunoblotting confirmed nuclear localization of YAP1 and TAZ, corresponding to their transcriptionally active pool. Suppression of YAP1/TAZ-TEAD mediated transcriptional activity significantly impaired sarcoma cell viability in vitro and in vivo. Our findings identify nuclear YAP1 and TAZ positivity as a common feature in subsets of sarcomas of soft tissue and bone and provide evidence of YAP1/TAZ-TEAD signaling as a specific liability to be considered as a new target for therapeutic intervention. Nuclear YAP1/TAZ expression may represent a biomarker suited to identify patients that could benefit from YAP1/TAZ-TEAD directed therapeutic approaches within future clinical trials.
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