Search

Owing to the rarity and heterogeneity in biology and presentation, there are multiple areas in the diagnosis, treatment and follow-up of soft tissue sarcoma (STS), with no, low-level or conflicting evidence.During the first Consensus Conference on the State of Science in Sarcoma (CSSS), we used a modified Delphi process to identify areas of controversy in the field of sarcoma, to name topics with limited evidence-based data in which a scientific and knowledge gap may remain and a consensus statement will help to guide patient management. We determined scientific questions which need to be addressed in the future in order to generate evidence and to inform physicians and caregivers in daily clinical practice in order to improve the outcomes of patients with sarcoma. We conducted a vote on STS key questions and controversies prior to the CSSS meeting, which took place in May 2022.Sixty-two European sarcoma experts participated in the survey. Sixteen strong consensus (≥95%) items were identified by the experts, as well as 30 items with a ≥75% consensus on diagnostic and therapeutic questions. Ultimately, many controversy topics remained without consensus.In this manuscript, we summarise the voting results and the discussion during the CSSS meeting. Future scientific questions, priorities for clinical trials, registries, quality assurance, and action by stakeholders are proposed. Platforms and partnerships can support innovative approaches to improve management and clinical research in STS.

Score chart with predicted probability (%) to remain on WW at 12 months This model was based on the number of IMDC Risk factors (0, 1, 2), the number or involved organ sites (0 - 4) and the geometric mean [¹⁸F]FDG SUVmax as a continuous variable. The underlying formula is 100*(exp(-0.531)^exp(0.198*[IMDC score] + 0.039*[No of affected organ sites] + 0.170*[geometric mean [¹⁸F]FDG SUVmax] - 1.09))

Lasso model

Purpose:Watchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with 18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT for WW duration in patients with mccRCC.Experimental Design:Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients.Results:The median WW time was 16.1 months [95% confidence interval (CI): 9.0–31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4–14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9–3.3; P = 0.13). Patients with “W&W criteria” had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9–3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the “W&W criteria” improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53).Conclusions:In patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of the “W&W criteria” for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this.

This file contains the following supplemental data: Supplemental Table 1. Specific information for MTT cell viability assays with single agents. Supplemental Table 2. Patient characteristics of synovial sarcoma cohort. Supplemental Table 3. Specifications of antibodies used for IHC and Western Blot. Supplemental Table 6. Summary of SS cell line sensitivity to specific tyrosine kinase inhibitors. Supplemental Figure 1. Integrated protein-protein interaction network for all sarcoma subgroups. Supplemental Figure 2. ALK expression and phosphorylation in ES and RMS cell lines. Supplemental Figure 3. Schematic representation of ALK exon 2-17 deletion in Aska-SS cells. Supplemental Figure 4. Deglycosylation of ALK in Aska-SS cells. Supplemental Figure 5. SS cell line sensitivity to foretinib, gefitinib and erlotinib. Supplemental Figure 6. Effects of ALK inhibition on cell cycle and apoptotic markers in Aska-SS cells. Supplemental Figure 7. Effects of ALK inhibition on Aska-SS in vivo tumors. Supplemental Figure 8. ALK, MET and PDGFRA mRNA expression in clinical SS versus other STS samples. Supplemental Figure 9. ALK IHC and patient characteristics of ALK-positive SS tumors. Supplemental Figure 10. Effect of PDGFR and MET inhibition on apoptosis in Yamato-SS cells. Brief sections of Supplementary methods and Supplementary references are included in this file as well.

Supplementary Table 3. Genetic variants associated with 5-year PFS

This file lists the siRNAs that are significantly associated with VX-970 resistance in SYO1 SS tumour cells in which siRNA effects in VX970-exposed vs. DMSO-exposed cells were compared, quantifying resistance-causing effects as Drug Effect (DE) Z-scores. Genes are ranked according to DE Z-scores.

PDF file, 77K, Association analysis between imatinib trough concentrations and progression free survival.

This file lists Z-score data of the synovial sarcoma (SS) specific hits from the siRNA screen. SS genetic dependencies were identified by comparing the siRNA Z-scores from the SS tumour cell line screens to siRNA Z-score profiles of >130 other tumour cell lines, and genes are ranked according to median difference between the SS tumour cell lines and other tumour cell lines.

Supplementary Figure from Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Purpose: Imatinib minimal (trough) plasma concentrations after one month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). Considering that a retrospective pharmacokinetic analysis has also suggested that imatinib clearance increases over time in patients with soft tissue sarcoma and GIST, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population pharmacokinetic study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib.Experimental Design: Full pharmacokinetic blood sampling was conducted in 50 patients with GIST on the first day of imatinib treatment, and after one, six, and 12 months. In addition, on day 14, and monthly during imatinib treatment, trough samples were taken. Pharmacokinetic analysis was conducted using a compartmental model. Volume of liver metastases was assessed by computed tomographic (CT) imaging.Results: After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared with baseline was observed (P < 0.01). For every 100 cm3 increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed.Conclusions: This is the first prospective pharmacokinetic study in patients with GIST, showing a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future "trough level – clinical benefit" analyses should be time point specific. GIST liver involvement, however, has a marginal effect on imatinib clearance. Clin Cancer Res; 18(20); 5780–7. ©2012 AACR.

Purpose:Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers.Experimental Design:In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks).Results:Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup.Conclusions:Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.

Purpose:DNA methylation profiling has previously uncovered biologically and clinically meaningful subgroups within many tumor types, but was not yet performed in angiosarcoma. Angiosarcoma is a rare sarcoma with very heterogeneous clinical presentations, which may be based on differences in biological background. In this exploratory study, DNA methylation profiling of 36 primary angiosarcoma samples from visceral, deep soft tissue, radiation-induced, and UV-induced localizations was performed.Experimental Design:Primary angiosarcoma formalin-fixed paraffin-embedded samples from visceral, soft tissue, radiation-induced, and UV-induced origin were collected from a nationwide search for angiosarcoma in the Netherlands. DNA was extracted for methylation profiling with the Illumina Infinium MethylationEPIC array. Quality control assessment and unsupervised hierarchical clustering were performed. Copy-number profiles were generated and analyzed for chromosomal stability. Clinical data were obtained from the Netherlands Cancer Registry.Results:DNA methylation profiling by unsupervised hierarchical clustering of 36 angiosarcoma samples (6 visceral, 5 soft tissue, 14 radiation-induced, 11 UV-induced) revealed two main clusters (A and B), which were divided into four subclusters. The clusters largely corresponded with clinical subtypes, showing enrichment of UV-induced cases in cluster A1 and radiation-induced cases in cluster A2. Visceral and soft tissue cases almost exclusively fell into cluster B. Cluster A showed significantly increased chromosomal instability and better overall survival (22 vs. 6 months, P = 0.046) compared with cluster B.Conclusions:In this novel methylation profiling study, we demonstrated for the first time four different angiosarcoma clusters. These clusters correlated with clinical subtype, overall survival, and chromosomal stability.

Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry–based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALKΔ2–17). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRα phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro, synergistic effects were observed upon drug combination. In vivo, both drugs were individually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRα expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS. Cancer Res; 77(16); 4279–92. ©2017 AACR.

This file contains the list of the 79 small molecule inhibitors currently used or in the late stages of clinical development for cancer treatment, that were included in our drug screen.

Purpose: To investigate whether indium-111–labeled R1507 (111In-R1507) immuno-SPECT (single—photon emission computed tomography), a novel noninvasive, in vivo screening method to visualize membranous insulin-like growth factor 1 receptor (IGF-1R) expression and accessibility, can be used to predict IGF-1R treatment (R1507) response in bone sarcomas.Experimental Design: BALB/c nude mice were subcutaneously implanted with IGF-1R–expressing human bone sarcoma xenografts (OS-1, EW-5, and EW-8) which showed high, modest, or no response, respectively, to R1507, a monoclonal antibody targeting the extracellular domain of IGF-1R. An IGF-1R–negative tumor (OS-33), unresponsive to IGF-1R inhibitors, was examined as well. Mice were injected with 111In-R1507. Biodistribution and immuno-SPECT/computed tomography imaging studies were carried out 1, 3, and 7 days p.i. in mice with OS-1 and EW-5 xenografts and 3 days p.i. in mice with EW-8 and OS-33 xenografts.Results: Biodistribution studies showed specific accumulation of 111In-R1507 in OS-1 and EW-5 xenografts (27.5 ± 6.5%ID/g and 14.0 ± 2.8%ID/g, 3 days p.i., respectively). Most importantly, 111In-R1507 uptake in IGF-1R positive, but unresponsive, EW-8 xenografts (6.5 ± 1.5%ID/g, 3 days p.i.) was similar to that of the IGF-1R–negative OS-33 tumor (5.5 ± 0.6%ID/g, 3 days p.i.). Uptake in normal tissues was low and nonspecific. Corresponding immuno-SPECT images clearly discriminated between high, modest, and nonresponding tumors by showing a homogeneous (OS-1), heterogeneous (EW-5), or nonspecific (EW-8 and OS-33) tumor uptake of 111In-R1507.Conclusions:111In-R1507 immuno-SPECT is an excellent method to visualize membranous IGF-1R expression and target accessibility in vivo in human bone sarcoma xenografts and may serve as an independent marker to predict IGF-1R therapy (R1507) response in bone sarcoma patients. Clin Cancer Res; 17(24); 7693–703. ©2011 AACR.

Protein-protein network analysis

Supplementary Table from Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Supplementary Methods: DNA methylation calculation and bootstrapping method

Supplementary Table 2. Genetic variants associated with histologic response

CCR Translation for This Article from A Long-term Prospective Population Pharmacokinetic Study on Imatinib Plasma Concentrations in GIST Patients

Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by expression of SS18–SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells with those in >130 non–SS tumor cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18–SSX family fusion genes are known to alter the composition of the BAF chromatin–remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18–SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but an SSX18–SSX1 Δ71–78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the antitumor cell effect of ATRi, suggesting that either single-agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment. Cancer Res; 77(24); 7014–26. ©2017 AACR.

Purpose: Overall survival in patients with osteosarcoma is only 60%. Poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can offer possibilities to optimize treatment and improve outcome. We applied a pathway-based approach to evaluate the cumulative effect of genes involved in the metabolism of cisplatin and doxorubicin in relationship to clinical outcome.Experimental Design: We included 126 patients with osteosarcoma. To comprehensively assess common genetic variation in the 54 genes selected, linkage disequilibrium (LD; r2 = 0.8)–based tag-single nucleotide polymorphisms (SNP) strategy was used. A final set of 384 SNPs was typed using Illumina Beadarray platform. SNPs significantly associated with 5-year progression-free survival (PFS) were replicated in another 64 patients with osteosarcoma.Results: We identified five variants in FasL, MSH2, ABCC5, CASP3, and CYP3A4 that were associated with 5-year PFS. Risk stratification based on the combined effects of the risk alleles showed a significant improvement of 5-year PFS. Patients that carried no or only one risk allele had a 5-year PFS of 100% compared with a 5-year PFS of 84.4% for carriers of two or three risk alleles, 66.7% PFS if a patient carried four to five alleles, and a 5-year PFS of 41.8% for patients with >5 risk alleles (P < 0.001).Conclusions: We identified several genes that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome and to stratify patients immediately after diagnosis and offer the possibility to improve treatment and outcome. Clin Cancer Res; 21(15); 3436–41. ©2015 AACR.

This file contains the complete list of Dharmacon SMARTpool 384 well plate-arrayed siRNA libraries used in this paper. It is designed to target 714 kinases and kinase-related genes, 320 Wnt-pathway associated genes, 80 tumour suppressor genes, and 480 genes recurrently altered in human cancers.

Supplementary Table 1. Set of 381 SNPs

PDF file, 104K, A: Digital Imaging and Communications in Medicine (DICOM) files were imported in OsiriX Imaging Software for MacOS X (OsiriX Foundation, Geneva, Switserland). Metastatic liver lesions were then drawn as areas of interest with the pencil selection tool. B: Volumes of 3-dimensional structures were automatically calculated by OsiriX Imaging Software.

Methylation-specific PCR MGMT

PDF file - 2.8MB

This file contains the details of all the primary and secondary antibodies used in this paper.

Cluster patient characteristics

Objective: The aim of the study is to assess the effect of perioperative chemo-therapy (CTX) in patients with grade II-III extremity soft tissue sarcoma (eSTS) on overall survival (OS) and evaluate whether the PERSARC prediction tool could identify patients with eSTS more likely to benefit from CTX.Methods: Patients (18-70 years) with primary high-grade eSTS surgically treated with cura-tive intent were included in the retrospective cohort study. The effect of any perioperative CTX and anthracycline + ifosfamide (AI)-based CTX on OS was investigated in three PERSARC-risk groups (high/intermediate/low). The PERSARC-risk groups were defined by the 33% and 66% quantile of the predicted 5-year OS of the study population equal to a 5-year OS of 65.8% and 79.8%, respectively. The effect of CTX on OS was investigated with weighted Kaplan-Meier curves and multivariable Cox models with an interaction between risk group and CTX.Results: This study included 5683 patients. The weighted Kaplan-Meier curves did not demonstrate a beneficial effect of any CTX and AI-based CTX on OS in the overall population. However, in the high PERSARC-risk group the 5-year OS of AI-based CTX was significantly better than no CTX (69.8% vs 59.0%, respectively, p Z 0.004) (HR 0.66, 95% CI 0.53-0.83).Conclusions: This study demonstrated a beneficial effect of AI-based CTX on OS in a selected group of high-risk patients with an absolute survival benefit of 11% as stratified by the PERSARC prediction tool. However, no beneficial effect of CTX on OS was found in the overall population of patients with primary high-grade eSTS younger than 70 years.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.

Purpose: Watchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with Experimental Design: Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients. Results: The median WW time was 16.1 months [95% confidence interval (CI): 9.0–31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4–14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9–3.3; P = 0.13). Patients with “W&W criteria” had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9–3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the “W&W criteria” improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53). Conclusions: In patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of the “W&W criteria” for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this.

Background: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. Methods: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021). Results: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. Conclusions: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.

Simple Summary Sarcomas are a heterogeneous group of diagnostically complex tumors with a poor prognosis and limited number of therapy options. Molecular profiling can aid pathological classification by detection of diagnostic biomarkers, and identify therapeutic opportunities for biomarker-based targeted treatment. Furthermore, pathogenic germline variants are present in ~10% of sarcoma patients, but remain often unrecognized. To explore the full spectrum of possible biomarkers in current molecular diagnostics, multiple and often iterative testing is required. In clinical practice, molecular profiling is selectively performed for specific patient groups with certain diagnoses already in mind. As a result, relevant diagnostic and/or actionable biomarkers are potentially overlooked. Whole genome sequencing (WGS) provides a complete, unbiased genomic characterization and detection of all possible genomic events within one diagnostic test. By applying prospective WGS in (suspected) advanced sarcoma patients in a tertiary sarcoma referral center, we uncover the missed potential of a targeted approach of molecular diagnostics. Abstract With more than 70 different histological sarcoma subtypes, accurate classification can be challenging. Although characteristic genetic events can largely facilitate pathological assessment, large-scale molecular profiling generally is not part of regular diagnostic workflows for sarcoma patients. We hypothesized that whole genome sequencing (WGS) optimizes clinical care of sarcoma patients by detection of diagnostic and actionable genomic characteristics, and of underlying hereditary conditions. WGS of tumor and germline DNA was incorporated in the diagnostic work-up of 83 patients with a (presumed) sarcomas in a tertiary referral center. Clinical follow-up data were collected prospectively to assess impact of WGS on clinical decision making. In 12/83 patients (14%), the genomic profile led to revision of cancer diagnosis, with change of treatment plan in eight. All twelve patients had undergone multiple tissue retrieval procedures and immunohistopathological assessments by regional and expert pathologists prior to WGS analysis. Actionable biomarkers with therapeutic potential were identified for 30/83 patients. Pathogenic germline variants were present in seven patients. In conclusion, unbiased genomic characterization with WGS identifies genomic biomarkers with direct clinical implications for sarcoma patients. Given the diagnostic complexity and high unmet need for new treatment opportunities in sarcoma patients, WGS can be an important extension of the diagnostic arsenal of pathologists.

Background: Recently, we performed a meta-analysis based on a literature review for STS trials (published 2003-2018, >= 10 adult patients) to update long-standing reference values for leiomyosarcomas. This work is extended for liposarcomas (LPS) and synovial sarcomas (SS).Materials and methods: Study endpoints were progression-free survival rates (PFSRs) at 3 and 6 months. Trial-specific estimates were pooled per treatment line (first-line or pre-treated) with random effects meta-analyses. The choice of the therapeutic benefit to target in future trials was guided by the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Results: Information was acquired for 1030 LPS patients (25 trials; 7 first-line, 17 pre-treated, 1 both) and 348 SS patients (13 trials; 3 first-line, 10 pre-treated). For LPS, the overall pooled first-line PFSRs were 69% (95%-CI 60-77%) and 56% (95%-CI 45-67%) at 3 and 6 months, respectively. These rates were 49% (95%-CI 40-57%)/28% (95%-CI 22-34%) for >1 lines. For SS, first-line PFSRs were 74% (95%-CI 58-86%)/56% (95%-CI 31-78%) at 3 and 6 months, and pre-treated rates were 45% (95%-CI 34-57%)/25% (95%-CI 16-36%). Following ESMO-MCBS guidelines, the minimum values to target are 79% and 69% for first-line LPS (82% and 69% for SS) at 3 and 6 months. For pre-treated LPS, recommended PFSRs at 3 and 6 months suggesting drug activity are 63% and 44% (60% and 41% for SS).Conclusions: New benchmarks are proposed for advanced/metastatic LPS or SS to design future histology-specific phase II trials. More data are needed to provide definitive thresholds for the different LPS subtypes. 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background: Health-related quality of life (HRQoL) has been shown to be a prognostic factor for cancer survival in randomized clinical trials. It is questioned whether this association also holds in the “real world” and which HRQoL scores as measured by the EORTC QLQ-C30 are the best prognosticators. The aims of the present observational, population-based study were to: (1) investigate the association of HRQoL with all-cause mortality; and (2) determine which QLQ-C30 scores (the summary score covering all HRQoL domains, the global QoL or the physical functioning scale) exhibits the strongest association with all-cause mortality. Methods: Between 2008 and 2015, cancer patients (colon, rectum, melanoma, basal/squamous cell, endometrial, ovarian, prostate, thyroid, Hodgkin, non-Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma) were invited to participate in PROFILES (‘Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship’) disease-specific registry studies (response 69%). In this secondary analysis on a collated patient sample with complete data (n = 6895) multivariate Cox proportional hazard regression models were used to analyze the association between the QLQ-C30 scores and all-cause mortality. Results: In the overall regression model including sociodemographic and clinical variables, the QLQ-C30 summary score was associated significantly with all-cause mortality (HR = 0.77; 95%CI = 0.72-0.82; p < 0.01). In stratified analyses, significant associations between the summary score and all-cause mortality were found for colon, rectal, prostate cancer, non-Hodgkin lymphoma, chronic lymphocytic leukemia and multiple myeloma only. The summary score had a stronger association with all-cause mortality than the global QoL (HR = 0.82; 95%CI = 0.78-0.85; p < 0.01) and the physical functioning scales (HR = 0.81; 95%CI = 0.78-0.84; p < 0.01). Conclusions: Our results indicate that, in a population-based setting, HRQoL, as assessed by the summary score of the QLQ-C30, has prognostic value for a number of cancer patient populations above and beyond that provided by clinical and sociodemographic variables.

Background The new anti-cancer drug imatinib mesylate inhibits the tyrosine kinase growth factor receptor, c-KIT, and has shown spectacular activity in patients with gastrointestinal stromal tumours (GISTs). Objective To assess whether fluorodeoxyglucose positron emission tomography (FDG PET) is suitable for response evaluation of this new type of tumour treatment. Methods Sixteen consecutive patients with irresectable or metastasized GIST or another c-KIT (CD117) positive mesenchymal tumour underwent FDG PET before and 1 week after the start of treatment with imatinib mesylate (Glivec(R)). Visual findings and standard uptake values (SUVs) were compared with the overall response to treatment, based on clinical and radiological response. Results PET visualized all known and some unknown tumour locations. The separation by PET after 1 week of treatment in 'PET responders' (11/16 patients, mean SUV reduction 65%) versus 'PET non-responders' (5/16 patients, mean SUV increase 16%) appeared to match almost perfectly with overall treatment response and proved correct in 14/15 patients (prediction sensitivity 93%). FDG uptake changes after 1 week of treatment were of greater magnitude than tumour volume changes on computed tomography at 8 weeks. Progression-free survival was significantly better in patients with a PET response (P=0.002). PET response predicted treatment outcome better than the radiological response. Finally, PET was helpful during follow-up, in discriminating side effects from tumour progression. Conclusion FDG PET is a valuable tool in patients with gastrointestinal stromal tumours treated with imatinib mesylate. It improves staging, accurately separates responders from non-responders in an early phase, and is helpful during follow-up.