Abstract
Background
Sarcomas comprise a heterogeneous group of malignant tumors of mesenchymal origin where diagnosis plays a crucial role in tailoring disease management and treatment. In this context, there is a lack of data assessing the potential benefit of next-generation sequencing (NGS) reflecting real-world scenarios across different countries. The aim of our analysis includes both the diagnostic refinement and the therapeutic guidance with the use of NGS in sarcoma treatment strategy.
Materials and methods
We retrospectively analyzed 694 samples from six sarcoma-expert institutions from three countries in Europe: Greece, Poland, and Spain, thus reflecting a variety of scenarios.
Results
We identified 90 different sarcoma histological subtypes, of which the most common were leiomyosarcomas (10.1%), Ewing sarcomas (7.5%), and undifferentiated pleomorphic sarcomas (7.3%). In 62 patients (8.9%), using NGS fusion panels specific for diagnosis resulted in a change in the diagnosis. From a therapeutic perspective, NGS panels used for this purpose were suitable to identify single-nucleotide variants and copy number alterations. The most common alterations were mutations that mostly occurred in TP53, followed by RB1, PIK3CA, CDKN2A, CTNNB1, IDH1, NF1, CHECK2, PTEN, BRCA1, and BRCA2. One hundred and thirty-five alterations (19.5%) were actionable according to OncoKB, while four additional alterations (0.6%) were actionable in disagreement with OncoKB.
Conclusions
In conclusion, our data support the clinical utility of NGS fusion panels in diagnosing sarcomas in specific contexts. The therapeutic value of NGS remains limited, as reported before. However, given the overall paucity of molecular data for most sarcoma subtypes, we emphasize the importance of an international effort to collect molecular profiling of sarcomas to guide the design of clinical trials for specific targetable alterations.
Key words: NGS, molecular diagnosis, targeted therapies, actionable mutations, sarcoma
Highlights
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NGS can be of aid during the diagnostic process in some specific challenging situations.
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Prior review by sarcoma-expert pathologists is key to establishing the need for NGS.
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NGS in clinical decision making based on actionable mutations detected is still a matter of dilemma.
Introduction
Sarcomas comprise a heterogeneous group of malignant tumors of mesenchymal origin that constitutes a challenge from both diagnosis and therapeutic perspectives. The recent version of the World Health Organization (WHO) classification of soft tissue sarcomas (STS) and bone sarcomas identifies >120 entities, of which more than one-third can be characterized only by a specific genomic aberration.1 Given that the tissue of origin may not be evident in some circumstances, even after a sarcoma-expert pathology evaluation, identifying novel subtype-specific genetic alterations can be crucial for diagnosis. From a therapeutic point of view, the design of prospective clinical trials and the use of off-label medications in this group of tumors remains challenging due to the lack of molecular data, given both their rarity and heterogeneity. Although sarcoma subtype-specific genetic alterations have been investigated retrospectively, only a minority have demonstrated prognostic and predictive value.2 Consequently, cytotoxic chemotherapy remains the standard of care for most sarcoma patients.3 Nevertheless, depending on the specific sarcoma subtype, modern diagnosis is evolving with the individualization of treatment approaches.
There is a disparity among oncology facilities of next-generation sequencing (NGS) panels and technologies that are increasingly used, especially for therapeutic purposes. In this regard, treatment options for sarcoma patients are limited; therefore, NGS testing allows for finding targetable alterations. However, given the intricacy, rarity, and large amount of histotypes; low mutational burden; and near-absence of recurrent and/or targetable alterations, the clinical value of NGS in real-world scenarios for patients with sarcoma remains controversial.4 Likewise, there is a lack of complex studies addressing the impact of NGS on sarcoma diagnosis and treatment in Europe.
This study aimed to evaluate the clinical value of NGS for sarcoma diagnosis and treatment and identify potential therapeutic targets in real-world scenarios across various European countries and institutions. The current study aimed to determine the proportion of patients sharing specific genetic alterations, the sarcomas subtypes with targetable events, and the clinical benefit yielded in patients who received matched targeted therapies.
Materials and methods
We enrolled retrospectively 694 patients diagnosed with bone and STS from six different sarcoma-expert institutions among three countries [Greece (n = 3), Poland (n = 1), and Spain (n = 2)] from 2008 to 2023. Relevant patients’ demographic and clinical data were retrieved retrospectively from medical records.
In all cases, the DNA and RNA for NGS were isolated from formalin-fixed paraffin-embedded tumor tissue. Mutational profiles (mutations, fusions, and amplifications) were detected using diagnostic and/or therapeutic NGS panels, including FoundationOne® CDx (Foundation Medicine, Inc., Cambridge, MA), Archer® FusionPlex® Sarcoma and Sarcoma v2 panels (ArcherDX, Boulder, CO), and Archer® FusionPlex® Comprehensive Thyroid and Lung Kit (ArcherDX, Boulder, CO), or specific libraries’ synthesis with the Ion AmpliSeq Library Kit 2.0 (WG-IAD186419, Custom AmpliSeq panel, Thermo Fisher Scientific, Waltham, MA), an in-house 300-gene amplicon-seq panel (Supplementary Material 1, available at https://doi.org/10.1016/j.esmoop.2025).
The NGS was carried out on Illumina® NovaSeq 6000 (NovaSeq, Illumina San Diego, CA) platform (FoundationOne® CDx), Miniseq and Nextseq 500 (Archer® panels), and Ion GeneStudio S5 System (an in-house 300-gene amplicon-seq specific NGS panel). The NGS data were analyzed using a proprietary software system developed by Foundation Medicine, Archer Analysis v6.2 software,5 or IonTorre Thermo Fisher Scientific version 5.2, respectively. Functional analysis of gene fusions was carried out using the ChimerDriver and Oncofuse tools (Modena, Italy).6,7
Descriptive statistics were carried out using frequencies and percentages for the categorical variables or medians and ranges or interquartile ranges for continuous variables. All computations and visualizations were conducted with the R language v4.4.1, with an abundant use of ‘dplyr’ and ‘ggplot2’ packages.8,9 ‘Potentially actionable mutations’ were defined as those that have therapeutic implications, i.e. predict response or resistance to systemic therapy as per the OncoKB v4.21 classification system (www.oncokb.org, accessed on 1 July 2024) of levels of actionability.10
Results
Description of the cohort
Six hundred and ninety-four STS and bone sarcoma patients from the six sarcoma-expert institutions were included. NGS for diagnosis and/or therapeutic purposes was requested individually at the discretion of the multidisciplinary team (pathologists and/or oncologists). Ninety distinctive sarcoma histological subtypes were identified (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025), of which 563 were STS (81.1%) and 124 were bone sarcomas (17.9%). Baseline patients’ characteristics are shown in Table 1. Median age was 46.5 years (0-89 years), with males being 54.5% of the total population. Most were patients with localized disease (58.1%), while 38.3% were metastatic. Most common STS included leiomyosarcoma (10.1%), undifferentiated pleomorphic sarcoma (7.3%), myxofibrosarcoma (4.5%), undifferentiated sarcoma not otherwise specified (NOS) (4.2%), synovial sarcoma (3.7%), undifferentiated spindle cell sarcoma (3.7%), malignant solitary fibrous tumor (3.5%), and malignant peripheral nerve sheath tumor (3.3%). Most common bone sarcomas included Ewing sarcoma (7.5%), chondrosarcoma (4.4%), and osteosarcoma (2.4%) of the total population.
Table 1.
Patients’ characteristics
| Total number of patients, n | 694 |
|---|---|
| Age, years (range) | 46.5 (0-89) |
| Sex, n (%) | |
| Female | 308 (44.4) |
| Male | 378 (54.5) |
| Unknown | 6 (0.9) |
| Clinical stage, n (%) | |
| Localized | 403 (58.1) |
| Metastatic | 266 (38.3) |
| Recurrent | 3 (0.4) |
| Unknown | 22 (3.2) |
Role of NGS in the diagnosis
Sarcoma-expert pathologists evaluated all cases, and diagnostic NGS panels were carried out at their discretion whenever the initial diagnosis was considered doubtful or inconclusive. The diagnosis was changed in 62 patients (8.9%) due to the NGS result. The initial sarcoma subtype was re-classified in 54 out of 62 patients as a different sarcoma subtype. In six additional patients, an initial diagnosis of other types of cancers was changed to sarcoma upon NGS results. Two cases had a primary diagnosis of melanoma to sarcoma. Finally, two more patients initially diagnosed, each with a benign mesenchymal lesion and a tumor of uncertain behavior, had the final diagnosis changed to sarcoma (Table 2, Figure 1).
Table 2.
Diagnoses changed after the NGS result
| Original diagnosis | Corrected diagnosis | Number of patients (%) |
|---|---|---|
| Total | 62 (8.9) | |
| Undifferentiated spindle cell sarcoma | Malignant SFT | 3 (0.4) |
| Undifferentiated spindle cell sarcoma | NTRK-rearranged spindle cell neoplasm | 2 (0.3) |
| Renal cell carcinoma NOS | Perivascular epithelioid tumor, malignant | 2 (0.3) |
| Renal cell carcinoma NOS | Alveolar soft part sarcoma | 1 (0.1) |
| Mesenchymal chondrosarcoma | Chondroblastic osteosarcoma | 1 (0.1) |
| Mesenchymal chondrosarcoma | Chondrosarcoma | 1 (0.1) |
| Ossifying fibromyxoid tumor | Chondrosarcoma | 1 (0.1) |
| Ewing sarcoma | CIC-rearranged sarcoma | 1 (0.1) |
| Histiocytic sarcoma | CIC-rearranged sarcoma | 1 (0.1) |
| Myxofibrosarcoma | CIC-rearranged sarcoma | 1 (0.1) |
| Undifferentiated epithelioid sarcoma | CIC-rearranged sarcoma | 1 (0.1) |
| Undifferentiated pleomorphic sarcoma | CIC-rearranged sarcoma | 1 (0.1) |
| Undifferentiated round cell sarcoma | CIC-rearranged sarcoma | 1 (0.1) |
| Undifferentiated spindle cell sarcoma | CIC-rearranged sarcoma | 1 (0.1) |
| Ewing sarcoma | Clear-cell sarcoma, NOS | 1 (0.1) |
| GIST | Clear-cell sarcoma, NOS | 1 (0.1) |
| Paraganglioma NOS | Clear-cell sarcoma, NOS | 1 (0.1) |
| GIST | Dedifferentiated liposarcoma | 1 (0.1) |
| Sarcoma NOS | Dedifferentiated liposarcoma | 1 (0.1) |
| MPNST | Dermatofibrosarcoma protuberans, NOS | 1 (0.1) |
| Myxofibrosarcoma | Dermatofibrosarcoma protuberans, NOS | 1 (0.1) |
| Neuroendocrine carcinoma NOS | Desmoplastic small round cell tumor | 1 (0.1) |
| Small-cell carcinoma NOS | Desmoplastic small round cell tumor | 1 (0.1) |
| Undifferentiated spindle cell sarcoma | Endometrial stromal sarcoma, high grade | 1 (0.1) |
| Undifferentiated epithelioid sarcoma | Epithelioid cell synovial sarcoma | 1 (0.1) |
| Epithelioid hemangioendothelioma | Epithelioid sarcoma NOS | 1 (0.1) |
| Mesenchymal chondrosarcoma | Ewing sarcoma | 1 (0.1) |
| MPNST | Ewing sarcoma | 1 (0.1) |
| Myxofibrosarcoma | Ewing sarcoma | 1 (0.1) |
| Myxofibrosarcoma | Extraskeletal myxoid chondrosarcoma | 1 (0.1) |
| Sarcoma NOS | Extraskeletal myxoid chondrosarcoma | 1 (0.1) |
| Undifferentiated pleomorphic sarcoma | Inflammatory myofibroblastic tumor | 1 (0.1) |
| MPNST | Malignant epithelioid neoplasm with GLI1 rearrangement | 1 (0.1) |
| Undifferentiated round cell sarcoma | Malignant SFT | 1 (0.1) |
| Undifferentiated sarcoma NOS | Malignant SFT | 1 (0.1) |
| Clear-cell sarcoma | Melanoma | 1 (0.1) |
| Ossifying fibromyxoid tumor, malignant | Myxofibrosarcoma | 1 (0.1) |
| Undifferentiated spindle cell sarcoma | Myxofibrosarcoma | 1 (0.1) |
| Myxoid liposarcoma | Myxosarcoma | 1 (0.1) |
| Undifferentiated epithelioid sarcoma | NTRK-rearranged spindle cell neoplasm | 1 (0.1) |
| Biphasic synovial sarcoma | Ossifying fibromyxoid tumor, malignant | 1 (0.1) |
| Undifferentiated epithelioid sarcoma | Ossifying fibromyxoid tumor, malignant | 1 (0.1) |
| Melanoma | Perivascular epithelioid tumor, malignant | 1 (0.1) |
| Sarcoma NOS | Perivascular epithelioid tumor, malignant | 1 (0.1) |
| Myxofibrosarcoma | Sclerosing epithelioid fibrosarcoma | 1 (0.1) |
| Undifferentiated round cell sarcoma | Sclerosing epithelioid fibrosarcoma | 1 (0.1) |
| Undifferentiated sarcoma NOS | Spindle and round cell sarcoma with EWSR1-PATZ1 gene fusion | 1 (0.1) |
| Carcinosarcoma | Spindle cell rhabdomyosarcoma | 1 (0.1) |
| Undifferentiated spindle cell sarcoma | Spindle cell rhabdomyosarcoma | 1 (0.1) |
| Sarcoma with BCOR genetic alterations | Spindle cell synovial sarcoma | 1 (0.1) |
| Undifferentiated round cell sarcoma | Synovial sarcoma NOS | 1 (0.1) |
| Ewing sarcoma | Undifferentiated round cell sarcoma | 1 (0.1) |
| Rhabdomyosarcoma NOS | Undifferentiated round cell sarcoma | 1 (0.1) |
| Sarcoma with BCOR genetic alterations | Undifferentiated round cell sarcoma | 1 (0.1) |
| Sclerosing epithelioid fibrosarcoma | Undifferentiated sarcoma | 1 (0.1) |
| Malignant SFT | Undifferentiated spindle cell sarcoma | 1 (0.1) |
| Sarcoma NOS | Undifferentiated spindle cell sarcoma | 1 (0.1) |
| Synovial sarcoma | Undifferentiated spindle cell sarcoma | 1 (0.1) |
BCOR, BCL6 corepressor gene; CIC, capicua transcriptional repressor; GIST, gastrointestinal stromal cancer; MPNST, malignant peripheral nerve sheath tumor; NOS, not otherwise specified; NTRK, neurotrophic tropomyosin receptor kinase; SFT, solitary fibrous tumor.
Figure 1.
Changes in the diagnosis after carrying out NGS. GIST, gastrointestinal stromal cancer; MPNST, malignant peripheral nerve sheath tumor; NGS, next-generation sequencing; NOS, not otherwise specified; NTRK, neurotrophic tropomyosin receptor kinase; SFT, solitary fibrous tumor.
In 31 cases, the genetic alteration found was pathognomonic for diagnosing a specific sarcoma. Importantly, in 24 cases, the change in the diagnosis had an impact on the subsequent therapeutic strategy (Table 2, Figure 1).
The sarcoma subtype which was most commonly re-classified into another sarcoma subtype after obtaining the NGS result was the undifferentiated spindle cell sarcoma—a total of nine patients with an initial diagnosis of this subtype had the final diagnosis changed. Three of them were ultimately diagnosed with malignant solitary fibrous tumor—two with NTRK-rearranged spindle cell neoplasm and one patient with each of the following subtypes: capicua transcriptional repressor (CIC)-rearranged sarcoma, endometrial stromal sarcoma, myxofibrosarcoma, and spindle cell rhabdomyosarcoma. Another commonly re-classified subtype was myxofibrosarcoma, with five patients having the diagnosis changed after the NGS result, to either: Ewing sarcoma, dermatofibrosarcoma protuberans, sclerosing epithelioid fibrosarcoma, CIC-rearranged sarcoma, or extraskeletal myxoid chondrosarcoma—each in one case. Of note, the total numbers of patients with undifferentiated spindle cell sarcoma and myxofibrosarcoma undergoing NGS were 26 and 31, implying that the diagnosis was changed in 35% and 16% of those patients, respectively.
Mutational profile and actionable alterations
A total of 519 mutations were found in 331 patients, with a mean of 1.57 alterations per patient. Genetic and genomic alteration included small-scale mutations (n = 269), fusions (n = 179)—including three truncations, and amplifications (n = 71) (Figure 2). Multiple genes were involved in fusions and truncations (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2025). The most frequently mutated genes in the study population were TP53 (14.9%), followed by RB1 (4.8%), PIK3CA (4%), CDKN2A (3.3%), CTNNB1 (3.3%), IDH1 (3.3%), NF1 (3.3%), CHECK2 (3%), PTEN (3%), and BRCA1/2 (2.2%). Regarding gene amplifications, CDK4 and MDM2 genes were amplified in 11.2% of the cases, respectively. Among those genes, PTEN alterations were associated mainly with endometrial stromal sarcomas (17 cases). In contrast, other associations between gene alterations and specific sarcoma subtypes were challenging due to the low number of cases with mutations (Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025). The most common gene fusions were EWSR1–FLI1, NAB2–STAT6, and CIC–DUX4 (Figure 2). EWSR1–FLI1, NAB2–STAT6, and CIC–DUX4 gene fusions were related to Ewing sarcoma, malignant solitary fibrous tumor, and CIC-rearranged sarcoma, respectively. In addition, SFPQ–TFE3 gene fusion was observed in cases with malignant perivascular epithelioid cell tumor (PEComa) (Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2025).
Figure 2.
Genetic and genomic alterations detected by NGS. Genetic and genomic alterations detected including (A) small-scale mutations, (B) fusions, and (C) amplifications. NA, not applicable.
The most commonly encountered fusion 5′-partner was EWSR1, in a total of 50 analyzed tumors. Its most common fusion 3′-partners were FLI1 (24 tumors), WT1 (6 tumors), and NR4A3 (4 tumors). Another common fusion 5′-partner was CIC, with almost all cases having the DUX4 fusion 3′-partner and DBET in one case. Also, in another single case, the CIC truncation was observed.
The most common fusion 3′-partners, besides those which were mentioned in the previous paragraph, included also STAT6 (15 tumors), PDGFB (9 tumors), TFE3 (8 tumors), and NTRK3 and NCOA2 (each in 6 tumors).
Furthermore, small-scale mutations and amplifications were more frequent in genomically complex sarcomas, while fusion genes were more frequent in translocation-related sarcomas, as expected (Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2025).
Regarding the actionability of the genetic findings detected, 135 alterations (19.5%) were actionable according to OncoKB, and 4 alterations (0.6%) were deemed actionable by the investigator, but not according to OncoKB, potentially being discordant findings. Only 21 out of these 135 alterations (15.6%) had a level 1 indication [Food and Drug Administration (FDA)-recognized biomarker predictive of response to an FDA-approved drug], according to OncoKB (Supplementary Figure S4, available at https://doi.org/10.1016/j.esmoop.2025). In another 45 patients (33.1%), there was level 3B actionability (drug available for another indication), and in another 51 cases (37.5%) there was only compelling biological evidence supporting the actionability (level 4). Of note, in two (1.5%) cases the found variant was classified as R2 level (compelling clinical evidence supporting the predictive role for resistance to the therapy).
Clinical benefit of NGS used for therapeutic purposes
NGS-matched therapies were administered to 17 patients (2.4% of the total cohort). Only five patients from this cohort exhibited clinical benefit, defined as the duration of treatment being longer than 6 months (Table 3). No objective responses were reported. BRAF mutation was detected in two of these five patients, and the duration of treatment with BRAF and mitogen-activated protein kinase kinase inhibition was 12 and 19 months for each one. Anaplastic lymphoma kinase (ALK) mutation was targeted with ALK inhibitor crizotinib, which led to a 20-month duration of treatment. Sirolimus was used for a TP53 mutation with 6 months of treatment duration. Finally, an IDH1 mutation in a chondrosarcoma was targeted with a novel IDH1 inhibitor, offering a duration of 6 months of treatment.
Table 3.
Targeted therapy regimens administered according to the NGS result
| Genetic aberrations found with NGS | Sarcoma | Agent name | Duration of the treatment (months) | |
|---|---|---|---|---|
| 1 | RAD50, BRCA2 | Epithelioid sarcoma | Olaparib | 2.5 |
| 2 | KRAS, TP53, CHEK2, KDR, ALK | Dedifferentiated liposarcoma | Olaparib | 1 |
| 3 | BRAF, FGFR3, ATM | MPNST | Dabrafenib/trametinib | 12 |
| 4 | ALK | Inflammatory myofibroblastic tumor | Crizotinib | 20 |
| 5 | MET amplification | Chondrosarcoma | Cabozantinib | 5 |
| 6 | MET amplification | Intimal sarcoma | Capmatinib | 1 |
| 7 | FANCD2, AR amplification | Leiomyosarcoma | Bicalutamide | 3 |
| 8 | FANCD2, AR amplification | Leiomyosarcoma | Olaparib | 3 |
| 9 | NF1 | Endometrial stromal sarcoma | Trametinib/everolimus | 3 |
| 10 | IDH1, KRAS | Chondrosarcoma | Olaparib | 0.75 |
| 11 | EWSR1–ATF1 fusion | Clear-cell sarcoma | Pazopanib | 3 |
| 12 | EWSR1–TFCP2 fusion, LOC101929418–ALK fusion | Spindle cell rhabdomyosarcoma | Alectinib | 4 |
| 13 | BRAF | Glomus tumor, malignant | Encorafenib + binimetinib | 19 |
| 14 | TP53 | Perivascular epithelioid cell tumor | Sirolimus | 6 |
| 15 | Amplification of: CDK4 MDM2, HMGA2 | Dedifferentiated liposarcoma | Milademetan | 2 |
| 16 | SPECC1L–NTRK3 fusion | MPNST | Larotrectinib | 2.5 |
| 17 | IDH1 | Chondrosarcoma | CIDH305X2101 | 6 |
ALK, anaplastic lymphoma kinase.
Discussion
NGS and other high-throughput technologies are increasingly used in the clinical routine for the detection of molecular alterations, mainly for therapeutic purposes. As a particularity, however, the role of non-NGS molecular studies in sarcomas is well established in terms of its relevance for diagnosis. The fact that the most recent WHO classification of bone and STS incorporated new tumor entities based only on the molecular findings highlights the profound importance of molecular biology diagnostics in these tumors.1 Additionally, several reports have shown the need for NGS for a more precise classification of specific sarcoma histotypes based on the pathologist’s differential diagnosis.11
Ray-Coquard et al. were historically the first to describe that expert pathologists’ opinion is crucial for the correct diagnosis of sarcomas, reporting 8% of full discordance and 35% of partial discordance from the second expert opinion.12 The Italian sarcoma group later reported a retrospective analysis of 150 cases of STS and bone sarcomas in which molecular diagnostics were carried out on a routine basis to detect clinically relevant fusion genes.13 The recent publication from the Greek sarcoma group has shown prospectively the importance of expert pathologists’ opinions combined with molecular diagnostic services, leading to 10.9% and 14.2% modifications in patients’ management after molecular analysis and expert pathologist review, respectively.14 Additionally, a Chinese study of 1048 patients with sarcomas reported the utility of molecular diagnostics to reach the correct diagnosis in sarcomas and to detect novel molecular targets with potential therapeutic significance, with 6.4% having actionable mutations.15
In our series, 8.9% had a change in diagnosis upon the results of NGS, with 8 out of 694 patients (1.15%) eventually being led to a different therapeutic approach. Therefore, diagnostic NGS panels carried out at the discretion of pathologists with sarcoma expertise are of aid in a minority of patients, albeit clinically significant. In this sense, these panels must capture all chromosomal rearrangements potentially involved in sarcomas, given the little-to-none presence of pathognomonic mutations. Indeed, the detection in our study of gene fusions specific for sarcoma histotypes in challenging cases, e.g. EWSR1-FLI1 in Ewing sarcoma,16 NAB2-STAT6 in solitary fibrous tumor,17 and CIC-DUX4 in CIC-rearranged sarcoma, was fundamental for the confirmation or change in their diagnosis of these cases. The numbers and proportions of these subtypes do not reflect their real incidence but the cases that required more common NGS to aid in the diagnostic procedure.
Various NGS-based studies with a major aim on the identification of therapeutic targets18, 19, 20, 21, 22 have consistently shown that alterations in TP53, RB1, CDK4, CDKN2A, MDM2, ATRX, and PTEN are the most commonly affected genes in metastatic sarcomas, which largely parallel the findings from our cohort. Specifically, and regarding the actionability of the alterations detected, ∼20% (19.5% according to OncoKB and 0.6% not to OncoKB) of the patients could be offered a matched targeted therapy. However, due to several constraints, only 2.6% of the total cohort received treatment according to the molecular finding, with even fewer of them achieving clinical benefit. Other studies carried out previously have shown numbers in the same range.
Taken together, the data obtained from our cohort, with various real-world scenarios from different European institutions and using a diversity of NGS panels, largely reproduce prior results from top-notch single institutions.23 In this sense, it seems quite conclusive that there is a low number of genetic alterations that can be found with NGS in sarcoma patients, alongside a small percentage of patients obtaining clinical benefit derived from the matched targeted therapies offered. The mutation that was targeted in our series with a durable clinical impact was BRAF in two cases. By contrast, the diagnostic significance of molecular analysis seems to be well established, and NGS can be of aid during the diagnostic process in some specific challenging situations. However, the prior review by sarcoma-expert pathologists is key to establishing the need for NGS.
Therefore, the value of high-throughput technologies in clinical decision making and, more specifically, in treatment options based on actionable mutations detected is still a matter of dilemma. The European Society for Medical Oncology has published recommendations regarding the use of genomic tests in solid tumors.2,4 Additionally, the difficulty in obtaining off-label use of alternative drugs significantly limits the potential impact of NGS on the therapeutics and outcomes of sarcomas. Due to the heterogeneity of the population included both in our analysis and the reported studies, it is difficult to conclude the relevance of specific targetable mutations in specific subtypes of sarcomas. Several reviews have discussed this question, and the main conclusion is that prospective clinical trials are needed to assess the utility of NGS to the therapeutics of sarcomas,24, 25, 26, 27 but this option may be unfeasible due to prior reasons.
Our study has several limitations, with the first one being the retrospective character of our analysis. Additionally, the vast heterogeneity of the sarcoma histotypes included limits the impact of the conclusions that could be drawn. Furthermore, the different platforms used for the molecular analyses are confounding factors regarding the concordance of the molecular data driven from Greek, Polish, and Spanish centers. It is also important to highlight that none of the patient samples included was analyzed with all the NGS panels.
Our results, combined with the reported studies mentioned in this manuscript, encourage an international database collecting actionable NGS mutations detected in sarcoma patients in order to better understand their role in specific subtypes and design prospective trials with meaningful rationale. The Hellenic group of sarcomas and rare cancers intends to fund and coordinate an international database which would be a publicly available pilot for future research projects and clinical trials.
Conclusion
NGS during the diagnostic process, requested by sarcoma-expert pathologists, can be of great significance in some specific challenging situations. However, regarding clinical decision making, the use of NGS in order to guide the treatment options targeting actionable mutations is still a matter of dilemma.
Acknowledgments
Funding
This work was supported in part by the CRIS Foundation [grant number excellence2023_44] to CS.
Disclosure
CS has received research funding (institution) from IDRX and Blueprint; consulting fees (advisory role) from NewBay, IDRX, Cogent, and Deciphera; payment for lectures from Roche, PharmaMar, and Deciphera; and travel grants from Gilead, PharmaMar, Pfizer, and Bayer AG. All other authors have declared no conflicts of interest.
Supplementary data
References
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