Molecular biomarkers impact survival after neoadjuvant chemoradiation in locally advanced soft tissue sarcoma patients

Molecular biomarkers impact survival after neoadjuvant chemoradiation in locally advanced soft tissue sarcoma patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Molecular biomarkers impact survival after neoadjuvant chemoradiation in locally advanced soft tissue sarcoma patients Klaudia Bobak, Jakub Piątkowski, Paweł Golik, Katarzyna A. Seliga, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8725409/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Locally advanced, marginally resectable soft tissue sarcomas (STS) are frequently treated with multimodal neoadjuvant strategies to enable limb-sparing, R0 resection. However, pathological response (PR) to neoadjuvant chemoradiation is heterogeneous, and robust molecular predictors of response are lacking. We performed comprehensive DNA/RNA profiling to identify genomic correlates of PR and clinical outcomes in a real-world cohort treated with a uniform neoadjuvant chemoradiation regimen. Methods We retrospectively analyzed pre-treatment biopsies from 27 patients with high-grade, marginally resectable STS treated at a single sarcoma center (median age 55 years; range 28–74; 62.96% male). Histological subtypes included undifferentiated pleomorphic sarcoma (44.44%), myxofibrosarcoma (29.63%), malignant peripheral nerve sheath tumor (14.82%), myxoid liposarcoma (7.41%), and pleomorphic liposarcoma (3.70%). Targeted DNA/RNA sequencing was performed using the TruSight Oncology 500 assay to identify single-nucleotide variants (SNV), copy number variation (CNV), and gene fusions. Pathological response was assessed in resection specimens based on the proportion of viable tumor. Overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were estimated using the Kaplan–Meier method. Results The cohort displayed a complex genomic landscape with recurrent SNV/CNV events and frequent fusion calls across STS subtypes. Presence of gene fusions was associated with improved OS ( p = 0.043), whereas PR itself was not significantly associated with survival ( p = 0.427). Exploratory analyses identified molecular features related to PR: ROS1 -associated gene fusions were observed exclusively in tumors with favorable PR, while MDM2 gene amplification and PTEN deletion were linked to poor PR. Additionally, likely pathogenic variants of TP53, PLCG2, PIK3C2B, GABRA6 , and KMT2C genes were clustered in poor-response cases. Molecular profiling also flagged potential diagnostic reclassification in selected tumors via highly specific fusion events, underscoring its value beyond prognostication. Conclusions Comprehensive DNA/RNA profiling in locally advanced STS treated with neoadjuvant chemoradiation suggests that fusion status and specific actionable alterations may stratify response biology and survival. These hypothesis-generating biomarkers, particularly ROS1 -associated gene fusions, MDM2 gene amplification, and PTEN loss — require validation in larger, histology-controlled cohorts and may inform future molecularly guided neoadjuvant strategies. Trial registration NCT03651375. neoadjuvant treatment soft tissue sarcoma treatment response genetic profile gene fusion CNV SNV diagnostic biomarker predictive biomarker Full Text Additional Declarations No competing interests reported. Supplementary Files Suplementaryfigures.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 14 Apr, 2026 Reviewers agreed at journal 13 Apr, 2026 Reviews received at journal 11 Apr, 2026 Reviewers agreed at journal 11 Apr, 2026 Reviewers invited by journal 02 Apr, 2026 Editor assigned by journal 31 Mar, 2026 Editor invited by journal 06 Mar, 2026 Submission checks completed at journal 05 Mar, 2026 First submitted to journal 05 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8725409","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":616498468,"identity":"ac1d41d7-d474-4a36-80de-c596ea14ec5c","order_by":0,"name":"Klaudia Bobak","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIiWNgGAWjYBACCXYgwWPAwGDAwMPA2FABJKFABqcWZhQtZxBaePBrYYBqaWxDyODUItnM/EziTYEdgzl778GPM+fdkeFnYL/4mIfhDk4t0sxsZpJzDJIZLHvOJUtu3PaMR7KBp9iYh+EZTi1yzAxm0jwGzAwGN3IMJB9uO8xjcIAnTXIGw2E8Wti/AbXUg7QY/3w4hwgt0sw8IFsOg7SYSW5sAGlhPybxAY8WyWaeYss5Bsd5gH5Js5xx7DAPUITZ4IMBbr9IHG/feOPNn2o5YIgdvtlTc9ien7394YOEijtyuLTAAJKZzOCYPUBIBwpgfwAkSNMyCkbBKBgFwxoAAPbUTZc8f6hIAAAAAElFTkSuQmCC","orcid":"","institution":"Maria Sklodowska-Curie National Research Institute of Oncology","correspondingAuthor":true,"prefix":"","firstName":"Klaudia","middleName":"","lastName":"Bobak","suffix":""},{"id":616498475,"identity":"fd3fa16c-5a66-4a39-8ed7-63fdbb658884","order_by":1,"name":"Jakub Piątkowski","email":"","orcid":"","institution":"Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw","correspondingAuthor":false,"prefix":"","firstName":"Jakub","middleName":"","lastName":"Piątkowski","suffix":""},{"id":616498477,"identity":"4acff948-769e-4e5f-883a-3acc06c5a1e5","order_by":2,"name":"Paweł Golik","email":"","orcid":"","institution":"Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw","correspondingAuthor":false,"prefix":"","firstName":"Paweł","middleName":"","lastName":"Golik","suffix":""},{"id":616498482,"identity":"ebe205aa-6a15-431c-be70-807df9647874","order_by":3,"name":"Katarzyna A. 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However, pathological response (PR) to neoadjuvant chemoradiation is heterogeneous, and robust molecular predictors of response are lacking. We performed comprehensive DNA/RNA profiling to identify genomic correlates of PR and clinical outcomes in a real-world cohort treated with a uniform neoadjuvant chemoradiation regimen.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed pre-treatment biopsies from 27 patients with high-grade, marginally resectable STS treated at a single sarcoma center (median age 55 years; range 28\u0026ndash;74; 62.96% male). Histological subtypes included undifferentiated pleomorphic sarcoma (44.44%), myxofibrosarcoma (29.63%), malignant peripheral nerve sheath tumor (14.82%), myxoid liposarcoma (7.41%), and pleomorphic liposarcoma (3.70%). Targeted DNA/RNA sequencing was performed using the TruSight Oncology 500 assay to identify single-nucleotide variants (SNV), copy number variation (CNV), and gene fusions. Pathological response was assessed in resection specimens based on the proportion of viable tumor. Overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were estimated using the Kaplan\u0026ndash;Meier method.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe cohort displayed a complex genomic landscape with recurrent SNV/CNV events and frequent fusion calls across STS subtypes. Presence of gene fusions was associated with improved OS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043), whereas PR itself was not significantly associated with survival (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.427). Exploratory analyses identified molecular features related to PR: \u003cem\u003eROS1\u003c/em\u003e-associated gene fusions were observed exclusively in tumors with favorable PR, while \u003cem\u003eMDM2\u003c/em\u003e gene amplification and \u003cem\u003ePTEN\u003c/em\u003e deletion were linked to poor PR. Additionally, likely pathogenic variants of \u003cem\u003eTP53, PLCG2, PIK3C2B, GABRA6\u003c/em\u003e, and \u003cem\u003eKMT2C\u003c/em\u003e genes were clustered in poor-response cases. Molecular profiling also flagged potential diagnostic reclassification in selected tumors via highly specific fusion events, underscoring its value beyond prognostication.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eComprehensive DNA/RNA profiling in locally advanced STS treated with neoadjuvant chemoradiation suggests that fusion status and specific actionable alterations may stratify response biology and survival. These hypothesis-generating biomarkers, particularly \u003cem\u003eROS1\u003c/em\u003e-associated gene fusions, \u003cem\u003eMDM2\u003c/em\u003e gene amplification, and \u003cem\u003ePTEN\u003c/em\u003e loss \u0026mdash; require validation in larger, histology-controlled cohorts and may inform future molecularly guided neoadjuvant strategies.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eNCT03651375.\u003c/p\u003e","manuscriptTitle":"Molecular biomarkers impact survival after neoadjuvant chemoradiation in locally advanced soft tissue sarcoma patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-08 18:13:58","doi":"10.21203/rs.3.rs-8725409/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"24264807639594541803948877386603504518","date":"2026-04-14T13:13:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"105654303853960504549373126877024169353","date":"2026-04-13T14:49:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-11T05:22:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"194343229099835478784165412898189583183","date":"2026-04-11T04:25:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-02T09:46:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-31T04:12:59+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-06T15:20:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-06T02:18:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-03-06T01:44:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8a64e386-9e81-4659-a462-d955a18e4f82","owner":[],"postedDate":"April 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-08T18:13:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-08 18:13:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8725409","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8725409","identity":"rs-8725409","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}