{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T03:51:11Z","timestamp":1793677871169,"version":"4.5.1"},"posted":{"date-parts":[[2024,12,12]]},"group-title":"Cancer Biology","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Chemotherapy regimens for triple-negative breast cancer (TNBC) combine agents without knowing which agents drive response. Consequently, predictors derived from multi-agent regimens cannot be assumed to generalize to individual drugs or other regimens, motivating development of treatment-matched predictors. Here, we used TNBC patient-derived xenografts (PDXs) treated with carboplatin, docetaxel, or the combination to deconvolute drug-specific responses and identify associated molecular features. Combination treatment rarely improved upon the best single agent, with enhanced responses in only 13% of PDXs and antagonism in a comparable fraction. Proteogenomic analyses identified high cytokeratin-5 (KRT5) as a general marker of chemotherapy responsiveness and KRT5 immunohistochemistry discriminated responsive PDXs (AUROC, 0.83). To train treatment-specific predictors, we integrated these data with independent PDX and clinical cohorts with responses assessed after anthracycline-free platinum, taxane, or platinum-taxane therapy, ensuring response corresponded to the modeled treatment. Four feature selection strategies yielded largely nonoverlapping biomarker panels converging on treatment-relevant pathways. On independent test data, RNA-based predictors of complete response (CR) to platinum-based (carboplatin or cisplatin) and taxane-based (docetaxel or paclitaxel) chemotherapy achieved AUROCs of 0.80 and 0.86, respectively. For platinum-taxane regimens (carboplatin plus docetaxel or paclitaxel), proteomic-guided feature selection generated a 10-biomarker, protein- informed RNA predictor of pathologic complete response (pCR) that outperformed RNA-only feature selection and achieved an AUROC of 0.85 in an independent clinical cohort, while retaining practicality as an RNA-based assay. Treatment-matched integration of multi-omic PDX and clinical datasets provides a framework for chemotherapy-specific predictors with clinically relevant performance, supporting biomarker-guided precision selection and treatment optimization for patients with TNBC.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of significance<\/jats:title>\n                  <jats:p>Integration of multi-omic data from patient-derived xenografts with treatment-matched clinical cohorts yielded three retrospectively validated predictors of platinum, taxane, and platinum+taxane response, enabling biomarker-guided chemotherapy selection for patients with triple-negative breast cancer.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.12.09.627518","type":"posted-content","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T23:19:59Z","timestamp":1734045599000},"source":"Crossref","is-referenced-by-count":5,"title":["Patient-Derived Xenograft-Guided Prediction of Chemotherapy Response in Triple-Negative Breast Cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0209-8051","authenticated-orcid":false,"given":"Jonathan T.","family":"Lei","sequence":"first","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lacey E.","family":"Dobrolecki","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Huang","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramakrishnan R.","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhas V.","family":"Vasaikar","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Translational Oncology Bioinformatics, Pfizer, Bothell, WA 98021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaina N.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Sallas","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8161-3380","authenticated-orcid":false,"given":"Na","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Cao","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Landua","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob B.","family":"Pilcher","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang In","family":"Moon","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Sage Bionetworks, Seattle, WA, 98121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Liao","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Research Informatics, Information Technology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan G.","family":"Hilsenbeck","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mothaffar F.","family":"Rimawi","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Ellis","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"State University of Campinas (UNICAMP), Campinas, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varduhi","family":"Petrosyan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2261-3150","authenticated-orcid":false,"given":"Bo","family":"Wen","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Li","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander B.","family":"Saltzman","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antrix","family":"Jain","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Malovannaya","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerburg M.","family":"Wulf","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Marangoni","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL University, 26 Rue d\u2019Ulm, Paris 75005, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunqiang","family":"Li","sequence":"additional","affiliation":[{"name":"Siteman Cancer Center, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Kraushaar","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew P.","family":"Goetz","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy C.","family":"Boughey","sequence":"additional","affiliation":[{"name":"Division of Breast and Melanoma Surgical Oncology, Department of Surgery, Mayo Clinic, Rochester, MN, 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