Immunomodulatory gene networks predict treatment response and survival to de-escalated, anthracycline-free neoadjuvant chemotherapy in triple-negative breast cancer in the WSG-ADAPT-TN trial
Abstract Background Anthracycline-containing neoadjuvant chemotherapy (NACT) is the standard treatment for early triple-negative breast cancer (eTNBC); however, it is associated with substantial toxicity. We performed whole transcriptome profiling of baseline tumor biopsies to identify gene networks...
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2025-03-01
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| Online Access: | https://doi.org/10.1186/s12943-025-02275-0 |
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| author | Darren Korbie Clare Stirzaker Oleg Gluz Christine zu Eulenburg Ulrike Nitz Matthias Christgen Sherko Kuemmel Eva-Maria Grischke Helmut Forstbauer Michael Braun Mathias Warm John Hackmann Christoph Uleer Bahriye Aktas Claudia Schumacher Rachel Wuerstlein Enrico Pelz Hans Heinrich Kreipe Susan J. Clark Matt Trau Monika Graeser Nadia Harbeck |
| author_facet | Darren Korbie Clare Stirzaker Oleg Gluz Christine zu Eulenburg Ulrike Nitz Matthias Christgen Sherko Kuemmel Eva-Maria Grischke Helmut Forstbauer Michael Braun Mathias Warm John Hackmann Christoph Uleer Bahriye Aktas Claudia Schumacher Rachel Wuerstlein Enrico Pelz Hans Heinrich Kreipe Susan J. Clark Matt Trau Monika Graeser Nadia Harbeck |
| author_sort | Darren Korbie |
| collection | DOAJ |
| description | Abstract Background Anthracycline-containing neoadjuvant chemotherapy (NACT) is the standard treatment for early triple-negative breast cancer (eTNBC); however, it is associated with substantial toxicity. We performed whole transcriptome profiling of baseline tumor biopsies to identify gene networks predictive and prognostic for pathological complete response (pCR) and survival after de-escalated, anthracycline-free NACT in the WSG-ADAPT-TN trial (NCT01815242). Methods eTNBC patients (cT1c-cT4c, cN +) were randomized to 12 weeks of nab-paclitaxel + gemcitabine (n = 182) or nab-paclitaxel + carboplatin (n = 154). The primary endpoint was pCR (ypT0/is, ypN0), and the secondary endpoints included survival and translational research. AmpliSeq RNA sequencing, allowing simultaneous analysis of the expression of > 20,000 genes, was performed in 135 patients. Differentially expressed genes were evaluated in training (n = 67) and validation (n = 68) sets, and a polygenic score (PS) for prediction of pCR (PS:pCR) and a PS for prediction of invasive disease-free survival (PS:iDFS) were found. Results 49/135 (36.3%) patients had pCR; 30 iDFS events occurred during 60-month median follow-up. Immune recruitment and viral defense gene networks were strongly associated with pCR, while metabolic pathways were associated with survival. PS:pCR and PS:iDFS predominantly included immune-related genes. Diagnostic accuracy (ROC AUC) in the validation cohort was 83% for PS:pCR and 64% for PS:iDFS. At optimized cut-off, PS:pCR identified a group with a 67.7% pCR rate (vs. 10.8%; p < .0001), and PS:iDFS detected a group with 79.5% (95%CI 64.1%, 88.8%) 5-year iDFS rate (vs. 55.0%, 95%CI 29.8%, 74.5%; p = .04). Conclusion Polygenic scores incorporating immunoregulatory genes can predict pCR and survival and represent an opportunity to select patients for de-escalated, anthracycline-free NACT. This transcriptome network analysis also identifies potential new targets for personalized medicine approaches in patients without response to NACT. Trial registration NCT01815242. |
| format | Article |
| id | doaj-art-8467cfdfc8f242d5bbfb136fc51fe036 |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
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| series | Molecular Cancer |
| spelling | doaj-art-8467cfdfc8f242d5bbfb136fc51fe0362025-08-20T03:40:47ZengBMCMolecular Cancer1476-45982025-03-012411810.1186/s12943-025-02275-0Immunomodulatory gene networks predict treatment response and survival to de-escalated, anthracycline-free neoadjuvant chemotherapy in triple-negative breast cancer in the WSG-ADAPT-TN trialDarren Korbie0Clare Stirzaker1Oleg Gluz2Christine zu Eulenburg3Ulrike Nitz4Matthias Christgen5Sherko Kuemmel6Eva-Maria Grischke7Helmut Forstbauer8Michael Braun9Mathias Warm10John Hackmann11Christoph Uleer12Bahriye Aktas13Claudia Schumacher14Rachel Wuerstlein15Enrico Pelz16Hans Heinrich Kreipe17Susan J. Clark18Matt Trau19Monika Graeser20Nadia Harbeck21Centre for Personalised Nanomedicine, The University of QueenslandEpigenetics Research Laboratory, Garvan Institute of Medical ResearchWest German Study GroupWest German Study GroupWest German Study GroupInstitute of Pathology, Hannover Medical SchoolWest German Study GroupWomen’s Clinic, University Clinics TuebingenPractice Network TroisdorfBreast Center, Rotkreuz Clinics MunichBreast Center, City Hospital HolweideBreast Center, Marien-HospitalPractice of Gynecology and OncologyWomen’s Clinic, University Clinics EssenBreast Center, St. Elisabeth HospitalWest German Study GroupInstitute for PathologyInstitute of Pathology, Hannover Medical SchoolEpigenetics Research Laboratory, Garvan Institute of Medical ResearchCentre for Personalised Nanomedicine, The University of QueenslandWest German Study GroupWest German Study GroupAbstract Background Anthracycline-containing neoadjuvant chemotherapy (NACT) is the standard treatment for early triple-negative breast cancer (eTNBC); however, it is associated with substantial toxicity. We performed whole transcriptome profiling of baseline tumor biopsies to identify gene networks predictive and prognostic for pathological complete response (pCR) and survival after de-escalated, anthracycline-free NACT in the WSG-ADAPT-TN trial (NCT01815242). Methods eTNBC patients (cT1c-cT4c, cN +) were randomized to 12 weeks of nab-paclitaxel + gemcitabine (n = 182) or nab-paclitaxel + carboplatin (n = 154). The primary endpoint was pCR (ypT0/is, ypN0), and the secondary endpoints included survival and translational research. AmpliSeq RNA sequencing, allowing simultaneous analysis of the expression of > 20,000 genes, was performed in 135 patients. Differentially expressed genes were evaluated in training (n = 67) and validation (n = 68) sets, and a polygenic score (PS) for prediction of pCR (PS:pCR) and a PS for prediction of invasive disease-free survival (PS:iDFS) were found. Results 49/135 (36.3%) patients had pCR; 30 iDFS events occurred during 60-month median follow-up. Immune recruitment and viral defense gene networks were strongly associated with pCR, while metabolic pathways were associated with survival. PS:pCR and PS:iDFS predominantly included immune-related genes. Diagnostic accuracy (ROC AUC) in the validation cohort was 83% for PS:pCR and 64% for PS:iDFS. At optimized cut-off, PS:pCR identified a group with a 67.7% pCR rate (vs. 10.8%; p < .0001), and PS:iDFS detected a group with 79.5% (95%CI 64.1%, 88.8%) 5-year iDFS rate (vs. 55.0%, 95%CI 29.8%, 74.5%; p = .04). Conclusion Polygenic scores incorporating immunoregulatory genes can predict pCR and survival and represent an opportunity to select patients for de-escalated, anthracycline-free NACT. This transcriptome network analysis also identifies potential new targets for personalized medicine approaches in patients without response to NACT. Trial registration NCT01815242.https://doi.org/10.1186/s12943-025-02275-0Neoadjuvant therapyTriple negative breast neoplasmsTranslational researchBiomedicalGene regulatory networksGene expression profiling |
| spellingShingle | Darren Korbie Clare Stirzaker Oleg Gluz Christine zu Eulenburg Ulrike Nitz Matthias Christgen Sherko Kuemmel Eva-Maria Grischke Helmut Forstbauer Michael Braun Mathias Warm John Hackmann Christoph Uleer Bahriye Aktas Claudia Schumacher Rachel Wuerstlein Enrico Pelz Hans Heinrich Kreipe Susan J. Clark Matt Trau Monika Graeser Nadia Harbeck Immunomodulatory gene networks predict treatment response and survival to de-escalated, anthracycline-free neoadjuvant chemotherapy in triple-negative breast cancer in the WSG-ADAPT-TN trial Molecular Cancer Neoadjuvant therapy Triple negative breast neoplasms Translational research Biomedical Gene regulatory networks Gene expression profiling |
| title | Immunomodulatory gene networks predict treatment response and survival to de-escalated, anthracycline-free neoadjuvant chemotherapy in triple-negative breast cancer in the WSG-ADAPT-TN trial |
| title_full | Immunomodulatory gene networks predict treatment response and survival to de-escalated, anthracycline-free neoadjuvant chemotherapy in triple-negative breast cancer in the WSG-ADAPT-TN trial |
| title_fullStr | Immunomodulatory gene networks predict treatment response and survival to de-escalated, anthracycline-free neoadjuvant chemotherapy in triple-negative breast cancer in the WSG-ADAPT-TN trial |
| title_full_unstemmed | Immunomodulatory gene networks predict treatment response and survival to de-escalated, anthracycline-free neoadjuvant chemotherapy in triple-negative breast cancer in the WSG-ADAPT-TN trial |
| title_short | Immunomodulatory gene networks predict treatment response and survival to de-escalated, anthracycline-free neoadjuvant chemotherapy in triple-negative breast cancer in the WSG-ADAPT-TN trial |
| title_sort | immunomodulatory gene networks predict treatment response and survival to de escalated anthracycline free neoadjuvant chemotherapy in triple negative breast cancer in the wsg adapt tn trial |
| topic | Neoadjuvant therapy Triple negative breast neoplasms Translational research Biomedical Gene regulatory networks Gene expression profiling |
| url | https://doi.org/10.1186/s12943-025-02275-0 |
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