Unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic, transcriptomic, and circulating tumor DNA analysis
Abstract Introduction Neoadjuvant chemotherapy (NAC) is a standard treatment for breast cancer (BC) to shrink tumors and facilitate surgery. However, the molecular underpinnings of response to NAC and prognosis have not been well characterized. Methods We enrolled 73 stage II/III BC patients who rec...
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| Language: | English |
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BMC
2025-05-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-025-02026-5 |
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| author | Menghao Dong Jian Chen Nannan Lu Song Wang Wenhui Wei Ziming Wang Jinnan Wang Jinguo Zhang Xinghua Han Fufeng Wang Qiuxiang Ou Hua Bao Xiaopeng Ma Benjie Shan Yueyin Pan |
| author_facet | Menghao Dong Jian Chen Nannan Lu Song Wang Wenhui Wei Ziming Wang Jinnan Wang Jinguo Zhang Xinghua Han Fufeng Wang Qiuxiang Ou Hua Bao Xiaopeng Ma Benjie Shan Yueyin Pan |
| author_sort | Menghao Dong |
| collection | DOAJ |
| description | Abstract Introduction Neoadjuvant chemotherapy (NAC) is a standard treatment for breast cancer (BC) to shrink tumors and facilitate surgery. However, the molecular underpinnings of response to NAC and prognosis have not been well characterized. Methods We enrolled 73 stage II/III BC patients who received NAC followed by surgery. Tumor tissue samples were available from 36 patients at baseline and 38 at the time of surgery. Plasma circulating tumor DNA (ctDNA) was collected at three time points: before NAC (n = 63), during NAC (n = 42), and after NAC (n = 40). Comprehensive genomic, transcriptomic, and ctDNA analyses were performed to identify biomarkers associated with pathological complete response (pCR) and survival outcomes. Results Nine baseline mutations, including DNHD1 and PLEC, along with HIPPO pathway alterations, were associated with pCR. Responsive tumors exhibited immune activation and downregulated PI3K-Akt and AGE-RAGE pathways, while non-pCR tumors showed reduced cytokine and immune receptor activity. Undetectable ctDNA during and after NAC was predictive of treatment efficacy and correlated with improved survival. Baseline mutations in USH2A were associated with shorter disease-free survival (hazard ratio: 11.9; 95% confidence interval: 2.8–50.8; P < 0.001), with a consistent trend observed for overall survival. Elevated NHSL1 expression in baseline tumors indicated an initial treatment response but was later associated with tumor relapse and poor overall survival (P = 0.026 and P = 0.023, respectively), findings that were validated in an independent clinical cohort (N = 30) through immunohistochemistry staining. Conclusion Our comprehensive multi-omics analysis identified promising biomarkers predictive of treatment response and survival in BC patients receiving NAC followed by surgery. These findings underscore the importance of early tumor assessment for improved patient stratification and prognostication. |
| format | Article |
| id | doaj-art-35d05ff3953645a8a04d0867ea77146c |
| institution | DOAJ |
| issn | 1465-542X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj-art-35d05ff3953645a8a04d0867ea77146c2025-08-20T02:55:32ZengBMCBreast Cancer Research1465-542X2025-05-0127111610.1186/s13058-025-02026-5Unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic, transcriptomic, and circulating tumor DNA analysisMenghao Dong0Jian Chen1Nannan Lu2Song Wang3Wenhui Wei4Ziming Wang5Jinnan Wang6Jinguo Zhang7Xinghua Han8Fufeng Wang9Qiuxiang Ou10Hua Bao11Xiaopeng Ma12Benjie Shan13Yueyin Pan14Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaDepartment of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaDepartment of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaNanjing Geneseeq Technology Inc.Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaDepartment of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaDepartment of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaDepartment of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaDepartment of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaNanjing Geneseeq Technology Inc.Nanjing Geneseeq Technology Inc.Nanjing Geneseeq Technology Inc.Department of Breast Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaDepartment of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaDepartment of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of ChinaAbstract Introduction Neoadjuvant chemotherapy (NAC) is a standard treatment for breast cancer (BC) to shrink tumors and facilitate surgery. However, the molecular underpinnings of response to NAC and prognosis have not been well characterized. Methods We enrolled 73 stage II/III BC patients who received NAC followed by surgery. Tumor tissue samples were available from 36 patients at baseline and 38 at the time of surgery. Plasma circulating tumor DNA (ctDNA) was collected at three time points: before NAC (n = 63), during NAC (n = 42), and after NAC (n = 40). Comprehensive genomic, transcriptomic, and ctDNA analyses were performed to identify biomarkers associated with pathological complete response (pCR) and survival outcomes. Results Nine baseline mutations, including DNHD1 and PLEC, along with HIPPO pathway alterations, were associated with pCR. Responsive tumors exhibited immune activation and downregulated PI3K-Akt and AGE-RAGE pathways, while non-pCR tumors showed reduced cytokine and immune receptor activity. Undetectable ctDNA during and after NAC was predictive of treatment efficacy and correlated with improved survival. Baseline mutations in USH2A were associated with shorter disease-free survival (hazard ratio: 11.9; 95% confidence interval: 2.8–50.8; P < 0.001), with a consistent trend observed for overall survival. Elevated NHSL1 expression in baseline tumors indicated an initial treatment response but was later associated with tumor relapse and poor overall survival (P = 0.026 and P = 0.023, respectively), findings that were validated in an independent clinical cohort (N = 30) through immunohistochemistry staining. Conclusion Our comprehensive multi-omics analysis identified promising biomarkers predictive of treatment response and survival in BC patients receiving NAC followed by surgery. These findings underscore the importance of early tumor assessment for improved patient stratification and prognostication.https://doi.org/10.1186/s13058-025-02026-5Pathological complete responseNeoadjuvant chemotherapyBreast cancerMolecular biomarkers |
| spellingShingle | Menghao Dong Jian Chen Nannan Lu Song Wang Wenhui Wei Ziming Wang Jinnan Wang Jinguo Zhang Xinghua Han Fufeng Wang Qiuxiang Ou Hua Bao Xiaopeng Ma Benjie Shan Yueyin Pan Unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic, transcriptomic, and circulating tumor DNA analysis Breast Cancer Research Pathological complete response Neoadjuvant chemotherapy Breast cancer Molecular biomarkers |
| title | Unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic, transcriptomic, and circulating tumor DNA analysis |
| title_full | Unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic, transcriptomic, and circulating tumor DNA analysis |
| title_fullStr | Unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic, transcriptomic, and circulating tumor DNA analysis |
| title_full_unstemmed | Unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic, transcriptomic, and circulating tumor DNA analysis |
| title_short | Unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic, transcriptomic, and circulating tumor DNA analysis |
| title_sort | unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic transcriptomic and circulating tumor dna analysis |
| topic | Pathological complete response Neoadjuvant chemotherapy Breast cancer Molecular biomarkers |
| url | https://doi.org/10.1186/s13058-025-02026-5 |
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