Impacts of genomic alterations on the efficacy of HER2-targeted antibody–drug conjugates in patients with metastatic breast cancer
Abstract Background HER2-targeted antibody–drug conjugates (ADCs) have revolutionized the treatment landscape of metastatic breast cancer. However, the efficacy of these therapies may be compromised by genomic alterations. Hence, this study aims to identify factors predicting sensitivity to HER2 ADC...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-025-06082-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594458404716544 |
|---|---|
| author | Riqing Huang Anqi Hu Qixiang Rong Ditian Shu Meiting Chen Wei Yang Yue Zhang Qiufan Zheng Xin An Cong Xue Haifeng Li Yanxia Shi |
| author_facet | Riqing Huang Anqi Hu Qixiang Rong Ditian Shu Meiting Chen Wei Yang Yue Zhang Qiufan Zheng Xin An Cong Xue Haifeng Li Yanxia Shi |
| author_sort | Riqing Huang |
| collection | DOAJ |
| description | Abstract Background HER2-targeted antibody–drug conjugates (ADCs) have revolutionized the treatment landscape of metastatic breast cancer. However, the efficacy of these therapies may be compromised by genomic alterations. Hence, this study aims to identify factors predicting sensitivity to HER2 ADC in metastatic breast cancer. Methods This comprehensive real-world retrospective study collected clinical data from patients diagnosed with metastatic breast cancer and performed genomic profiling using targeted next-generation sequencing. The study analyzed the associations between genomic alterations and clinical outcomes of HER2 ADC treatment. Results Sixty-three patients were included in this study, 33 with HER2-low breast cancer and 30 with HER2-positive breast cancer, respectively. The most frequently altered genes were TP53 (69%), PIK3CA (45%), MYC (35%), and ERBB2 (35%). Patients with amplifications in cell cycle-related genes showed inferior median progression-free survival (PFS) than those without amplifications (2.07 months vs. 8.40 months; HR = 5.24; 95% CI 2.11–13.01; p < 0.001), particularly in HER2-low patients (2.07 months vs. 8.27 months; HR = 4.23; 95% CI 1.50–11.91; p = 0.004). Additionally, ERBB2/CDK12 co-amplification exhibited a superior median PFS in all patients (19.33 months vs. 5.43 months; HR = 0.13; 95% CI 0.04–0.45; p < 0.001) and in HER2-positive patients (19.33 months vs. 6.87 months; HR = 0.18; 95% CI 0.05–0.72; p = 0.007). Multivariate analysis indicated that amplification in cell cycle-related genes was an independent predictor of inferior PFS (HR = 4.46; 95% CI 1.08–18.40; p = 0.039), while the presence of ERBB2/CDK12 co-amplification was independently correlated with superior PFS (HR = 0.16; 95% CI 0.04–0.65; p = 0.010). Conclusions Amplification in cell cycle genes may contribute to primary resistance of HER2 ADC in HER2-low breast cancer. ERBB2/CDK12 co-amplification may be a potential biomarker for favorable responses in HER2-positive breast cancer. |
| format | Article |
| id | doaj-art-104492bed55d438e93a5b637f875e33e |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-104492bed55d438e93a5b637f875e33e2025-01-19T12:37:20ZengBMCJournal of Translational Medicine1479-58762025-01-0123111110.1186/s12967-025-06082-5Impacts of genomic alterations on the efficacy of HER2-targeted antibody–drug conjugates in patients with metastatic breast cancerRiqing Huang0Anqi Hu1Qixiang Rong2Ditian Shu3Meiting Chen4Wei Yang5Yue Zhang6Qiufan Zheng7Xin An8Cong Xue9Haifeng Li10Yanxia Shi11State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterAbstract Background HER2-targeted antibody–drug conjugates (ADCs) have revolutionized the treatment landscape of metastatic breast cancer. However, the efficacy of these therapies may be compromised by genomic alterations. Hence, this study aims to identify factors predicting sensitivity to HER2 ADC in metastatic breast cancer. Methods This comprehensive real-world retrospective study collected clinical data from patients diagnosed with metastatic breast cancer and performed genomic profiling using targeted next-generation sequencing. The study analyzed the associations between genomic alterations and clinical outcomes of HER2 ADC treatment. Results Sixty-three patients were included in this study, 33 with HER2-low breast cancer and 30 with HER2-positive breast cancer, respectively. The most frequently altered genes were TP53 (69%), PIK3CA (45%), MYC (35%), and ERBB2 (35%). Patients with amplifications in cell cycle-related genes showed inferior median progression-free survival (PFS) than those without amplifications (2.07 months vs. 8.40 months; HR = 5.24; 95% CI 2.11–13.01; p < 0.001), particularly in HER2-low patients (2.07 months vs. 8.27 months; HR = 4.23; 95% CI 1.50–11.91; p = 0.004). Additionally, ERBB2/CDK12 co-amplification exhibited a superior median PFS in all patients (19.33 months vs. 5.43 months; HR = 0.13; 95% CI 0.04–0.45; p < 0.001) and in HER2-positive patients (19.33 months vs. 6.87 months; HR = 0.18; 95% CI 0.05–0.72; p = 0.007). Multivariate analysis indicated that amplification in cell cycle-related genes was an independent predictor of inferior PFS (HR = 4.46; 95% CI 1.08–18.40; p = 0.039), while the presence of ERBB2/CDK12 co-amplification was independently correlated with superior PFS (HR = 0.16; 95% CI 0.04–0.65; p = 0.010). Conclusions Amplification in cell cycle genes may contribute to primary resistance of HER2 ADC in HER2-low breast cancer. ERBB2/CDK12 co-amplification may be a potential biomarker for favorable responses in HER2-positive breast cancer.https://doi.org/10.1186/s12967-025-06082-5Breast cancerAntibody–drug conjugateCell cycleCDK12 |
| spellingShingle | Riqing Huang Anqi Hu Qixiang Rong Ditian Shu Meiting Chen Wei Yang Yue Zhang Qiufan Zheng Xin An Cong Xue Haifeng Li Yanxia Shi Impacts of genomic alterations on the efficacy of HER2-targeted antibody–drug conjugates in patients with metastatic breast cancer Journal of Translational Medicine Breast cancer Antibody–drug conjugate Cell cycle CDK12 |
| title | Impacts of genomic alterations on the efficacy of HER2-targeted antibody–drug conjugates in patients with metastatic breast cancer |
| title_full | Impacts of genomic alterations on the efficacy of HER2-targeted antibody–drug conjugates in patients with metastatic breast cancer |
| title_fullStr | Impacts of genomic alterations on the efficacy of HER2-targeted antibody–drug conjugates in patients with metastatic breast cancer |
| title_full_unstemmed | Impacts of genomic alterations on the efficacy of HER2-targeted antibody–drug conjugates in patients with metastatic breast cancer |
| title_short | Impacts of genomic alterations on the efficacy of HER2-targeted antibody–drug conjugates in patients with metastatic breast cancer |
| title_sort | impacts of genomic alterations on the efficacy of her2 targeted antibody drug conjugates in patients with metastatic breast cancer |
| topic | Breast cancer Antibody–drug conjugate Cell cycle CDK12 |
| url | https://doi.org/10.1186/s12967-025-06082-5 |
| work_keys_str_mv | AT riqinghuang impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT anqihu impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT qixiangrong impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT ditianshu impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT meitingchen impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT weiyang impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT yuezhang impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT qiufanzheng impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT xinan impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT congxue impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT haifengli impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer AT yanxiashi impactsofgenomicalterationsontheefficacyofher2targetedantibodydrugconjugatesinpatientswithmetastaticbreastcancer |