ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025
TOP1 Mutations and Cross-Resistance to Antibody-Drug Conjugates in Patients with Metastatic Breast Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 2 of them syntheses that pooled it.
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Who cites it
33 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Efficacy and safety of antibody-drug conjugates in HER2-positive and HER2-low advanced gastric cancer: a systematic review and update.Journal of the Egyptian National Cancer Institute · 2026Pooled it
- Datopotamab deruxtecan in breast cancer treatment: a systematic review of clinical efficacy and safety.Frontiers in immunology · 2026Pooled it
- A modular framework for antibody-drug conjugate biomarkers.Nature reviews. Clinical oncology · 2026Review
- Antibody-drug conjugates in breast cancer: redefining targeted therapy.The Journal of clinical investigation · 2026Review
- Real-world outcomes of datopotamab deruxtecan after trastuzumab deruxtecan in hormone receptor-positive, HER2-negative metastatic breast cancer.Breast cancer (Tokyo, Japan) · 2026Article
- Review
- The next generation of antibody-drug conjugates.Nature medicine · 2026Review
- Advancing antibody drug conjugates in gastrointestinal cancers.British journal of cancer · 2026Review
- Antibody drug conjugates in gynaecological cancers: navigating between opportunities and challenges.EClinicalMedicine · 2026Review
- Review
- Dynamic monitoring of antibody drug conjugates targeting TROP2 or HER2 in breast cancer using circulating tumor cells.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Antibody-drug conjugates in breast cancer: Progress and future directions.Cell reports. Medicine · 2026Review
- From biology to the clinic: research evidence and therapeutic advances of TROP2-targeted antibody-drug conjugates in small cell lung cancer.Translational lung cancer research · 2026Review
- Beyond CDK4/6 Inhibition: Current Strategies in Hormone Receptor-Positive Metastatic Breast Cancer.Current treatment options in oncology · 2026Review
- Topoisomerase I inhibitor antibody-drug conjugates in breast cancer: the relevance of the DNA damage response to resistance, response, and combination treatment strategies.Breast cancer research and treatment · 2026Review
- Payload Diversification Overcomes Resistance and Guides Sequential Antibody-Drug Conjugate Therapy in Breast Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Antibody-Drug Conjugates: Pharmacotherapeutic Properties and Future Perspectives.Pharmaceutics · 2026Review
- Drug resistance to antibody-drug conjugates: mechanisms, challenges, and perspectives.Cancer biology & medicine · 2026Review
- Therapeutic Strategies to Overcome Payload Resistance of Trastuzumab Deruxtecan in HER2-Positive Cancers.Cancer science · 2026Article
- B7-H4: a multifaceted immune checkpoint and oncoprotein in cancer biology and immunotherapy.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
21 authors.
Funding
Abstract
purposeAntibody-drug conjugates (ADC) harboring topoisomerase I (TOP1) inhibitor payloads have improved survival for patients with metastatic breast cancer. However, knowledge of ADC resistance mechanisms and potential impact on the sequential use of ADCs is limited. In this study, we report the incidence and characterization of TOP1 mutations arising in the setting of ADC resistance in metastatic breast cancer. EXPERIMENTAL
designPatients with metastatic breast cancer treated with ADCs with available posttreatment plasma-based genotyping were included. TOP1 mutation incidence, mutant allele frequency, and functional characterization were assessed, and incidence was compared with that in patients with metastatic breast cancer not receiving ADC treatment and in The Cancer Genome Atlas.
resultsPlasma-based genotyping identified distinct TOP1 mutations (S57C, R364H, W401C, and G359E) in 12.9% of patients (4/31) at the time of disease progression on ADC, compared with 0.7% (3/420) in non-ADC-treated patients with metastatic breast cancer and 0.5% in The Cancer Genome Atlas. The appearance of mutations was associated with clinical cross-resistance, as median duration on the first ADC was 455 versus 52 days for the second ADC. The functional characterization of three novel TOP1-mutant proteins demonstrated that all exhibited reduced enzymatic activity, attenuated covalent DNA binding, and resistance to TOP1 inhibitor ADC payloads SN38 and deruxtecan.
conclusionsWe describe the recurrent emergence of functionally altered, resistance-associated TOP1 mutations in vivo under selective pressure from ADCs and the potential impact on mediating cross-resistance to sequential ADCs. TOP1 mutation may represent a biomarker of resistance in this setting, and additional work is needed to optimize biomarkers and ADC payload design to improve outcomes for the sequential use of ADCs. See related commentary by Gwin and Hurvitz, p. 1824.
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Registered trials
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