Dynamic monitoring of antibody drug conjugates targeting TROP2 or HER2 in breast cancer using circulating tumor cells

• 成果类型: Article
• 署名作者: Mishra, Avanish; Abelman, Rachel O.; Cunneely, Quinn; Putaturo, Victor; Deshpande, Akansha A.; Bell, Remy; Seider, Elizabeth M.; Xu, Katherine H.; Shan, Mythreayi; Kelly, Justin; Huang, Shih-Bo; Rieur, Olivia; Knape, Justine; Gopinathan, Kaustav A.; Kikkeri, Kruthika; Edd, Jon F.; Walsh, John; Dai, Charles S.; Ellisen, Leif W.; Ting, David T.; Nieman, Linda; Toner, Mehmet; Bardia, Aditya; Haber, Daniel A.; Maheswaran, Shyamala
• 署名单位: University of California System; UCLA Jonsson Comprehensive Cancer Center; University of California Los Angeles; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2601563123
• 发表日期: 2026-06-23
• 页码: e2601563123
• 关键词: antibody-drug-conjugate; breast cancer; circulating tumor cells; TROP2; HER2; SACITUZUMAB GOVITECAN SG; PHYSICIANS CHOICE TPC; DERUXTECAN T-DXD; phase-iii; 1ST-LINE 1L; blood; expression; trastuzumab; antigen; ADCS

摘要

Antibody-drug conjugates (ADCs) target surface proteins on cancer cells, leading to internalization and delivery of a drug payload, thereby enhancing selectivity and minimizing toxicity. ADCs against TROP2 (Sacituzumab govitecan) or HER2 (T-DXd) have demonstrated efficacy in metastatic breast cancer, yet paradoxically, outside of HER2-amplified breast cancers, expression levels of these breast cancer-enriched epitopes in tumor biopsies have not been strongly correlated with clinical response. We undertook serial quantitative imaging of circulating tumor cells (CTCs) in a prospective cohort of 35 patients treated with either of these ADCs. At the single-cell level, expression of TROP2 and HER2 within individual patients is highly heterogeneous in both CTCs and paired tumor biopsies. Measurement of these epitopes on CTCs immediately prior to ADC therapy does not predict depth of clinical response. However, absence of CTCs or >80% reduction in CTC numbers after three weeks of treatment (CTCLow) predicts durable response, compared with CTCHigh cases (TROP2: HR 5.15, P = 0.012; HER2: HR 6.01, P < 0.001). Targeted epitopes are not commonly downregulated on CTCs at the time of acquired clinical resistance, and switching between TROP2- and HER2-targeting ADCs sharing similar payloads infrequently leads to second-line response. Thus, while CTC burden is correlated with response to these ADCs, the level of TROP2 or HER2 expression is poorly predictive. These findings point to sensitivity to the drug payload as a potential driver of clinical response to currently approved ADCs in breast cancer.