Dynamic monitoring of antibody drug conjugates targeting TROP2 or HER2 in breast cancer using circulating tumor cells
5 affiliations
- 1Center for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School
- 2Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
- 3Division of Hematology Oncology, Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School
- 4Howard Hughes Medical Institute
- 5Shriners Children’s Hospital
Abstract
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 (CTC Low ) predicts durable response, compared with CTC High 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. SIGNIFICANCE STATEMENT The clinical efficacy of ADCs may depend both on differential targeting of cancer cells, using antibodies to tumor-enriched epitopes, and on the cleavage and release of drug payloads to which cancer cells are sensitive. ADCs currently used to treat breast cancer target either of two epitopes, TROP2 or HER2, but they share chemically related payloads. While CTC numbers track with response, we find that epitope expression is not strongly predictive. The limited success of sequentially switching between TROP2- or HER2-targeting ADCs as second-line treatment, following progression on a first-line ADC, highlights the need to incorporate non-cross-resistant drug payloads on ADCs to overcome such acquired resistance.
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BibTeX
@article{mishra2026dynamic,
title = {{Dynamic monitoring of antibody drug conjugates targeting TROP2 or HER2 in breast cancer using circulating tumor cells}},
author = {Avanish Mishra and Rachel O. Abelman and Quinn E. Cunneely and Victor R. Putaturo and Akansha Deshpande and Remy Bell and Elizabeth M. Seider and Katherine H. Xu and Mythreayi Shan and J. Kelly and Shih‐Bo Huang and Olivia Rieur and Justine Knape and Kaustav A. Gopinathan and Kruthika Kikkeri and Jon F. and John Walsh and Charles S. Dai and Leif William Ellisen and David Tsai Ting and Linda T. Nieman and Mehmet Toner and Aditya Bardia and Daniel A. Haber and Shyamala Maheswaran},
journal = {Proceedings of the National Academy of Sciences},
year = {2026},
month = jun,
doi = {10.1073/pnas.2601563123},
url = {https://doi.org/10.1073/pnas.2601563123},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dynamic monitoring of antibody drug conjugates targeting TROP2 or HER2 in breast cancer using circulating tumor cells
AU - Avanish Mishra
AU - Rachel O. Abelman
AU - Quinn E. Cunneely
AU - Victor R. Putaturo
AU - Akansha Deshpande
AU - Remy Bell
AU - Elizabeth M. Seider
AU - Katherine H. Xu
AU - Mythreayi Shan
AU - J. Kelly
AU - Shih‐Bo Huang
AU - Olivia Rieur
AU - Justine Knape
AU - Kaustav A. Gopinathan
AU - Kruthika Kikkeri
AU - Jon F.
AU - John Walsh
AU - Charles S. Dai
AU - Leif William Ellisen
AU - David Tsai Ting
AU - Linda T. Nieman
AU - Mehmet Toner
AU - Aditya Bardia
AU - Daniel A. Haber
AU - Shyamala Maheswaran
PY - 2026
DA - 2026/06/17
JO - Proceedings of the National Academy of Sciences
DO - 10.1073/pnas.2601563123
UR - https://doi.org/10.1073/pnas.2601563123
AB - 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 (CTC Low ) predicts durable response, compared with CTC High 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. SIGNIFICANCE STATEMENT The clinical efficacy of ADCs may depend both on differential targeting of cancer cells, using antibodies to tumor-enriched epitopes, and on the cleavage and release of drug payloads to which cancer cells are sensitive. ADCs currently used to treat breast cancer target either of two epitopes, TROP2 or HER2, but they share chemically related payloads. While CTC numbers track with response, we find that epitope expression is not strongly predictive. The limited success of sequentially switching between TROP2- or HER2-targeting ADCs as second-line treatment, following progression on a first-line ADC, highlights the need to incorporate non-cross-resistant drug payloads on ADCs to overcome such acquired resistance.
SN - 0027-8424
SN - 1091-6490
ER -