{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Center for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School",
    "Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School",
    "Division of Hematology Oncology, Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School",
    "Howard Hughes Medical Institute",
    "Shriners Children’s Hospital"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 25,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Avanish Mishra"
    },
    {
      "affs": [
        2
      ],
      "name": "Rachel O. Abelman",
      "orcid": "0000-0002-3946-7420"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Quinn E. Cunneely",
      "orcid": "0000-0002-9086-8908"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Victor R. Putaturo",
      "orcid": "0009-0005-7434-787X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Akansha Deshpande"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Remy Bell",
      "orcid": "0000-0002-4737-6553"
    },
    {
      "affs": [
        1
      ],
      "name": "Elizabeth M. Seider"
    },
    {
      "affs": [
        1
      ],
      "name": "Katherine H. Xu"
    },
    {
      "affs": [
        1
      ],
      "name": "Mythreayi Shan"
    },
    {
      "affs": [
        1
      ],
      "name": "J. Kelly"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Shih‐Bo Huang",
      "orcid": "0000-0002-1048-2344"
    },
    {
      "affs": [
        2
      ],
      "name": "Olivia Rieur"
    },
    {
      "affs": [
        2
      ],
      "name": "Justine Knape"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kaustav A. Gopinathan",
      "orcid": "0000-0002-4082-1052"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kruthika Kikkeri",
      "orcid": "0000-0002-6180-2870"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jon F.",
      "orcid": "0000-0002-2195-2938"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "John Walsh"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Charles S. Dai"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Leif William Ellisen",
      "orcid": "0000-0003-0444-7910"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "David Tsai Ting",
      "orcid": "0000-0002-3261-2322"
    },
    {
      "affs": [
        1
      ],
      "name": "Linda T. Nieman",
      "orcid": "0000-0002-0141-8308"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Mehmet Toner",
      "orcid": "0000-0002-3647-3665"
    },
    {
      "affs": [
        2
      ],
      "name": "Aditya Bardia",
      "orcid": "0000-0003-4885-1157"
    },
    {
      "affs": [
        2,
        3,
        1
      ],
      "name": "Daniel A. Haber",
      "orcid": "0000-0003-1378-6551"
    },
    {
      "affs": [
        1
      ],
      "name": "Shyamala Maheswaran",
      "orcid": "0000-0002-9356-1709"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/73ty4nn99d3hf.bib",
  "cited_by": 9,
  "doi": "10.1073/pnas.2601563123",
  "fulltext_url": null,
  "id": "73ty4nn99d3hf",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://doi.org/10.1073/pnas.2601563123",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1306|Cancer Genomics and Diagnostics"
    ]
  ],
  "openalex": "W7165042248",
  "pdf_url": "https://www.pnas.org/doi/pdf/10.1073/pnas.2601563123",
  "pmcid": "PMC11996558",
  "pmid": "40235972",
  "published": "2026-06-17",
  "publisher": "National Academy of Sciences",
  "ris": "https://research.draconitic.com/paper/73ty4nn99d3hf.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:46Z",
      "native_id": "W7165042248",
      "source": "openalex",
      "url": "https://doi.org/10.1073/pnas.2601563123"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Cancer Genomics and Diagnostics",
      "subfield": "oncology"
    }
  ],
  "title": "Dynamic monitoring of antibody drug conjugates targeting TROP2 or HER2 in breast cancer using circulating tumor cells",
  "title_text": "Dynamic monitoring of antibody drug conjugates targeting TROP2 or HER2 in breast cancer using circulating tumor cells",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T13:20:47Z",
  "url": "https://research.draconitic.com/paper/73ty4nn99d3hf",
  "venue": "Proceedings of the National Academy of Sciences",
  "versions": []
}