{
  "abstract": "Background\n\nCDK4/6 inhibitors have reshaped treatment for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer, but resistance frequently emerges and may interact with metastatic phenotypic evolution. We developed an integrated resistance-discordance framework and explored its clinical interpretability in invasive ductal carcinoma (IDC) with gastric metastasis.Methods\n\nPublic MSK-INK4 (cBioPortal study ID: breast_ink4_msk_2021) and MBCproject (brca_mbcproject_wagle_2017) cohorts were curated for HR+/HER2-negative disease. A five-module CDK4/6 inhibitor resistance score (0-5) was constructed from predefined mutation and copy-number events. In MBCproject RNA-seq samples, single-sample gene-set enrichment analysis quantified proliferation and estrogen-response activity. Discordance burden was defined as z(proliferation score) minus z(ER score), using primary tumors as the reference. Three institutional IDC gastric-metastasis cases were projected onto the framework for interpretability but not inferential testing.Results\n\nSeventy HR+/HER2-negative MBCproject samples and 1116 deduplicated MSK-INK4 metastatic samples were analyzed. MBCproject metastases had higher resistance scores than primary tumors (P = 0.001), whereas metastatic scores were similar between MBCproject and MSK-INK4 (P = 0.202). Metastases showed higher proliferation activity (P = 0.014) and a trend toward lower ER activity (P = 0.071). The high-resistance/high-discordance quadrant was enriched for PI3K-axis events (OR = 16.52; P = 0.034), chromatin-remodeling loss-of-function events (OR = 12.47; P = 0.001), and cell-cycle/RB-axis events (OR = 9.03; P = 0.001). Among the three IDC gastric-metastasis cases, two available gastric NGS profiles mapped to predefined resistance modules, and the case with increased gastric Ki-67 showed the strongest IHC-adapted discordance and projected toward the high-resistance/high-discordance phenotype.Conclusion\n\nCoupling resistance-associated genomic events with metastatic phenotype discordance may provide a clinically interpretable lens for HR+/HER2-negative metastatic breast cancer and for rare IDC gastric-metastasis presentations.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.",
    "School of Medicine, South China University of Technology, Guangzhou, China.",
    "Department of Breast Oncology, Jieyang People's Hospital, Jieyang, China.",
    "Guangdong Provincial People's Hospital Clinical Medical College, Southern Medical University, Guangzhou, China.",
    "Department of Rehabilitation Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Minyi Cheng"
    },
    {
      "affs": [
        0
      ],
      "name": "Dongqing Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yingyi Lin"
    },
    {
      "affs": [
        2
      ],
      "name": "Cangui Wu"
    },
    {
      "affs": [
        3
      ],
      "name": "Ruobing Hong"
    },
    {
      "affs": [
        4
      ],
      "name": "Juanjuan Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jieqing Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9n0ngjnpx3504.bib",
  "cited_by": 0,
  "doi": "10.3389/fonc.2026.1918231",
  "fulltext_url": "https://europepmc.org/articles/PMC13680221",
  "id": "9n0ngjnpx3504",
  "issns": [
    "2234-943X"
  ],
  "landing_url": "https://europepmc.org/article/MED/42903090",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2740|Advanced Breast Cancer Therapies"
    ]
  ],
  "openalex": "W7220695913",
  "pdf_url": "https://europepmc.org/articles/PMC13680221?pdf=render",
  "pmcid": "PMC13680221",
  "pmid": "42903090",
  "published": "2026-10-06",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/9n0ngjnpx3504.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:57Z",
      "native_id": "MED:42903090",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42903090"
    },
    {
      "first_seen": "2026-10-30T12:20:13Z",
      "native_id": "10.3389/fonc.2026.1918231",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fonc.2026.1918231/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:2234-943X",
      "subfield": "oncology"
    }
  ],
  "title": "Integrated CDK4/6 inhibitor resistance and primary-metastatic discordance in hormone receptor-positive/HER2-negative metastatic breast cancer: a translational framework focused on invasive ductal carcinoma with gastric metastasis.",
  "title_text": "Integrated CDK4/6 inhibitor resistance and primary-metastatic discordance in hormone receptor-positive/HER2-negative metastatic breast cancer: a translational framework focused on invasive ductal carcinoma with gastric metastasis.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:13Z",
  "url": "https://research.draconitic.com/paper/9n0ngjnpx3504",
  "venue": "Frontiers in oncology",
  "versions": []
}