{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:54:49Z","timestamp":1791262489138,"version":"4.1.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>CDK4\/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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Public 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Seventy HR+\/HER2-negative MBCproject samples and 1116 deduplicated MSK-INK4 metastatic samples were analyzed. MBCproject metastases had higher resistance scores than primary tumors (P\u00a0=\u00a00.001), whereas metastatic scores were similar between MBCproject and MSK-INK4 (P\u00a0=\u00a00.202). Metastases showed higher proliferation activity (P\u00a0=\u00a00.014) and a trend toward lower ER activity (P\u00a0=\u00a00.071). The high-resistance\/high-discordance quadrant was enriched for PI3K-axis events (OR\u00a0=\u00a016.52; P\u00a0=\u00a00.034), chromatin-remodeling loss-of-function events (OR\u00a0=\u00a012.47; P\u00a0=\u00a00.001), and cell-cycle\/RB-axis events (OR\u00a0=\u00a09.03; P\u00a0=\u00a00.001). 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Coupling 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1918231","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:26:32Z","timestamp":1791260792000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"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"],"prefix":"10.3389","volume":"16","author":[{"given":"Minyi","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Breast Cancer, Cancer Center, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Breast Cancer, Cancer Center, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingyi","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Medicine, South China University of Technology","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cangui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Breast Oncology, Jieyang People\u2019s Hospital","place":["Jieyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruobing","family":"Hong","sequence":"additional","affiliation":[{"name":"Guangdong Provincial People\u2019s Hospital Clinical Medical College, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieqing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast Cancer, Cancer Center, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1607303","article-title":"Palbociclib and letrozole in advanced breast cancer","volume":"375","author":"Finn","year":"2016","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1609709","article-title":"Ribociclib as first-line therapy for HR-positive, advanced breast cancer","volume":"375","author":"Hortobagyi","year":"2016","journal-title":"N Engl J 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