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.
5 affiliations
- 1Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
- 2School of Medicine, South China University of Technology, Guangzhou, China.
- 3Department of Breast Oncology, Jieyang People's Hospital, Jieyang, China.
- 4Guangdong Provincial People's Hospital Clinical Medical College, Southern Medical University, Guangzhou, China.
- 5Department of Rehabilitation Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Abstract
Background
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.Methods
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.Results
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 = 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
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.
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BibTeX
@article{cheng2026integrated,
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.}},
author = {Minyi Cheng and Dongqing Wang and Yingyi Lin and Cangui Wu and Ruobing Hong and Juanjuan Zhang and Jieqing Li},
journal = {Frontiers in oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1918231},
url = {https://europepmc.org/article/MED/42903090},
note = {CC BY},
}
RIS
TY - JOUR
TI - 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.
AU - Minyi Cheng
AU - Dongqing Wang
AU - Yingyi Lin
AU - Cangui Wu
AU - Ruobing Hong
AU - Juanjuan Zhang
AU - Jieqing Li
PY - 2026
DA - 2026/10/06
JO - Frontiers in oncology
DO - 10.3389/fonc.2026.1918231
UR - https://europepmc.org/article/MED/42903090
AB - Background 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.Methods 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.Results 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 = 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 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.
SN - 2234-943X
ER -