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

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.