Postmenopausal women with large, hormone receptor (HR)-positive/HER2-negative and low-proliferative breast cancer derived a benefit from neoadjuvant endocrine therapy (NET) in the CARMINA02 trial. This study was designed to correlate gene expression and mutation profiles with both response to NET and prognosis. Gene expression profiling using RNA sequencing was performed in 86 pre-NET and post-NET tumor samples. Targeted next-generation sequencing of 91 candidate breast cancer-associated genes was performed on DNA samples from 89 patients. Molecular data were correlated with radiological response and relapse-free survival. The transcriptional profile of tumors to NET in responders involved immune-associated genes enriched in activated Th1 pathway, which remained unchanged in non-responders. Immune response was confirmed by analysis of tumor-infiltrating lymphocytes (TILs). The percentage of TILs was significantly increased post-NET compared to pre-NET samples in responders (p = 0.0071), but not in non-responders (p = 0.0938). Gene expression revealed that lipid metabolism was the main molecular function related to prognosis, while PPARγ is the most important upstream regulator gene. The most frequently mutated genes were PIK3CA (48.3%), CDH1 (20.2%), PTEN (15.7%), TP53 (10.1%), LAMA2 (10.1%), BRCA2 (9.0%), MAP3K1 (7.9%), ALK (6.7%), INPP4B (6.7%), NCOR1 (6.7%), and NF1 (5.6%). Cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway were altered significantly more frequently in non-responders than in responders (p = 0.0017 and p = 0.0094, respectively). The average number of mutations per sample was significantly higher in endocrine-resistant tumors (2.88 vs. 1.64, p = 0.03), but no difference was observed in terms of prognosis. ESR1 hotspot mutations were detected in 3.4% of treatment-naive tumors. The Th1-related immune system and lipid metabolism appear to play key roles in the response to endocrine therapy and prognosis in HR-positive/HER2-negative breast cancer. Deleterious somatic mutations in the cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway may be relevant for clinical management. This trial is registered with ClinicalTrials.gov ( NCT00629616 ) on March 6, 2008, retrospectively registered.

We retrospectively analyzed consecutive patients with HER2-positive metastatic breast cancer who received T-DXd at a single Chinese cancer center between March 2023 and March 2026. Progression-free survival (PFS), overall survival (OS), systemic and intracranial response, safety, prognostic factors, and exploratory subsequent treatment strategies were assessed. Among 173 eligible patients, 80.3% had received prior HER2-directed TKIs and 41.6% had CNS metastases. After a median follow-up of 14.3 months, median PFS and OS were 14.1 and 31.1 months, respectively. The objective response rate was 54.5% among 154 patients with measurable systemic disease, while the CNS objective response rate was 46.3% among 67 patients with measurable CNS lesions. Among patients with measurable CNS lesions, the CNS-ORR was comparable between patients with and without peri-T-DXd local treatment (53.8% vs. 44.4%, p = 0.21). Greater prior treatment exposure was associated with shorter PFS, whereas HER2 IHC 3+ disease was independently associated with longer OS and showed a trend toward improved PFS compared with HER2 IHC 2+/FISH-positive disease. Interstitial lung disease occurred in 13 patients (7.5%), all grade 1–2. Among 148 patients included in the maintenance analysis, 23 switched to alternative maintenance regimens after initial benefit from T-DXd. In an exploratory analysis, no statistically significant differences in PFS or OS were observed between patients who continued T-DXd and those who switched to maintenance therapy. However, these findings require cautious interpretation because of immortal-time bias, selection bias, and limited sample size. T-DXd demonstrated clinically meaningful systemic and intracranial activity with manageable toxicity in this heavily pretreated real-world cohort.