Exploration of the new classification of hormone receptor-positive breast cancer: Based on the genomic landscape of 2111 early to mid-stage Asian patients.

596 Background: The molecular classification of breast cancer using omics data has led to varied prognoses; however, with the increase of targeted therapy options, current classifications may not adequately guide treatment strategies. Methods: This study analyzed 2,111 HR + Asian breast cancer patients using next-generation sequencing of 1,021 genes for targeted therapy classification. Results: The majority of patients had invasive ductal carcinoma (67.0%) and were at stages 0 to III (89.6%), with 29.7% being HER2 positive. Variations were widespread, with SNV/Indel mutations found in 99.4% and CNV detected in 44.6% of the samples, respectively. The key signaling pathways, including PAM, RTK/RAS, DDR, and TP53, each showed a prevalence of 50% or higher and co-existed. Interestingly, 76.1% of patients had actionable mutations, predominantly in the PAM (54.8%), RTK/RAS (22.2%), and DDR (11.7%) pathways, which were found to be mutually exclusive (p < 0.01). Subsequently, Patients were categorized into two groups, C and M, based on CNV presence, revealing significant differences in the prevalence of actionable genes and pathways. The C group stood out for its high prevalence of PAM (43.7%) and HER2 (38.4%), while the M group exhibited prominence in PAM (64.1%) and DDR (15.0%). Notably, responses to neoadjuvant treatment (NAT) varied as well, with higher pCR rates (51.9% vs. 22.1%, p < 0.001) for the combination of chemotherapy and HER2-targeted therapy (Chemo + HP) and lower pCR rates (6.0% vs. 15.2%, p = 0.017) for chemotherapy alone (Chemo) observed in the C group compared to those in the M group. Additionally, subsequent subgroup analyses based on actionable signaling pathways between the two groups showed similar patterns, with the C-HER2 + subgroup having the highest pCR rate (64.1%) for Chemo + HP and M-PAM - -DDR - subgroup showing the highest pCR rate (21.5%) for Chemo. Besides, clinical characteristics among the various groups and subgroups showed differences. For instance, the M-PAM - -DDR + subgroup had an earlier onset (p < 0.001) and included more premenopausal individuals (p=0.034), along with higher ER and PR expression (p < 0.001) and lower Ki-67 levels (p < 0.001). Multivariate logistic regression analysis identified HER2 amplification, PR negativity, and TP53 mutation as independent risk factors for the efficacy of Chemo + HP NAT. Conclusions: The study suggested that classifying breast cancer patients based on CNVs and actionable pathways may enhance neoadjuvant pCR rates. This underscored the potential implications for expanding neoadjuvant treatment strategies and facilitating tailored precision treatment options based on distinct molecular profiles and therapy responses.