Background: Neoadjuvant chemotherapy is the backbone treatment modalities for BC patients for locally advanced breast cancer (BC) improves R0 resection rate. Determinants of differentially therapeutic response to anthracycline or platinum-based neoadjuvant therapy were largely unknown but were urgently needed to maximize patients’ benefit. Methods: A total of 149 local advanced (cT2-3, cN0-2, cM0-1) BC patients (HER2 positive BC, n = 54 and TNBC, n = 95) were retrospectively enrolled in the study, whole-exon sequencing (WES), mRNA sequencing and (phosphor-)proteomics were systematically conducted and comprehensively analyzed. The primary end point of the study was the pathological complete response (pCR) rate. The Cancer Genome Atlas (TCGA) BC dataset and GSE130787 set were used to validate our analysis. Cancer cell line encyclopedia (CCLE) dataset was utilized to screen putative small molecular inhibitors to BC cells with molecular features of resistance. Results: Through integrated analysis of multi-omics data, three subtypes with distinct molecular features were identified: immune-activated (IA) subtype, vesicular transport pathways activation (VTs) subtype, and kinase activation (KA) subtype. Same scenario of molecular subtypes can be repeated in TCGA dataset and prognosis of these subtypes can be differentiate (p= 0.02). Patients with IA subtype majorly favored cisplatin-based treatment (p= 0.005). And this phenomenon was confirmed in external dataset (GSE130787, n = 26, HER2-positive BC receiving TCbH treatment). Patients with VTs subtype, with significant enrichment of vesicular transport-related pathways, displayed anthracycline sensitivity. Anthracycline transporter, ABCB1 expression was significantly reduced in VTs subtype at both mRNA (p < 0.001) and protein (p < 0.05) levels. CCLE breast cancer cells with the characteristics of VTs subtype and lower ABCB1 expression also displayed the sensitivity of epirubicin (p = 0.0037). Patient with KA subtype was insensitive to both platinum and anthracycline-based therapy. Multiple kinase pathways, especially, non-canonical TGF-β signaling pathway-related genes were overexpressed (p < 0.05), and significantly correlated with non-pCR (p= 0.002). Phosphor-proteomic analysis indicated TGFβ1-mediated RhoA/ROCK pathway (Cofilin, RhoA kinase, MYH14 proteins) were highly activated. Eleven drugs were found in CCLE inhibiting growth of BC cell lines with upregulated non-canonical TGF-β pathway genes (p < 0.05). Conclusions: Three multi-omic subtypes with distinct response to anthracycline or platinum-based therapy were identified. Moreover, activated non-canonical TGF-β pathway may mediate therapeutic resistance, but also indicated therapeutic vulnerabilities of several kinase inhibitors.