Triple negative breast cancer (TNBC) is the subtype defined as ER (<1%), PR (<1%), and HER2-negative (IHC 0/1+ or IHC 2+/ISH-), accounting for 10-15% of all breast cancers. Compared with other subtypes it is diagnosed at younger ages (median below 50), is more frequent in African American women, shows a strong association with BRCA1 mutation (about 70% of BRCA1 carriers develop TNBC), and presents with rapidly growing, high-grade tumors. Historically, the limited number of targeted options gave TNBC a worse prognosis, but in recent years immunotherapy (atezolizumab, pembrolizumab), PARP inhibitors (olaparib, talazoparib), and antibody-drug conjugates (sacituzumab govitecan, T-DXd in HER2-low cases) have transformed the treatment landscape.
TNBC is molecularly heterogeneous and can be subdivided by gene expression profiling into at least four subtypes (Lehmann classification): (1) Basal-like 1 (BL1) — DNA damage response pathways and high proliferation; (2) Basal-like 2 (BL2) — growth factor signaling and metabolic pathways; (3) Mesenchymal (M) — epithelial-mesenchymal transition and cell motility pathways; (4) Luminal androgen receptor (LAR) — androgen receptor expression and slower clinical course. These subtypes guide targeted therapy research. PD-L1 expression is generally elevated in TNBC (Combined Positive Score — CPS ≥10 in roughly 40% of cases), serving as a key biomarker for immunotherapy response. Tumor mutational burden (TMB) and tumor-infiltrating lymphocyte (TIL) levels also act as prognostic and treatment-selection markers.
Treatment approach: (1) Early stage TNBC — neoadjuvant chemotherapy plus pembrolizumab (KEYNOTE-522 improved pCR and survival in high-risk cases; standard for T2-4/N0-2 disease). A typical regimen is carboplatin + paclitaxel + pembrolizumab followed by AC + pembrolizumab, surgery, and adjuvant pembrolizumab to complete one year. In residual disease, adjuvant capecitabine (CREATE-X) or olaparib (OlympiA — for BRCA-mutated cases) is used. (2) Metastatic disease — in PD-L1-positive (CPS ≥10) tumors, nab-paclitaxel + atezolizumab (IMpassion130) or chemotherapy + pembrolizumab (KEYNOTE-355). PD-L1-negative cases receive chemotherapy. BRCA-mutated patients receive olaparib or talazoparib (OlympiAD, EMBRACA). Platinum-refractory or third-line setting: sacituzumab govitecan (ASCENT — superior to standard chemotherapy). HER2-low cases benefit from T-DXd. Brain metastases are common (most frequent in TNBC); tucatinib is ineffective (HER2-negative), so local therapy and other systemic options are used.