Triple negative breast cancer: Pitfalls and progress

Abstract

Triple negative breast cancer (TNBC) is characterized by the lack of estrogen and progesterone receptor expression and lacks HER2 overexpression or gene amplification. It accounts for 10-15% of incident breast cancers and carries the worst prognosis. TNBC is overrepresented among Black and pre-menopausal women and is associated with significant psychological and treatment-related burdens, including financial toxicity. Like other breast cancers, TNBC is biologically heterogeneous, leading to diverse clinical and epidemiological behaviors, however, unlike the other clinical subtypes, in TNBC we still lack tumor-specific targeted therapy. Early TNBC outcomes have improved due to the intensification of therapies, including improvements in polychemotherapy and the addition of immunotherapy. Future efforts are needed to identify targetable aberrations for specific drug therapy, prevent immune evasion, and increase social-economic support. Given that the name TNBC illustrates its lack of specifically targeted and effective therapy, we look forward to being able to retire the name in favor of a group of targetable entities within what is now called "TNBC".

Fig. 1. Intrinsic molecular subtypes of breast cancer.

Within each clinical subtype there are multiple molecular subtypes. ER endocrine receptor; TNBC triple negative breast cancer; HER2 Human Epidermal Growth Factor Receptor 2.

Fig. 2. Tumor microenvironment.

a Immune-stimulating microenvironment with homogeneous distribution of CD8+ and CD4+ T cells, M1 polarized macrophages, APC and dendritic cells, in proximity with cancer cells. b Immune-escaping microenvironment with higher ratio of CD68+:CD3+ T cells, and M2 polarized macrophages, and more distance between cancer and immune cells. CD4+and CD8+:Tcells marker; CD68+: pan-macrophage marker; APC: antigen presenting cells; CC: cancer cells; DC: dendritic cells. Figure includes modified templates from Servier Medical Art (smart.servier.com).

Fig. 3. Current multidisciplinary treatment of TNBC, including neoadjuvant chemotherapy plus immunotherapy, surgery and radiation, and adjuvant treatment with ongoing immunotherapy.

Adjuvant PARP inhibitors are given for those with germline BRCA1 or 2 mutations and capecitabine for those with residual disease, although optimal integration in the immunotherapy era is uncertain. In blue neoadjuvant treatment; in green adjuvant treatments. *only for germline carriers of BRCA1-2 mutations. Figure includes modified templates from Servier Medical Art (smart.servier.com).

Fig. 4. Relationship of pCR and RD with EFS in TNBC.

pCR pathological complete response; RD residual disease; EFS event-free survival; TNBC triple negative breast cancer.

Fig. 5. Therapeutic approaches in metastatic TNBC (red: current approaches, Blue: future directions).

ADC antibody drug conjugate; PARPi: poly-ADP ribose polymerase inhibitors; HRD homologous recombination deficiency; AR androgen receptors. Figure includes modified templates from Servier Medical Art (smart.servier.com).