Abstract
Triple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer, comprising 10-20% of invasive breast cancers and typically affecting younger individuals. It lacks expression of estrogen receptors (ER), progesterone receptors (PR), and HER2/neu, leading to higher recurrence rates, shorter survival, and a greater risk of metastasis, particularly to the brain and lungs. Hormonal factors, genetic mutations, and precursor lesions such as microglandular adenosis (MGA) with TP53 mutations contribute to its pathophysiology. Nulliparity and extended breastfeeding decrease TNBC risk, while oral contraceptive use in younger women, higher BMI, and a high waist-to-hip ratio increased risk, especially in premenopausal women.1,2 TNBC is predominantly basal-like, though 30% of cases show discordance with this subtype, and it involves pathways like MAP kinase, Akt, and PARP1. Approximately 15% of TNBCs harbor germline mutations in HRD-related genes, including BRCA1 and BRCA2. 2 Future research should explore single-cell transcriptomics, tumor microenvironment, and minimal residual disease to enhance understanding and treatment of TNBC.
Single Cell Transcriptomics, also known as single-cell RNA sequencing (scRNA-seq) provide insights into intratumoral heterogeneity of TNBC at single-cell level, identifying distinct cell populations and their roles in cancer progression. It was found that a single gene ETV6 was upregulated in all subtypes including basal like patients. Hence, tumor therapy targeting the dysregulated ETV6 gene can also be incorporated in future trials. 3 Tumor microenvironment is the interaction between cancer cells and their microenvironment which plays a crucial role in TNBC progression and response to therapy. Tumor microenvironment includes non-immune cells and immune cells. Non-immune cells include fibroblasts, endothelial cells and vascular smooth muscle cells. Increased expression of immune cells such as vascular endothelial growth factors and tumor associated macrophages, by regulating the expression of PD-1/PDL-1 favours tumor growth and metastasis. High levels of tumor infiltrating lymphocytes (CD8+, CD4+, FOXP3+) predicts positive long-term progression. Research on the tumor microenvironment can reveal new therapeutic targets such as immunotherapy and targeted cell therapy. 4 Minimal Residual Disease (MRD) or persister cells can help us in understanding TNBC recurrence and resistance to therapy. Studies say, detection of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) after neo-adjuvant chemotherapy in early-staged TNBC patients is independently associated with disease recurrence, inferior disease-free survival and overall survival. Detection of ctDNA indicates persistence of disease. Understanding MRD could lead to the development of strategies to eradicate these cells and improve patient outcomes. 5 The pathophysiology of TNBC is highly complex, hence understating the disease pathogenesis and progression is very crucial. This article briefs about TNBC pathogenesis and its ongoing research. More and more data needs to be published for identifying definite targeted therapy for reducing mortality and increasing disease free survival.
