Abstract
Simple SummaryThe role of the immune system in breast cancer has been debated for decades. It is generally accepted that tumor-infiltrating lymphocytes are associated with positive prognostic and predictive effects, especially in triple negative breast cancer. This subset of breast cancer is characterized by the absence of hormone receptors and human epidermal growth factor receptor 2. Compared to other breast cancer subtypes, triple-negative breast cancer has more mutations and neoantigens, making it more immunogenic. Releasing the brakes on the immune system with the help of so-called immune checkpoint inhibitors leads to activation of the immune system and destruction of cancer cells. This, in turn, improves survival, especially in early and advanced triple-negative breast cancer. A new and promising strategy is the enhancement of the immune response using individualized mRNA vaccines against tumor-specific neoantigens.The role of the immune system in breast cancer has been debated for decades. The advent of technologies such as next generation sequencing (NGS) has elucidated the crucial interplay between somatic mutations in tumors leading to neoantigens and immune responses with increased tumor-infiltrating lymphocytes and improved prognosis of breast cancer patients. In particular, triple-negative breast cancer (TNBC) has a higher mutational burden compared to other breast cancer subtypes. In addition, higher levels of tumor-associated antigens suggest that immunotherapies are a promising treatment option, specifically for TNBC. Indeed, higher concentrations of tumor-infiltrating lymphocytes are associated with better prognosis and response to chemotherapy in TNBC. An important target within the cancer immune cell cycle is the “immune checkpoint”. Immune checkpoint inhibitors (ICPis) block the interaction of certain cell surface proteins that act as “brakes” on immune responses. Recent studies have shown that ICPis improve survival in both early and advanced TNBC. However, this comes at the price of increased toxicity, particularly immune-mediated toxicity. As an alternative approach, individualized mRNA vaccination strategies against tumor-associated neoantigens represent another promising approach leading to neoantigen-specific immune responses. These novel strategies should help to improve treatment outcomes, especially for patients with triple negative breast cancer.
Highlights
Breast cancer is the most common cancer and the leading cause of cancer death for women worldwide [1]
In a phase III trial (KEYNOTE-119) in pretreated advanced triple-negative breast cancer (TNBC), monotherapy with pembrolizumab did not significantly improve overall survival compared with chemotherapy, the effect of pembrolizumab treatment increased with increasing programmed cell death 1 ligand 1 (PD-L1) positivity [48]
The results showed a significant prolongation of Progression-free survival (PFS) in both the intention-to-treat (ITT) population and the PD-L1-positive subgroup: PFS was 7.2 months in the experimental arm compared with 5.5 months in the placebo arm (HR 0.80; 95% CI 0.69–0.92; p = 0.002)
Summary
Breast cancer is the most common cancer and the leading cause of cancer death for women worldwide [1]. In a comprehensive immunogenomic analysis of over 10,000 tumors using TCGA data, Thorsson and co-workers identified six stable and reproducible immune subtypes C1–C6 (i.e., wound-healing, IFN-γ-dominant, inflammatory, lymphocyte-depleted, immunologically quiet, and TGF-β-dominant) [8] These immune subtypes include multiple tumor types, and are characterized by a dominance of either macrophage or lymphocyte signatures, T-helper phenotype, extent of intratumoral heterogeneity, and proliferative activity. Stanton and colleagues showed that the extent of tumor-infiltrating lymphocytes (TILs) varies within and between breast cancer subtypes, with TNBC having numerous TILs [11]. This may identify breast cancers that are more suitable for immunotherapy
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