Abstract
Over the last few decades, improved knowledge of oncogenic activation mechanisms of HER2 protein has led to the development of HER2 targeted therapies that are currently commonly used in HER2-positive advanced breast cancer, such as trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine. The management of this breast cancer subgroup has thus been revolutionized and its prognosis has changed dramatically. Nevertheless, HER2-positive advanced breast cancer remains an incurable disease and resistance to conventional anti-HER2 drugs is almost unavoidable. Nowadays, biochemical and pharmaceutical advances are meeting the challenge of developing increasingly sophisticated therapies directed against HER2, including novel anti HER2 antibodies with increased affinity. New antibody-drug conjugates (ADC) with more advanced pharmacological properties, and dual targeting of epitopes via bispecific monoclonal antibodies are also emerging. In addition, more potent and more specific HER2 tyrosine kinase inhibitors have shown interesting outcomes and are under development. Finally, researchers’ interest in tumor microenvironment, particularly tumor-infiltrating lymphocytes, and the major role that signaling pathways, such as the PI3K/AKT/mTOR pathway, play in the development of resistance to anti-HER2 therapies have spurred the development of clinical trials evaluating innovative combinations of anti-HER2 with PD-1/PDL-1, CDK4/6 and PI3K inhibitors. However, several questions remain unresolved, like the optimal management of HER2-positive/HR-positive advanced breast cancer and the identification of predictive biomarkers to better define populations that can benefit most from these new therapies and approaches.
Highlights
The amplification of the Human Epidermal Growth Factor Receptor-2, ErbB2 (HER2), identified in 15 to 20% of breast cancers (BCs), is a factor of tumor aggressiveness that has been associated with more frequent relapses and poor survival rates since a long time [1]
SDY985 is being evaluated in a phase III trial (TULIP study) in which T-DM1-pretreated HER2-positive metastatic breast cancer (MBC) are randomized between SYD985 vs
tumor-infiltrating lymphocytes (TILs) in BC are described as immune-cell populations (cytotoxic T-cells (CD8+), helper T-cells (CD4+), B-cells (CD19+), macrophages, and rare Natural killer (NK) cells and dendritic cells) that infiltrate breast tumors and their adjacent stroma, and which are provided with anti-tumor cytolytic activity according to in vivo data [73]
Summary
The amplification of the Human Epidermal Growth Factor Receptor-2, ErbB2 (HER2), identified in 15 to 20% of breast cancers (BCs), is a factor of tumor aggressiveness that has been associated with more frequent relapses and poor survival rates since a long time [1]. There was no standard third-line treatment and patients have been usually offered, a combination based on capecitabine with either lapatinib or tratuzumab, or a combination of trastuzumab with chemotherapy, or trastuzumab and lapanitib [4]. These different therapies have significantly improved patient survival, but the disease often ends up recurring or progressing. We will review the current therapeutic development and recent achievements in the field These novel agents may act on several levels and have different targets and mediators. The drugs that indirectly target HER2 include novel therapeutics modulating HER2-connected pathways, which may synergize with direct anti-HER2 targeting through innovative associations, such as immune check point inhibitors (ICIs), cell cycle inhibitors, and PI3K inhibitors
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