New Therapeutics in HER2-Positive Advanced Breast Cancer: Towards a Change in Clinical Practices?

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.

The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

“…Nevertheless, only a limited number of targeted therapies have been approved and are currently used in breast cancer patients. In this context, anti-human epidermal growth factor receptor 2 (HER2) therapeutics such as trastuzumab, lapatinib, and pertuzumab have been proposed and used even in combination therapies [ 3 , 4 , 5 ]; nevertheless, the lack of responsiveness has been also observed [ 6 ]. Indeed, the intrinsic and acquired resistance to classical therapeutic agents and/or novel targeted drugs still represents a main problem in the treatment of breast cancer and a major cause of relapse and cancer death.…”

Molecular Mechanism of HER2 Rapid Internalization and Redirected Trafficking Induced by Anti-HER2 Biparatopic Antibody

“…Because of this, HER2 has become an important target for breast cancer therapeutics [9]. HER2-directed therapies, such as anti-HER2 monoclonal antibodies and kinase inhibitors (lapatinib [10]), have been extensively used for the treatment of HER2-positive breast cancer patients [11]. Trastuzumab, a humanized anti-HER2 monoclonal antibody, in combination with chemotherapy is now the standard care treatment for HER2-positive breast cancer patients [12].…”

HER2 splice variants in breast cancer: investigating their impact on diagnosis and treatment outcomes

“…Mammalian target of rapamycin (mTOR) can be activated by PTEN loss or PI3KCA mutations and is linked to trastuzumab resistance, again through the PI3K/Akt pathway. The mTOR inhibitor, everolimus, has been trialled in combination with trastuzumab and chemotherapy in HER2+ patients with advanced breast cancer which gave a moderate benefit to patients but increased toxicity [131]. The addition of the mTOR inhibitor, everolimus, can prolong progression free survival for patients with PI3KCA mutations, PTEN loss or hyperactivation of the PI3K/Akt signalling pathway but more specific inhibitors may need to be developed to reduce toxicity [130].…”

“…The addition of the mTOR inhibitor, everolimus, can prolong progression free survival for patients with PI3KCA mutations, PTEN loss or hyperactivation of the PI3K/Akt signalling pathway but more specific inhibitors may need to be developed to reduce toxicity [130]. Biomarkers to determine the cause of PI3k/Akt pathway upregulation would enable clinicians to choose combinations of these inhibitors with anti-HER2 therapies to enhance prolonged response in patients [131].…”

“…Genetic and epigenetic alterations are frequently identified in cancers and high activity may supress cancer cell senescence [134]. Cyclin D1 mutations (of its gene CCND1) can cause hyperactivation of the MAPK pathway and so induce resistance to HER2 therapies [131]. In vitro inhibition of CDK4/6 has increased cell cycle arrest in synergy with trastuzumab and tamoxifen in HER2+ and ER+ cells respectively [137].…”