Antibody-Drug Conjugates for the Treatment of HER2-Positive Breast Cancer

Abstract

Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20–30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted monoclonal antibodies with the potent cytotoxic effects of various small molecules, such as tubulin inhibitors and topoisomerase inhibitors. To date, two HER2-targeting ADCs have been approved by the FDA for the treatment of HER2-positive breast cancer: Ado-trastuzumab emtansine (T-DM1; Kadcyla®) and fam-trastuzumab deruxtecan-nxki (T-Dxd; Enhertu®). Kadcyla and Enhertu are approved for use as a second-line treatment after trastuzumab-taxane-based therapy in patients with HER2-positive breast cancer. The success of ADCs in the treatment of HER2-positive breast cancer provides novel therapeutic advancements in the management of the disease. In this review, we discuss the basic biology of HER2, its downstream signaling pathways, currently available anti-HER2 therapeutic modalities and their mechanisms of action, and the latest clinical and safety characteristics of ADCs used for the treatment of HER2-positive breast cancer.

Discordance of Biomarker Expression Profile between Primary Breast Cancer and Synchronous Axillary Lymph Node Metastasis in Preoperative Core Needle Biopsy

“…It is acknowledged that patients diagnosed with these latter types of tumors are unlikely to take advantage of traditional "pure" anti-HER2 agents in the adjuvant setting [36]. However, these patients could benefit from anti-HER2 drugs conjugated with chemotherapeutics in the case of a near recurrence (within six months), as well as ab initio metastatic patients affected by similar tumors that did not respond to previous lines of systemic therapy [37]. When comparing histological specimens from PTs and distant metastases, a shift from HER2-negativity to HER2-low expression has been reported much more frequently than the opposite trend [38].…”

Targeting the Oxytocin Receptor for Breast Cancer Management: A Niche for Peptide Tracers

“…ER-negative (ER – ) breast tumors overexpressing HER2 (incidence of ∼20%) initially had poor therapy outcomes, which have improved in recent years due to the introduction of combination therapies . FDA-approved anti-HER2 agents include monoclonal antibodies Pertuzumab, Trastuzumab, and Ado-Trastuzumab emtansine (T-DM1); tyrosine kinase inhibitors Lapatinib (TYKERB), , Neratinib (Nerlynx), and Tucatinib (Tukysa); and the antibody–drug conjugate fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU) . Finally, tumors that are negative for the biomarkers mentioned above (ER – , PR – , HER2 – ) fall in the TNBC category.…”

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

“…2 HER2 overexpression is associated with a biologically aggressive tumor phenotype, poor prognosis, increased risk of disease recurrence, and limited benefit from chemotherapy. 1,[3][4][5] HER2-directed therapy is standard of care for HER2-expressing unresectable or metastatic breast cancer, HER2-positive locally advanced or metastatic gastric cancers, colorectal and gastroesophageal junction adenocarcinomas, and HER2-mutant non-small-cell lung cancer. [6][7][8][9] However, many patients with other HER2-expressing solid tumors will progress on standard therapy, with poor prognosis and limited alternatives.…”