Profiling and targeting HER2-positive breast cancer using trastuzumab emtansine

Abstract

PurposeThis article reviews the mechanism of action of trastuzumab emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent.BackgroundThe development of HER2-targeted therapies has dramatically improved clinical outcomes for patients with any stage of HER2-positive breast cancer. Although the positive effect of these treatments cannot be overstated, treatment resistance develops in the vast majority of those diagnosed with stage IV HER2-positive breast cancer. Moreover, HER2-directed therapies are most effective when combined with cytotoxic chemotherapy. The need for chemotherapy leads to significant adverse effects and a clear decrease in quality of life for those dealing with a chronic incurable disease. T-DM1 is a recently developed, novel antibody–drug conjugate in which highly potent maytanisinoid chemotherapy is stably linked to the HER2-targeted monoclonal antibody, trastuzumab.ResultsPreclinical and phase 1–3 clinical data support the significant antitumor activity of T-DM1. Importantly, several randomized studies also now demonstrate its clear superiority in terms of tolerability compared with standard chemotherapy-containing regimens. Its role in the treatment of trastuzumab-resistant metastatic breast cancer has now been established on the basis of the results of two phase 3 randomized studies, EMILIA (An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) and TH3RESA (A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician’s Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy). The most common toxicities seen with T-DM1 are thrombocytopenia and an elevation in liver transaminases. Significant cardiac toxicity has not been demonstrated. Both in vitro cell line–based studies as well as exploratory analyses of archived tumor samples from the clinical trials are seeking to understand potential mechanisms of resistance to T-DM1. Ongoing studies are also evaluating the use of T-DM1 in the first-line metastatic, neoadjuvant, and adjuvant settings, as well as in combination with other targeted therapies.ConclusionT-DM1 represents the first successfully developed antibody drug conjugate for the treatment of HER2-positive advanced breast cancer.

Prognostic value of programmed cell death-ligand 1 expression in patients with non-small-cell lung cancer: evidence from an updated meta-analysis

“…In the treatment of several kinds of cancer, including lung cancer, potential therapeutic targets such as epidermal growth factor receptor (EGFR), 7 Kirsten rat sarcoma viral oncogene, 8 and human EGFR-2, 9 have been the focus of recent attention. Yet, the development of drugs aimed at these targets has been hampered by drug resistance and a high mutation rate of the relevant genes.…”

Bioresponsive polymer coated drug nanorods for breast cancer treatment

“…Conjugation of TTZ to the surface of CPT-PCL NRs significantly inhibited the growth of BT-474 breast cancer cells. Overexpression of HER-2 increases breast cancer cell proliferation in part by transactivation of enhanced growth factor receptor signaling [37,49,64]. Blocking of HER-2 by TTZ binding proved to suppress the cells growth.…”

Tribody [(HER2)2xCD16] Is More Effective Than Trastuzumab in Enhancing γδ T Cell and Natural Killer Cell Cytotoxicity Against HER2-Expressing Cancer Cells

“…An attempt to combat trastuzumab resistance was the development of the ADC trastuzumab emtansine (T-DM-1). The cytotoxic agent emtansine (DM-1), which destroys tumor cells by binding to tubulin, has been conjugated to trastuzumab which inhibits the PI3K signaling ( 13 , 49 ). An improvement of progression-free and overall survival in heavily pretreated patients with advanced HER2 + breast cancer and an acceptable toxicity profile has been demonstrated in phase III clinical trials ( 66 , 67 ).…”

“…In an attempt to optimize anti-HER2 therapies, the initial monotherapy with humanized anti-HER2 mAb trastuzumab (Herceptin ® , Genentech, South San Francisco, CA, USA) against metastatic gastric or breast cancer was gradually replaced by combination therapies with cytostatic agents (e.g., docetaxel, capecitabine, paclitaxel) and/or other anti-HER2 mAb (e.g., pertuzumab), and/or tyrosine kinase inhibitors (e.g., lapatinib) ( 2 , 3 , 6 – 12 ). Alternatively, the antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM-1) consisting of the anti-HER2 mAb trastuzumab linked to the cytotoxic agent emtansine (DM-1), which enters and destroys the HER2-overexpressing cells by binding to tubulin, was successful in patients with advanced breast cancer ( 13 , 14 ). Trastuzumab and pertuzumab induce antibody-dependent cell-mediated cytotoxicity (ADCC) and/or cell death of tumor cells by inhibition of HER2 signaling ( 15 – 17 ).…”