New developments in the treatment of HER2-positive breast cancer

Abstract

Approximately 20%–30% of metastatic breast cancers show increased expression of the human epidermal growth factor receptor-2 (HER2) tyrosine kinase. Two HER2-specific therapies are currently approved for clinical treatment of patients with HER2-overexpressing metastatic breast cancer. Trastuzumab is a monoclonal antibody against HER2 and is approved for first-line treatment of HER2-positive metastatic breast cancer. Lapatinib is a small molecule dual inhibitor of epidermal growth factor receptor and HER2 tyrosine kinases, and is approved for trastuzumab-refractory disease. Although trastuzumab is a highly effective therapy for patients with HER2-overexpressing metastatic breast cancer, a significant number of patients in the initial clinical trials of trastuzumab monotherapy showed resistance to trastuzumab-based therapy. Further, among those who did respond, the initial trials indicated that the median time to progression was less than 1 year. Similarly, lapatinib is effective in a subset of trastuzumab-refractory cases, but the majority of patients display resistance. This review discusses the multiple molecular mechanisms of resistance that have been proposed in the literature. In addition, novel agents that are being tested for efficacy against HER2-positive breast cancer, including the antibodies pertuzumab and trastuzumab-DM1 and the immunotoxin affitoxin, are reviewed. The introduction of trastuzumab has revolutionized the clinical care of patients with HER2-positive metastatic breast cancer and has resulted in dramatic reductions in recurrences of early-stage HER2-positive breast cancer. The development and implementation of gene- and protein-based assays that measure potential molecular predictors of trastuzumab resistance will allow individualization of HER2-targeted therapeutic approaches, and may ultimately improve treatment of HER2-positive breast cancer.

Artemin, a Member of the Glial Cell Line-derived Neurotrophic Factor Family of Ligands, Is HER2-regulated and Mediates Acquired Trastuzumab Resistance by Promoting Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells

“…Hence, ARTN could utilize TWIST1-dependent expression of BCL-2 to mediate acquired trastuzumab resistance by promotion of a CSClike cell population in mammary carcinoma. Given herein that we have demonstrated the requirement of BCL-2 in the ARTNmediated increase in the CSC-like population in trastuzumabresistant cells, we postulate that BCL-2 may act as an ARTNdependent potential downstream target in a wide a range of mammary carcinoma subtypes including HER2-dependent mammary carcinoma (20). In this regard it is important to note that regardless of the prognostic value of BCL-2 expression (40 -42), it is the interactions among the various BCL-2 family member proteins (e.g.…”

“…HER2-overexpressing cell lines possess a higher level of BCL-2 expression (19), and increased BCL-2 expression has been reported to contribute to the development of trastuzumab resistance (20). Previously, ARTN has also been demonstrated to regulate BCL-2 in mammary carcinoma (15,16) and enhance the CSC population in a BCL-2-dependent manner.…”

Detection of Chromosomal Abnormalities with Different In Situ Hybridisation Techniques - the Usefulness in Cancer Patients Qualification for Molecularly-Targeted Therapies

“…On the other hand, the EGF100151 study estimated the effectiveness of lapatinib in combination with capecitabine in such a group of patients, prolonged median time to progression (TTP) for 8.4 months. Moreover, improvement of the overall response rate (22%) and clinical benefit rate (27%), without increase in serious toxic effects was achieved [16,34,35].…”

“…Luis et al suggested that the IHC technique should be used as a screening test for HER2 status diagnosis, wherein patients with high expression of HER2 protein (IHC3+) are the major candidates for molecularly-targeted therapy. However, IHC2+ results must be confirmed by more sensitive in situ hybridization methods [34][35][36][37]. On the other hand, the EMILIA study also indicated the prolongation of PFS and OS time after treatment with trastuzumab emtansine (T-DM1) in primary breast cancer patients after acquired resistance to trastuzumab and taxanes.…”

“…Moreover, it has been reported that dacomitinib -pan-HER inhibitor can be used in the effective treatment of gastric cancer. Till now, it has not been strictly defined which method of HER2 disorder determination should be carried out in the correct qualification of patients for trastuzumab therapy [34,[36][37][38][39].…”