Her2low breast cancer. New opportunities and challenges

Abstract

Background. Breast cancer is an increasingly prevalent cancer pathology. In developed countries, breast cancer hits almost every eighth woman and ranks first in the incidence of patients with malignant tumors. The success of breast cancer therapy is apparently connected with the effectiveness of a strategy of impact on typical breast cancer targets, such as estrogen and progesterone receptors, HER2/neu oncoprotein. Implementation of modern achievements of fundamental science into routine clinical practice will allow the prognosis of patients with breast cancer at both earlier and later stages (in cases of the metastatic lesion) to be improved.
 Purpose. To review modern literature sources that cover biological and clinical relevance of expanding molecular genetic classification of breast cancer for the purpose of singling out additional clinically significant breast cancer subtypes with special emphasis on HER2-low-positive tumors.
 Materials and methods. The literature search was performed manually by the keywords (breast cancer, HER2-low-positive breast cancer), and also literature sources from evidential databases PubMed, and Web of Science were reviewed. The data from meta-analyses, randomized trials, systematic reviews, cohort trials, and the data of fundamental works were taken into consideration. 41 literature sources were analyzed in total. We opted for the sources which were published over the last ten years.
 Results. Breast cancer is a heterogeneous disease. Overexpression of the HER2 receptor is peculiar to 15–20% of breast tumors, usually due to amplification of the ERBB2 gene. Taking into account that the ERBB2 gene is a very powerful proto-oncogene, tumors with such phenotype are characterized by aggressive course and unfavorable prognosis. Starting from the 1990s, the development of target drugs aimed at the blockade of HER2 receptors beginning from monoclonal antibodies – trastuzumab, later – pertuzumab, tyrosine kinase inhibitors (lapatinib, neratinib, tucatinib) and the new class of antitumor drugs – conjugates of a monoclonal antibody with a cytostatic drug (trastuzumab emtansine, trastuzumab deruxtecan, trastuzumab duocarmazine) and their implementation into clinical practice changed the course and the prognosis of the patients with HER2-positive breast cancer. In opposition to earlier clinical trials, the results of the more modern ones demonstrate the clinical effectiveness of new antitumor drugs such as conjugates of HER2 monoclonal antibody with a cytostatic drug (trastuzumab deruxtekan, trastuzumab duokarmazine) not only in patients with HER2-positive breast cancer but also in some patients with metastatic breast cancer with low HER2 expression. In order to determine the patients who may potentially benefit from the new target drugs among the patients with HER2-negative breast cancer, a new concept of HER2/neu-low breast cancer has been suggested, which is used for the selection of patients in modern clinical trials, and in the measurable future it will be used in routine clinical practice.
 Conclusions. Today’s scientific data confirm biological and clinical relevance of expanding molecular genetic classification of breast cancer for the purpose of singling out additional clinically significant breast cancer subtypes with special emphasis on HER2-low-positive tumors. The development of a new class of antitumor drugs, namely conjugates of HER2 monoclonal antibody with a cytostatic drug (trastuzumab deruxtekan, trastuzumab duokarmazine) gives new therapeutic possibilities for patients with breast cancer, and also for patients with other types of malignant tumors.