The Exciting New Field of HER2-Low Breast Cancer Treatment

Abstract

Since human epidermal growth factor receptor-2 (HER2) characterization, going through clinical research and regulatory approval of HER2-targeted therapies, much has elapsed and is still unfolding. Hitherto, only breast cancer (BC) patients with HER2 immunohistochemistry 3+ or with HER2 gene fluorescence in-situ hybridization (FISH) amplification (a.k.a., HER2-positive BC) have benefited from anti-HER2 agents. In recent years, however, much of the research effort has been expanded, with positive outcomes being reached for formerly known HER2-negative BC that yet express HER2 to some degree (HER2 immunohistochemistry 1+ or 2+, but FISH negative) and are currently being classified as HER2-low BC for the purpose of trial enrollment. In this sense, our aim is to review the body of evidence of HER2-low BC that led to the study of first-generation anti-HER2 agents, like trastuzumab, and how they have failed to achieve any clinical applicability in this setting. In addition, we review new data that is leading to the growing success of the new generation of drugs, especially the promising HER2-directed antibody–drug conjugates. A narrative review is also performed regarding the rationale behind the consolidated and ongoing clinical trials studying anti-HER2 agents in combination with unrelated agents, such as immunotherapy, endocrine therapy, and CDK4/6 inhibitors. Hopefully, all this ongoing research effort will be able to extend the survival benefits seen with anti-HER2 agents in HER2-positive disease, at least to some degree, to the greater proportion of patients with HER2-low BC.

HER2-low status and response to neoadjuvant chemotherapy in HER2 negative early breast cancer

“…Although the activity of new ADCs is being extensively studied in advanced HER2-low BC, clinical trials testing theses agents in the early stage setting are lacking [21]. In this scenario, the only data presented was the adjuvant trial of the HER2 targeting vaccine, Nenelipepimut-S, associated with Trastuzumab with negative results [22,23].…”

HER2-Low Breast Cancer: Molecular Characteristics and Prognosis

“…However, a relevant proportion (≈45–55%) of tumors that are classified as HER2− are in fact what is now called HER2-low [ 7 , 8 , 9 ]. The HER2-low BC subtype represents a new recently proposed nomenclature for those tumors with an immunohistochemistry (IHC) assay score of 1+ or 2+ but with negative in situ hybridization (ISH) assay [ 7 , 10 ]. In clinical practice, these tumors are classified as triple-negative BC (TNBC) or, if hormone receptors (HRs) are expressed, as luminal BC, thus being considered to not benefit from anti-HER2 treatments.…”

“…In clinical practice, these tumors are classified as triple-negative BC (TNBC) or, if hormone receptors (HRs) are expressed, as luminal BC, thus being considered to not benefit from anti-HER2 treatments. HER2-low BCs comprise a majority of HR-positive (HR+) tumors (≈83%) [ 10 , 11 ]; however, little is known about their molecular characterization. Recently, Schettini et al have presented the distribution of PAM50 intrinsic subtypes of a large retrospective cohort ( n = 1576) of HER2-negative BCs extracted from databases pertaining to different studies [ 12 ].…”

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

“…Trastuzumab duocarmycin, also named SYD985, consists of duocarmycin linked to HER-2 receptors via an enzymatically cleavable linker [ 130 , 131 ]. This formulation has proved an excellent antitumor efficacy in xenograft mouse model of ovarian and also in uterine carcinomas [ 152 , 153 ].…”