Dissecting the biological heterogeneity of HER2-positive breast cancer

Abstract

HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease.

Impact of Human Epidermal Growth Factor Receptor 2 (HER2) Low Status in Response to Neoadjuvant Chemotherapy in Early Breast Cancer

“…More particularly, HER2+ BC represents 15-20% of all breast tumors and is defined by the Erb-B2 receptor tyrosine kinase 2 (ERBB2)/HER2 gene amplification that leads to overexpression of the transmembrane tyrosine kinase receptor protein [ 1 , 2 ]. These aspects are associated with more aggressive behavior, which leads to a decreased overall survival (OS) and disease-free survival (DFS), if untreated.…”

“…These aspects are associated with more aggressive behavior, which leads to a decreased overall survival (OS) and disease-free survival (DFS), if untreated. However, the development and institution of multiple agents targeting HER2 in the medical practice have provided substantial clinical benefits, reducing the risk of recurrence in the early stage and/or improving survival in the advanced setting [ 1 , 2 ]. Regardless of therapeutic advances, about 4-23% of patients with the localized disease still face recurrence after (neo)adjuvant anti-HER2 treatments.…”

“…Regardless of therapeutic advances, about 4-23% of patients with the localized disease still face recurrence after (neo)adjuvant anti-HER2 treatments. In the metastatic setting, median survival rates have systematically improved in recent years, reaching a median of ~57 months, although it may be even longer for patients receiving novel therapies [ 2 , 3 ].…”

Plant Derived Bioactive Compounds, Their Anti-Cancer Effects and In Silico Approaches as an Alternative Target Treatment Strategy for Breast Cancer: An Updated Overview

“…Approximately 5–10% of all breast carcinomas are normal breast-like tumors. Since the expression of ER, PR, and HER2 are lacking in normal breast-like tumors, these can be classified as triple-negative and different from basal-like as they are CK5 and EGFR negativity [ 18 , 26 ]. The subtypes of breast cancer and its details are given in Table 1 .…”

HER2+ Breast Cancer Escalation and De-Escalation Trial Design: Potential Role of Intrinsic Subtyping

“…Furthermore, this distribution seems to be heavily influenced by HR status, with HER2-E subtype representing 30% of the molecular subtypes within HR+/clinically HER2+ BC and 75% within HR-/clinically HER2+ tumours. Of note, the concordance rate between the pathology-based subtypes and the intrinsic subtypes is moderate (67.4%; kappa statistic: 0.50) [4,5]. Moreover, there is enough clinical evidence to support the idea that intrinsic subtypes might identify a subgroup of clinically HER2+ tumours that highly respond to anti-HER2 therapies regardless of chemotherapy and HR status [6].…”