Biomarkers for HER2-positive metastatic breast cancer: Beyond hormone receptors

Abstract

The overexpression of human epidermal growth factor receptor-2 (HER2) results in a biologically and clinically aggressive breast cancer (BC) subtype. Since the introduction of anti-HER2 targeted agents, survival rates of patients with HER2-positive metastatic BC have dramatically improved. Currently, although the treatment decision process in metastatic BC is primarily based on HER2 and hormone-receptor (HR) status, a rapidly growing body of data suggests that several other sources of biological heterogeneity may characterize HER2-positive metastatic BC. Moreover, pivotal clinical trials of new anti-HER2 antibody-drug conjugates showed encouraging results in HER2-low metastatic BC, thus leading to the possibility, in the near future, to expand the pool of patients suitable for HER2-targeted treatments. The present review summarizes and puts in perspective available evidence on biomarkers that hold the greatest promise to become potentially useful tools for optimizing HER2positive metastatic BC patients' prognostic stratification and treatment in the next future. These biomarkers include HER2 levels and heterogeneity, HER3, intrinsic molecular subtypes by PAM50 analysis, DNA mutations, and immune-related factors. Molecular discordance between primary and metastatic tumors is also discussed.

Trastuzumab-lapatinib as neoadjuvant therapy for HER2-positive early breast cancer: Survival analyses of the CHER-Lob trial

“…Consistently, although pCR is prognostic in all traditionally defined BC subtypes (hormone receptorepositive/ HER2-negative, HER2-positive and triple-negative), this association is stronger in most chemosensitive subgroups, namely triple-negative and HER2-positive. These observations [7,9,16,29,30] suggest that even among patients with HER2-positive BC, PAM50 analysis may add a further layer of stratification, beyond hormone receptor status [31]. Indeed, PAM50 analysis may allow controlling for those causal variables potentially affecting the strength of the association between pCR and prognosis and which would otherwise dilute the observed prognostic impact of pCR itself.…”

Breast Cancer Aptamers: Current Sensing Targets, Available Aptamers, and Their Evaluation for Clinical Use in Diagnostics

“…It is apparent why HER2 is considered a prognostic factor and indicates an increased metastatic potential, poor clinical outcomes, and a more aggressive BC subtype [99]. Identifying breast cancer as HER2-positive allows for targeted treatment and has been shown to improve survival rates compared to nontargeted treatment [100,101]. Multiple antibody assays are currently in use for HER2 detection, but many require specialized personnel to operate, leading to difficulties in quality assurance [102].…”

Nature-Inspired Nanoparticles as Paclitaxel Targeted Carrier for the Treatment of HER2-Positive Breast Cancer

“…Among the new cases of BC that are diagnosed, around 15–20% overexpress the human epidermal growth factor receptor-2 (HER2) [ 2 ]. HER2, also overexpressed in other types of solid tumors [ 3 , 4 ], can dimerize with other members of its receptor family, and this fact leads to cancer cell proliferation and survival, angiogenesis and metastasis [ 4 ].…”

“…HER2, also overexpressed in other types of solid tumors [ 3 , 4 ], can dimerize with other members of its receptor family, and this fact leads to cancer cell proliferation and survival, angiogenesis and metastasis [ 4 ]. In this way, HER2-overexpression may result in more aggressive clinical behavior and has been linked to worse patient outcomes [ 2 ]. However, as the overexpression of this tyrosine kinase (TK) receptor does not occur under normal physiological conditions [ 3 ], on the other hand, it has allowed the development of anti-HER2 targeted agents that have dramatically improved the survival rate of patients suffering from HER2-positive (HER2+) BC [ 2 ].…”

“…In this way, HER2-overexpression may result in more aggressive clinical behavior and has been linked to worse patient outcomes [ 2 ]. However, as the overexpression of this tyrosine kinase (TK) receptor does not occur under normal physiological conditions [ 3 ], on the other hand, it has allowed the development of anti-HER2 targeted agents that have dramatically improved the survival rate of patients suffering from HER2-positive (HER2+) BC [ 2 ]. Undoubtedly, the most widely used HER2-targeted agent to date has been trastuzumab (Herceptin ® , Basilea, Switzarland), a humanized monoclonal antibody (mAb) approved by the major drug regulatory agencies for the past two decades for the treatment of both early and metastatic BC [ 5 ].…”