AUTHOR=Venetis Konstantinos , Crimini Edoardo , Sajjadi Elham , Corti Chiara , Guerini-Rocco Elena , Viale Giuseppe , Curigliano Giuseppe , Criscitiello Carmen , Fusco Nicola 

TITLE=HER2 Low, Ultra-low, and Novel Complementary Biomarkers: Expanding the Spectrum of HER2 Positivity in Breast Cancer

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 9 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2022.834651

DOI=10.3389/fmolb.2022.834651

ISSN=2296-889X

ABSTRACT=HER2 status in breast cancer is assessed to select patients eligible for targeted therapy with anti-HER2 therapies. According to the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), the HER2 test positivity is defined by protein overexpression (score 3+) at immunohistochemistry (IHC) and/or gene amplification at in situ hybridization (ISH). The introduction of novel anti-HER2 compounds, however, is changing this paradigm because some breast cancers with lower levels of protein expression (i.e. score 1+/2+ with no gene amplification) benefited from HER2 antibody-drug conjugates (ADC). In addition, recent evidence suggests a potential opportunity for HER2 targeting in HER2 “ultra-low” (i.e. score 0 with incomplete and faint staining in ≤10% of tumor cells) and MutL-deficient estrogen receptor (ER)-positive/HER2-negative breast cancers. All these novel findings are pulverizing the traditional dichotomy of HER2 testing and have dramatically raised the expectations in this field. Still, a more aware HER2 status assessment coupled with the comprehensive characterization of the clinical and molecular features of these tumors is required. Here, we seek to provide a comprehensive overview of the current state of HER2 targeting in breast cancers beyond the canonical HER2 positivity and to discuss the practical implications for pathologists and oncologists.