Evolving landscape of HER2-low breast cancer: New diagnosis and treatment paradigm shift

In the US, breast cancer is the most common cancer and the second most common cause of cancer death among women.1 Like other cancers, breast cancer is a heterogeneous disease with various oncogenic drivers. Treatment decisions rely on evaluating the intrinsic biological factors that distinguish the four primary clinical subtypes, which are then further differentiated based on receptor status: luminal-A like (estrogen receptor (ER) and progesterone receptor (PR)-positive, human epidermal growth factors receptor 2 (HER2)- negative with low proliferative rate), luminal B-like (ER/PR-positive, HER2-negative with high proliferative rate), HER2-enriched, and triple-negative or basal-like breast cancer.

ER, PR, and HER2 drive tumorigenesis of most breast cancers, and their expression signifies a dependence on these hormones or growth factors that further suggests targeted therapies may be effective. ER and PR are cytoplasmic hormone receptors (HR) that translocate to the nucleus upon binding their respective ligands, and most breast cancer patients, about 84 percent, will have tumors that express HR.

In contrast to ER and PR, HER2 is a membranous cell surface receptor that activates upon dimerization, causing a signaling cascade that promotes cancer growth. ERBB2, the gene that encodes the HER2 protein, is amplified in about 15 percent of breast cancers, resulting in its overexpression. HER2-positive tumors display a more aggressive behavior than HER2-negative tumors, but the development of HER2-directed therapies has changed the trajectory of HER2-positive breast cancer.

In clinical practice, testing for ER, PR, and HER2 is generally performed at the time of initial diagnosis due to the prognostic and therapeutic importance of these biomarkers. Immunohistochemical evaluation alone is adequate for evaluation of ER and PR but a combination of immunohistochemistry (IHC) and in situ hybridization (ISH) is utilized for HER2 analysis.2 In this paper, we discuss the use of a complex testing algorithm for HER2 that has historically been used to standardize test results and select for patients who might benefit the most from HER2-targeting therapies.