ER-low and HER2-low breast cancers have emerged as clinically significant subtypes that challenge traditional diagnostic categories and treatment paradigms. These subtypes, representing a spectrum of disease, exhibit distinct biological behaviors, therapeutic responses, and prognostic outcomes. HER2-low breast cancer, defined by low HER2 protein expression (IHC score of 1+ or 2+ without HER2 gene amplification), has achieved clinical significance, particularly following the DESTINY-Breast trials, which demonstrated the efficacy of trastuzumab deruxtecan (T-DXd) in the population of patients with advanced HER2-low disease. Similarly, ER-low breast cancer, characterized by low estrogen receptor expression (in 1%–10 % invasive tumor cells), poses unique challenges due to its intermediate biological behavior and uncertain response to endocrine therapies. The identification of these subtypes is further complicated by inconsistencies in testing methodologies, which can lead to misclassification and impact treatment decisions. As our understanding of these subtypes improves, the need for standardized diagnostic approaches and individualized therapeutic decisions becomes increasingly urgent. Ongoing research and collaboration between pathologists and oncologists are essential for refining diagnostic criteria and improving outcomes for patients with breast cancers characterized by low expression of these theragnostic biomarkers. This review aims to consolidate current knowledge on HER2-low and ER-low breast cancers, focusing on the challenges associated with their identification, the implications for treatment, and future directions in clinical management. By examining recent studies and interlaboratory assessments, this review emphasizes the critical need for accurate and reproducible testing and reporting, and for the development of tailored therapeutic strategies for these “low” expression cancers.
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