HER2-Low Breast Cancers: Current Insights and Future Directions

The human epidermal growth factor receptor 2 (HER2) in breast cancers represents the best example of tumor biomarkers with significant prognostic and therapeutic implications, and testing guidelines have been shifted and updated based on the evolving data in this field 1, 2, 3. Earlier results from clinical trials have shown that only patients with HER2-positive breast cancers benefit from the addition of HER2-directed therapies to standard chemotherapy 4,5,6,7,8,9,10. This led to the approval of HER2-targeted agents in breast cancers by the US Food and Drug Administration (FDA), including trastuzumab, pertuzumab, tyrosine kinase inhibitors (lapatinib, neratinib and tucatinib), and most recently trastuzumab-emtansine (T-DM1) - the first generation of antibody-drug conjugate (ADC) therapeutic interventions. The current binary HER2 scoring system classifies breast cancers into: 1) HER2 positive, when HER2 expression is scored either 3+ by immunohistochemistry (IHC) or 2+ by IHC with gene amplification tested by in-situ hybridization (ISH); and 2) HER2 negative, when HER2 expression is scored either 0+ or 1+ by IHC, or scored 2+ by IHC without ISH gene amplification3.

The binary categorization of HER2 status in breast cancers has been recently challenged by emerging evidence from the clinical trials11, 12, 13. Phase I trials have demonstrated significant clinical benefits in advanced breast cancers with “HER2-low” expression (HER2 IHC score of 1+, or 2+ without gene amplification) associated with the use of novel HER2-directed ADCs, including trastuzumab-duocarmazine (SYD-985) and trastuzumab-deruxtecan (T-Dxd)11,12. Furthermore, recent results from a Phase III international clinical trial (DESTINY-Breast04) demonstrated that T-Dxd significantly improved the progression-free survival (PFS, median 9.9 vs 5.1 months) and overall survival (OS, median 23.4 vs 16.8 months) in patients with HER2-low expressing metastatic breast cancer who had received one or two previous lines of chemotherapy compared with physician's choice of chemotherapy, irrespective of hormone receptor (HR) status13. Risks of progression and death were reduced by 50% and 36% in patients treated with T-Dxd, respectively13. These promising trial results will almost certainly lead to a significant change in the treatment landscape for breast cancers, and have garnished increasing attention for the addition of a HER2-low category (HER2 IHC score of 1+, or 2+ without gene amplification) (Figure 1) in the evaluation of breast cancers. In a previous review article, our group introduced the evolving concepts of HER2-low breast cancers and discussed the challenges and unanswered questions regarding the accurate, reliable, and reproducible identification of HER2-low patients14. In the past year, the “HER2-low” category in breast cancers has been under active investigation by both oncologists and pathologists. In this current review, we update the recent cutting-edge research on HER2-low breast cancers, with a focus on the biology of HER2-low breast cancers, the issues regarding the identification of HER2-low breast cancers by IHC in current practice of pathology, and the future directions in this emerging category.

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