Abstract 50P
Background
HER2-low breast cancer is emerging as a specific subtype of breast tumor against which trastuzumab-containing antibody-drug conjugates, specifically trastuzumab-deruxtecan, are effective. However, attempts to define HER2-low breast tumors as a unique biological entity have thus far concluded that low HER2 expression does not categorize these tumors as having distinct molecular features beyond low immunohistochemical (IHC) cytoplasmic membrane expression of HER2. Our aim in this study is to characterize these tumors as separate biological entities and establish whether there are other mechanisms at play in these tumors that can be exploited as therapeutical approaches beyond trastuzumab-deruxtecan.
Methods
We have selected a cohort of patients within the large population-based SCAN-B prospective study. We included all patients diagnosed in Region Skåne between 2010 and 2014 with a follow-up of ≥ 5 years. We only included tumors with histology of invasive ductal carcinoma (IDC) to ensure homogeneity. All included cases had complete RNA-sequencing profiling. Tumors were ER positive, defined as IHC staining ≥10% of cells, HER2 negative (0-1+ by IHC or 2+ and no amplification by ISH). The HER2-low disease included all cases with HER2 IHC staining scores of 1+ or 2+ with no gene amplification, per international guidelines.
Results
We have identified and included 1299 patients in this cohort. As with earlier described cohorts, HER2-low tumors do not show a worse prognosis regarding breast cancer event-free interval or overall survival. HER2 IHC membrane staining strength correlates with ERBB2 mRNA expression data linearly. Intriguingly, we have found a positive correlation with ERBB3 gene expression but not with other potential heterodimerization partners such as EGFR, ERBB4, and AXL.
Conclusions
The correlation between ERBB2 and ERBB3 mRNA expression suggests that heterodimers form to activate internal signaling in HER2-low disease. We are now specifically looking at mRNA expression patterns to elucidate if this HER2/HER3 signaling association corresponds with distinct biological entities within the HER2-low breast tumors.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
A. Bosch: Other, Advisory Board, Participated in Advisory Board meetings: Pfizer, Novartis; Other, Institutional honoraria for consultations ans lectures: Pfizer; Other, Institutional honoraria for consultations and lectures: Roche, Lilly; Other, Member of the Board of Directors, Co-founder and board chair: SACRA therapeutics. All other authors have declared no conflicts of interest.