Decoding HER2 dynamics: Exploring HER2 expression across a real-world breast cancer cohort.

Abstract

1026 Background: HER2 expression in breast cancer (BC) has evolved from a binary scoring system to a continuum-based approach, driven by the therapeutic benefits of trastuzumab deruxtecan (T-DXd) in patients with HER2-Low tumors. Our understanding of HER2 expression is complicated by several factors, including tumor heterogeneity, altered expression as tumors progress, and variations in assay technique and scoring. Here we describe HER2 expression patterns in a large cohort of patients with BC, including a subset with longitudinal results. Methods: HER2 expression levels were determined by IHC using the VENTANA 4B5 antibody. HER2 copy number and HER2/CEP17 ratios were determined using a validated dual-probe ISH assay. Tumors were retrospectively identified as HER2-Zero (IHC 0), HER2-Low (IHC 1+ or 2+ with negative ISH) or HER2-positive (IHC3+ or IHC2+ with positive ISH) based on the established IHC and ISH values scored at the time of reporting (Apr 2013 to Nov 2024). Estrogen and progesterone receptor (HR) levels were determined using validated IHC assays. All testing was performed in a CAP/CLIA accredited referral laboratory. Tumor histology, specimen collection site (CS), and patient demographics were abstracted from test requisition forms. Results are descriptive and presented in aggregate. Results: A total of 30,023 BC specimens from 27,055 patients were included in the analysis. Most patients were female (99%; 26,687) with a median age at testing of 63.5 years. Among HER2-Low specimens, 87% were HR-positive (HR+) and 13% were HR-negative/HR-Low (ER IHC < 10%). Longitudinal specimens were available for 1,267 patients with a median of 77 days between collection dates. 69% (869) of longitudinal specimens demonstrated the same level of HER2 expression, including in 69% (597/868) of cases where both specimens were collected from breast and 69% (203/294) of cases where the first specimen was collected from breast and the second was collected from another site. Among 398 patients who had HER2 expression levels changes, 46% went from HER2-Low to HER2-Zero and 33% went from HER2-Zero to HER2-Low. Conclusions: HER2-Low status is common in BC, especially among HR-positive cases.HER2 expression status changed between longitudinal specimens in 31% of patients, which may inform therapeutic eligibility. This reaffirms current guidelines recommending a biopsy at first distant recurrence and suggests that serial biopsies might be helpful in detecting HER2 expression in an originally HER2-Zero tumor. Longitudinal HER2 expression levels changes. HER2 Expression Level Change Both CSs Breast Breast to Other CS Other CS combinations Total Positive to Low 27 3 3 33 Positive to Zero 5 2 1 8 Low to Positive 23 6 3 32 Low to Zero 116 51 17 184 Zero to Positive 6 3 9 Zero to Low 94 26 12 132 No Change (Positive) 71 32 7 110 No Change (Low) 365 104 41 510 No Change (Zero) 161 67 21 249