Discordance of HER2-low Status between Breast Primary and Distant Metastases with Clinical-pathological Correlation

Abstract Introduction Breast cancer with HER2 immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization (ISH) (HER2-low) can now be targeted by HER2 antibody drug conjugates. We set out to compare HER2 status between matched primary invasive breast carcinoma (IBC) and distant metastases (DM) with clinical-pathological correlation, with specific interest in HER2-low. Methods Biomarker studies and clinical-pathological features of primary IBC with matched DM diagnosed between 2021-2022 were retrospectively analyzed. HER2 status was assessed per 2023 ASCO/CAP guidelines for IHC (Ventana, 4B5) and ISH (IQFISH pharmDX, DAKO). Bilateral breast primaries were excluded. HER2 IHC 0 to 1+ were reassessed. Results 147 cases of primary IBC with matched DM were identified (Table 1). Biomarkers were performed on core biopsy (n=74) and resection (n=73). 126 cases (86%) were initially classified as “HER2 negative”; of these 67 (46%) were reclassified as HER2-low. Patients with HER2 positive primaries were younger (p=0.01) and had an increased incidence of micropapillary carcinoma (p=0.02). HER2-low primaries also had increased incidence of micropapillary carcinoma (p=0.02) and estrogen receptor (ER) positivity (p=0.02) comparing to HER2 0. 169 matched DM cases excluding bone metastasis were identified (range of 1-7 metastases per IBC). The most common sites of metastases were liver (50/169, 30%), lung (36/169; 21%), distant lymph node (26/169, 15%). 138 DM cases (82%) were previously classified as “HER2 negative”, and 62 (37%) were reclassified as HER2-low. Like HER2-low primaries, HER2-low metastases were frequently ER positive (52/62; 84%) (p=0.02). Brain metastases were more frequently HER2 positive (5/32; 16%) (p=0.04). Comparing HER2 status in matched primaries and DM, HER2 status was discordant in 62 cases (37%). Most changes occurred from HER2-low to HER2 0 (33/169, 20 %), HER2 0 to HER2-low (17/169, 10%), and HER2-low to positive (10/169, 6%). All HER2-low to HER2 0 changes were HER2 1+ to 0. In 30 patients with multiple DM sites (47 cases), HER2 status among different DM samples was discordant in 16 patients (53%), mostly from HER2-low to HER2 0 (16/47, 34 %). Conclusion Significant proportion of previous “HER2 negative” primaries and DM cases are reclassified as HER2-low. Discordant HER2 status between IBC primary and metastasis and between different DM sites demonstrated tumor heterogeneity and highlights the need for HER2 retesting in distant metastasis.