Clinical and genomic characteristics of HER2-IHC 0 (membrane staining +) breast cancer and implications for T-DXd therapy.

e13158 Background: The clinical benefit of T-DXd in advanced breast cancer with hormone receptor-positive (HR+), HER2-IHC 0 with membrane staining (MS+) tumors in the DESTINY-Breast06 trial has drawn attention to this subtype. However, the role of HER2-IHC 0 (MS+) expression remain unclear. Methods: We re-evaluated 473 pathological specimens from 302 HER2-negative breast cancer patients in our database, classifying HER2-negative status into IHC 0 (MS+), IHC 0 without membrane staining (MS-), and HER2-low. Clinicopathologic characteristics and genomic profiles were analyzed by HER2 status. Results: Among tumors re-evaluated as HER2-IHC 0, 35.5% of primary and 49.0% of metastatic tumors were reclassified as IHC 0 (MS+). No HR+ phenotype differences were observed between HER2-IHC 0 (MS+) and IHC 0 (MS-) primary tumors, but metastatic IHC 0 (MS+) tumors showed a higher HR+ proportion (40.8% vs. 17.6%, p = 0.01). Subtype analysis based on HR status showed no distinct clinicopathological characteristics in HER2-IHC 0 (MS+) subgroup. Upon metastasis, 40% of HER2-IHC 0 (MS+) primary tumors converted to IHC 0 (MS-) and 46.7% to HER2-low. In the metastatic tumors, 60% of HER2-IHC 0 (MS-) and 50% of IHC 0 (MS+) translated to other HER2 statuses in re-obtained samples. HER2-IHC 0 (MS+) status was associated with worse disease-free survival than HER2-IHC 0 (MS-) and HER2-low status in HR-negative breast cancer, but no differences of overall survival were observed among different HER2 statuses. The median progression-free survival for first-line chemotherapy was 7.2 months in HR+HER2-low, 6.8 months in IHC 0 (MS+), and 8.8 months in IHC 0 (MS-) (p = 0.06). Some differences in genetic alterations were observed in HER2-low tumors compared to HER2-IHC 0 (MS+) and HER2-IHC 0 (MS-) tumors when stratified by HR status. However, no distinct genetic alterations were found between HER2-IHC 0 (MS+) and HER2-IHC 0 (MS-) tumors. Conclusions: HER2-IHC 0 (MS+) status may indicate a poor response to chemotherapy, but is not associated with distinct clinicopathologic or genomic characteristics. HER2-IHC 0 (MS-) and IHC 0 (MS+) statuses often coexist within the same patient.