Clinical and genomic characteristics of HER2-ultralow breast cancer and implications for T-DXd therapy.

Background: The clinical benefit of T-DXd in advanced breast cancer with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-ultralow tumors in the DESTINY-Breast06 trial has drawn attention to this subtype. Methods: We re-evaluated 473 pathological specimens from 302 HER2-negative breast cancer patients in our next generation sequencing database, classifying HER2-negative status into HER2-ultralow, IHC 0 without membrane staining (MS-) and HER2-low. Clinicopathologic characteristics and genomic profiles were analyzed by HER2 status. Results: Overall, 35.5% of primary and 49.0% of metastatic HER2-IHC 0 tumors were reclassified as ultralow. Subtype analysis based on HR status showed no distinct clinicopathological characteristics in the HER2-ultralow subgroup. Upon metastasis, 40% of HER2-ultralow 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 HER2-ultralow translated to other HER2 statuses in re-obtained samples. HER2-ultralow 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. The median progression-free survival for first-line chemotherapy was 7.2 months in HR+ HER2-low, 6.8 months in ultralow, and 8.8 months in IHC 0 (MS-) patients (P = 0.06). PIK3CA mutations were more common in the HER2-low subtype than in HER2-ultralow tumors in the HR- subtype. Conclusion: In conclusion, HER2-ultralow status is not associated with distinct clinicopathologic or genomic characteristics. HER2-IHC 0 (MS-) and ultralow statuses often coexist within the same patient.