Clinical features, genomic landscapes, and survival outcomes of HER2-low breast cancer.

1027 Background: Novel human epidermal growth factor receptor 2 (HER2)-directed antibody‒drug conjugates prompt the identification of the HER2-low subtype. To investigate whether HER2-low breast cancer can be defined as a distinct biological subtype, our study conducted a comprehensive analysis on the clinical and molecular features among patients with different HER2 statuses. Methods: Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database. Genomic data of breast tumor samples was generated by targeted NGS using a cancer-related gene panel. The cohort included 220 HER2-zero, 194 HER2-low and 165 HER2-positive patients according to the HER2 status from the most recent pathological results. Results: First, the clinicopathological characteristics of HER2-low patients were associated with hormone receptor (HR) status. Less lymph node invasion and higher bone metastasis in HER2-low patients were probably because of the higher percentage of HR-positive tumors in HER2-low patients than HER2-zero and HER2-positive patients (63.19%, 42.02% and 28.00%, respectively, p<0.0001). Second, HER2 status shifting from primary to recurrent breast cancer was common, with 38.1% and 48.4% of HER2-zero primary tumors converting to HER2-low tumors when they metastasized in the whole population and the HR-positive subgroup, respectively. Third, HER2-low patients had more brain and lung metastases and cases of de novo stage IV breast cancer than HER2-zero patients in the HR-positive subgroup. Fourth, germline BRCA2 mutations were observed only in HER2-low patients (11/139, 7.91%) and HER2-low tumors had more somatic PIK3CA mutations than HER2-zero tumors in the HR-negative subgroup. Fifth, HER2-low patients had a longer median overall survival (mOS) and median disease-free survival (mDFS) than HER2-zero patients (mOS:49.1 vs. 30.3 months, log rank P = 0.0005; mDFS: 28.17 vs. 20.27 months, log rank P =0.036), but difference was not evident when paired by HR status. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, and Cluster 2, which enriched in TP53 mutations, was significantly associated with worse outcomes, which provided novel insights into heterogeneity in HER2-low breast cancer. Conclusions: The clinical and molecular significance of HER2-low status was influenced by HR expression, and HER2-low tumors had distinct features in subtype analyses based on HR status. Our elaboration of molecular subtypes in HER2-low tumors encourages clinicians to consider the heterogeneity in HER2-low breast cancer.