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

person Jin Juan Department of Breast and Urological Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China info_outline Jin Juan, Bin Li, Biyun Wang, Zhonghua Tao, Xichun Hu

Authors person Jin Juan Department of Breast and Urological Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China info_outline Jin Juan, Bin Li, Biyun Wang, Zhonghua Tao, Xichun Hu Organizations Department of Breast and Urological Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China, Shanghai Medical College, Fudan University, Shanghai, Shanghai, China, Department of Breast and Urological Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai/China, China Abstract Disclosures Research Funding Other Government Agency National Natural Science Foundation of China (ID: 81903084) 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.