FGFR Aberrations Increase the Risk of Brain Metastases and Predict Drug Resistance in Metastatic Breast Cancer Patients

Abstract

The survival status of patients with breast cancer with brain metastases (BCBM) receiving current treatments is poor. We designed a real-world study to investigate patient clinical and genetic aberrations to determine appropriate treatment regimens and forecast the prognoses of BCBM patients. 146 BCBM patients were recruited and their clinical features were analyzed for evaluating overall survival (OS). For genetic testing, 30 BCBM and 165 non-BM BC patients from Hunan Cancer Hospital, and 86 BCBM and 1416 non-BM BC patients from Geneplus database received ctDNA testing was compared and analyzed. Ki67 >14% and >3 metastatic brain tumors were significant risk factors associated with poor OS, while chemotherapy and brain radiotherapy were beneficial factors for better OS. Compared with non-BM metastatic breast cancer (MBC) patients, BCBM patients had significantly more fibroblast growth factor receptor (FGFR) aberrations. The combination of FGFR, TP53 and FLT1 aberrations plus immunohistochemisty (IHC) HER2-positive could effectively predict brain metastases (AUC=77.13%). FGFR aberration alone was not only a prediction factor (AUC=67.90%), but also a significant risk factor for poor PFS (Logrank p=0.029). Among FGFR family members, FGFR1 was the most frequent aberration and significantly higher in BMBC patients. Most FGFR1-amplified MBC patients progressed within 3 months. In conclusion, a group of clinical and genetic events, including FGFR, TP53 and FLT1 genetic aberrations, and HER2-positivity, could forecast the occurrence of BM in breast cancers. Moreover, FGFR genetic aberration alone could predict poor prognosis; FGFR aberrations, especially FGFR1 amplification, resulted in drug resistance and disease progression. Funding Statement: Hunan Provincial Health and Sanitation Committee Project No. 2019070 (Recipient: Zhe-Yu Hu); Hunan Provincial Natural Science Youth Foundation Project No.20190988 (Recipient: Zhe-Yu Hu). Declaration of Interests: The authors declare that they have no conflict of interests. Ethics Approval Statement: The study was approved by the Ethics Committee at Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine / Central South University. Patients consented to participate.