Comparing the mutation profiles of primary HER2-positive breast cancers in patients with and without brain metastases.

e13018 Background: Brain metastasis is a frequent and devastating event of HER2-positive breast cancer. Identifying the driver genes of brain metastasis is important for the prevention and treatment of brain metastasis. In this study, we compared the gene mutation profiles of primary breast cancers between patients with and without brain metastases, aiming to identify new candidate genes associated with brain metastases. Methods: HER2-positive and lymph node-positive early breast cancers of 21 patients who eventually developed brain metastases (BM group) and 27 patients without any metastasis (NM group) at a minimum 5-year follow-up were retrieved from the Sun Yat-sen University Cancer Center. Whole-exome sequencing was performed on primary breast cancers (FFPE) and matched normal breast tissues or peripheral blood. Mutect2 was used to detect somatic mutations, and Fisher’s exact test was used to identify genes mutated at different frequencies in the BM and NM groups. The mRNA expression changes of genes mutated at higher frequencies in the BM group were further analyzed in 16-pair matched HER2-positive primary breast cancers and brain metastases using the public dataset (1). Results: The BM and NM groups exhibited similar TP53 (33.3% vs. 55.6%, p=0.15) and PIK3CA (23.8% vs. 25.9%, p=1) mutation rates. The mutation rates of AP3B1 (38.1% vs. 3.7%), DHTKD1 (23.8% vs. 0), ERCC6L2 (38.1% vs. 7.4%), DNAH5 (33.3% vs. 3.7%), ZNF207 (33.3% vs. 7.4%), SPATA31E1 (19.0% vs. 0), FAM111B (19.0% vs. 0), ATG3 (19.0% vs. 0), CDK14 (19.0% vs. 0), TUT4 (19.0% vs. 0), CCNB3 (19.0% vs. 0), MGA (19.0% vs. 0), CLCA1 (28.6% vs. 3.7%), BBS7 (28.5% vs. 3.7%) and GABRG1 (38.1% vs. 11.1%) were significantly (p<0.05) higher in the BM group than in the NM group. Among these genes, CDK14 and TUT4 were significantly downregulated, and ZNF207 and FAM111B were significantly upregulated in brain metastases compared to their matched primary breast cancers. Conclusions: We identified several genes with higher mutation rates in primary breast cancer of patients who eventually developed brain metastases. These genes warrant further investigation in the development of brain metastases in HER2-positive breast cancer. 1. Cosgrove et al. NC 2022.