HER2 amplification is associated with higher tumor mutation burden in breast cancer

Background: ErbB family consists of four transmembrane proteins (ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4) and plays a prominent role in the process of cell growth. Previous studies suggested that EGFR gene driven non-small-cell-cancer exhibited a suppressive immunity with lower tumor mutation burden (TMB) level. HER2 gene amplification (HER2+) is a well-known poor prognosis predictor in breast cancer and anti-HER2 target therapy has significantly improved the clinical prognosis of HER2+ patients. However, the association between HER2 gene alteration and TMB in breast cancer is still unclear. Methods: Whole-exome sequencing data and clinical data of 366 breast tumors from The Cancer Genome Altas (TCGA) and next generation sequencing (NGS) data of 335 breast tumors from clinical dataset were analyzed to explore the association between HER2 gene alteration and TMB. TMB was defined as total number of somatic non-synonymous mutations in coding region. Results: 20.5% (75/366) of breast tumors in TCGA cohort and 20.3% (68/335) in clinical cohort harbored HER2 amplification. HER2 amplification was significantly associated with higher TMB in both TCGA cohort (P = 0.010) and clinical cohort (P = 0.008). HER2 somatic alteration occurred in 3.7% (12/366) of breast tumors in TCGA cohort and 7.2% (24/335) in clinical cohort. HER2 somatic alteration was also associated with higher TMB level in TCGA cohort (P = 0.016), but no association was observed in clinical cohort (P = 0.339). In addition, hormonal receptor (HR) + HER2- breast tumors exhibited the lowest TMB level compared with HR+ HER2 + (P = 0.001), HR-HER2 + (P = 0.052) and triple negative breast cancer (P = 0.000). Patients with low TMB level also tended to have a better overall survival than patients with higher TMB level (median, 216.6 vs. 112.0 months; HR, 0.572; 95% CI 0.31-3.05; P = 0.067). Conclusions: HER2 amplification is associated with higher TMB in breast cancer. These findings may assist the selection of breast cancer patients likely to benefit from immunotherapy. Legal entity responsible for the study: Yongmei Yin and Shaoqiang Zhou. Funding: National Natural Science Foundation of China. Disclosure: All authors have declared no conflicts of interest.