Survival is associated with repressive histone trimethylation markers in both HR-positive HER2-negative and triple-negative breast cancer patients

About 30% of patients with hormone receptor (HR)-positive breast cancers and up to 50% of human epidermal growth factor receptor 2 (HER2)-positive patients develop progression due to treatment resistance, highlighting the need for more differentiated tumor classifications within the breast cancer molecular subtype to optimize the therapies. We aim to examine the roles of histone modification markers. The levels of common repressive histone markers, histone H3 lysine 9 trimethylation (H3K9me3), histone H3 lysine 27 trimethylation (H3K27me3), and histone H4 lysine 20 trimethylation (H4K20me3), in tumors were evaluated by immunohistochemistry for 914 breast cancer patients. The subjects were followed up until December 2021. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were estimated using Cox regression models. For H3K27me3, patients with the high level had a longer PFS rate (81.3%) than that with the low level (73.9%) within HR-positive/HER2-negative subtype during a follow-up of 85 months only in univariate analysis (P < 0.05). For H3K9me3, the significant association between the high level of it and the longer OS [HR = 0.57, P < 0.05] was found within HR-positive/HER2-negative subtype in multivariate analysis. For H4K20me3, patients with the high level had a longer both OS [HR = 0.38] and PFS [HR = 0.46] within HR-positive/HER2-negative subtype, while had a shorter OS [HR = 3.28] in triple-negative breast cancer (TNBC) in multivariate analysis (all P < 0.05). H3K9me3 and H3K27me3 were the potential prognostic markers for breast cancer patients with HR-positive/HER2-negative subtype. Importantly, H4K20me3 was a robust prognostic marker for both HR-positive/HER2-negative and TNBC patients.

Automated summary

About 30% of HR-positive breast cancer patients and up to 50% of HER2-positive patients develop progression due to treatment resistance, highlighting the need for more differentiated tumor classifications. Histone modification markers, including H3K9me3, H3K27me3, and H4K20me3, were evaluated in 914 breast cancer patients. Higher levels of H3K9me3 and H3K27me3 were associated with longer overall survival and progression-free survival in HR-positive/HER2-negative subtype, while higher levels of H4K20me3 were associated with longer overall survival and progression-free survival in this subtype as well as shorter overall survival in triple-negative breast cancer.