Tumor mutation burden and gene alteration are associated with short disease-free survival in locally advanced triple-negative breast cancer.

BACKGROUND

In locally advanced triple-negative breast cancer (TNBC), patients who did not achieve pathologic complete response (non-pCR) after neoadjuvant chemotherapy develop rapid tumor metastasis. Tumor mutation burden (TMB) is a potential biomarker of cancer therapy, though whether it is applicable to TNBC is still unclear.

METHODS

A total of 14 non-pCR TNBC patients were enrolled, and tissue samples from radical operation were collected. Of these, 7 cases developed disease progression within 12 months after operation [short disease-free survival (short DFS)], while others showed longer DFS over 1 year (long DFS). Next generation sequencing (NGS) analysis targeting 422 cancer-related genes and studies were performed.

RESULTS

A total of 72 mutations were detected within 14 patients, which ranged from 1 to 8 per patient with a median mutations number of 5. The median number of mutations in the short-DFS group was higher than that in the long-DFS group (6.0 . 4.3; P0.094). Furthermore, 6 gene mutation types were detected, with missense mutations displayed in the majority (36/72, 50.0%). No correlation between mutation type and DFS was found. Among 422 cancer-related genes, alterations in 30 genes were detected. (12/14, 85.7%) was the most common mutation gene in the entire cohort. mutations significantly occurred in patients with high Ki-67 scores (P=0.013). Additionally, 4 mutations of (57.1%, 4/7) and 3 of (42.9%, 3/7) were only detected in the short-DFS group, while patients with mutation had a significantly shorter DFS period (P=0.026). Experiments confirmed that gene was widely expressed in various breast cancer cell lines. Knockdown of in MD-MBA-231 cells by small interfering RNA (siRNA) decreased the expression of , and increased the levels of vimentin, , and .

CONCLUSIONS

In non-pCR TNBC, mutation and TMB elevated in patients with short-DFS, indicating the potential prognostic biomarkers and therapeutic molecular targets for locally advanced TNBC.