Genomic spectra of lymphovascular invasion in breast cancer.

OBJECTIVE

Lymphovascular invasion (LVI) is a crucial step in metastasis and is closely associated with poor prognosis in patients with breast cancer. However, its clinical and molecular characteristics remain insufficiently defined. We aimed to identify molecular targets for LVI-positive (LVI+) breast cancer and predict patient prognosis via the analysis of genomic variations using targeted sequencing.

METHODS

We established a large-scale targeted sequencing cohort of 4,079 breast cancer samples, which included 3,159 early-stage and locally advanced patients with available LVI statuses. Comparisons of somatic mutation frequencies and germline pathogenic/likely pathogenic (P/LP) mutation frequencies, mutational signature analyses, and mutual exclusivity and co-occurrence analyses were performed to identify key genomic features involved in LVI+ patients. Additionally, Kaplan-Meier survival analysis was conducted to further explore the prognostic value of co-mutations in LVI+ cases.

RESULTS

We observed that LVI+ patients with the hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) and triple-negative breast cancer (TNBC) subtypes exhibited worse disease-free survival. Notably, HR+/HER2- and HER2+ breast cancer patients with LVI displayed distinct genomic features compared with LVI- tumors. Specifically, LVI+ HR+/HER2- tumors exhibited greater frequencies of somatic mutations in and , germline P/LP variations, and an enrichment of clock-like single-base substitution (SBS)1 mutational signatures. In contrast, LVI+ HER2+ tumors demonstrated a higher incidence of somatic mutations and increased activity of the apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC)-associated SBS2 signature. Furthermore, we revealed that the co-mutation of and could serve as a potential prognostic marker for LVI+ HR+/HER2- patients.

CONCLUSIONS

Our findings provide a comprehensive overview of the genomic characteristics of LVI in breast cancer, thereby offering insights that may help in refining precision treatment strategies for LVI+ breast cancer patients.