Prognosis and Genomic Landscape of Liver Metastasis in Patients With Breast Cancer

Abstract

ObjectiveThe prognosis of breast cancer liver metastasis (BCLM) is poor, and its molecular mechanism is unclear. We aimed to determine the factors that affect the prognosis of patients with BCLM and investigate the genomic landscape of liver metastasis (LM).MethodsWe described the prognosis of patients with BCLM and focused on prognosis prediction for these patients based on clinicopathological factors. Nomogram models were constructed for progression-free survival (PFS) and overall survival (OS) by using a cohort of 231 patients with BCLM who underwent treatment at Shandong Cancer Hospital and Institute (SCHI). We explored the molecular mechanism of LM and constructed driver genes, mutation signatures by using a targeted sequencing dataset of 217 samples of LM and 479 unpaired samples of primary breast cancer (pBC) from Memorial Sloan Kettering Cancer Center (MSKCC).ResultsThe median follow-up time for 231 patients with BCLM in the SCHI cohort was 46 months. The cumulative incidence of LM at 1, 2, and 5 years was 17.5%, 45.0%, and 86.8%, respectively. The median PFS and OS were 7 months (95% CI, 6–8) and 22 months (95% CI, 19–25), respectively. The independent factors that increased the progression risk of patients with LM were Karnofsky performance status (KPS) ≤ 80, TNBC subtype, grade III, increasing trend of CA153, and disease-free interval (DFS) ≤ 1 year. Simultaneously, the independent factors that increased the mortality risk of patients with LM were Ki-67 ≥ 30%, grade III, increasing trend of CA153, pain with initial LM, diabetes, and DFI ≤ 1 year. In the MSKCC dataset, the LM driver genes were ESR1, AKT1, ERBB2, and FGFR4, and LM matched three prominent mutation signatures: APOBEC cytidine deaminase, ultraviolet exposure, and defective DNA mismatch repair.ConclusionThis study systematically describes the survival prognosis and characteristics of LM from the clinicopathological factors to the genetic level. These results not only enable clinicians to assess the risk of disease progression in patients with BCLM to optimize treatment options, but also help us better understand the underlying mechanisms of tumor metastasis and evolution and provide new therapeutic targets with potential benefits for drug-resistant patients.

Systematic Construction and Validation of a Prognostic Model for Hepatocellular Carcinoma Based on Immune-Related Genes

“…Recent studies revealed the inhibition of MMP9 which is regulated by α1-ACT, could suppress liver cancer development ( Zhu et al, 2017 ). Previous studies on ESR1 focused on breast cancer, and breast cancer patients highly expressing the ESR1 gene were shown to have a better prognosis; however, recent studies showed that ESR1 is also associated with breast cancer liver metastasis ( De Santo et al, 2019 ; Tian et al, 2021 ). We further found that MMP9 and ESR1 were independent predictors of HCC patient prognosis by performing multifactorial Cox regression analysis and we found that there are strong and significant correlation between MMP9 and ESR1 with CTLA-4.…”

Breast Cancer Genomics: Primary and Most Common Metastases

“…Defective DNA mismatch repair further contributes to the progression of liver metastasis. ESR1 has been discovered as the most mutually exclusive mutant gene pair in liver metastasis [96]. ESR1 is an estrogen receptor protein coding gene that is a biological indicator of tumor status in BC.…”

Clinical, Pathological, and Molecular Features of Breast Carcinoma Cutaneous Metastasis

“…Focusing on studies that analyzed specific metastases, Tian et al [ 62 ], using the MSKCC Dataset and POTUAM dataset, studied cases of hepatic metastases and unpaired primary breast tumors. They found that the driver genes for liver metastasis (LM) were ESR1 , AKT1 , ERBB2 , and FGFR4 and that LM matched three prominent mutation signatures: APOBEC cytidine deaminase, ultraviolet exposure, and defective DNA mismatch repair.…”