Tian Chonglin, Liu Sujing, Wang Yongsheng, Song Xianrang
Graduate School, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Front Oncol. 2021 Mar 11;11:588136. doi: 10.3389/fonc.2021.588136. eCollection 2021.
The 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).
We 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).
The 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.
This 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.
乳腺癌肝转移（BCLM）的预后较差，其分子机制尚不清楚。我们旨在确定影响BCLM患者预后的因素，并研究肝转移（LM）的基因组格局。
我们描述了BCLM患者的预后，并基于临床病理因素重点对这些患者进行预后预测。通过使用在山东省肿瘤防治研究院（SCHI）接受治疗的231例BCLM患者队列构建无进展生存期（PFS）和总生存期（OS）的列线图模型。我们利用纪念斯隆凯特琳癌症中心（MSKCC）的217例LM样本和479例原发性乳腺癌（pBC）未配对样本的靶向测序数据集，探索LM的分子机制并构建驱动基因、突变特征。
SCHI队列中231例BCLM患者的中位随访时间为46个月。1年、2年和5年时LM的累积发生率分别为17.5%、45.0%和86.8%。中位PFS和OS分别为7个月（95%CI，6 - 8）和22个月（95%CI，19 - 25）。增加LM患者进展风险的独立因素为卡氏功能状态（KPS）≤80、三阴性乳腺癌（TNBC）亚型、Ⅲ级、CA153呈上升趋势以及无病生存期（DFS）≤1年。同时，增加LM患者死亡风险的独立因素为Ki-67≥30%、Ⅲ级、CA153呈上升趋势、初发LM时伴有疼痛、糖尿病以及无病间期（DFI）≤1年。在MSKCC数据集中，LM驱动基因有ESR1、AKT1、ERBB2和FGFR4，且LM匹配三种显著的突变特征：载脂蛋白B mRNA编辑酶催化多肽样（APOBEC）胞苷脱氨酶、紫外线暴露和DNA错配修复缺陷。
本研究从临床病理因素到基因水平系统地描述了LM的生存预后和特征。这些结果不仅使临床医生能够评估BCLM患者疾病进展的风险以优化治疗方案，而且有助于我们更好地理解肿瘤转移和演变的潜在机制，并为耐药患者提供具有潜在益处的新治疗靶点。
