Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Sci Rep. 2019 Nov 15;9(1):16942. doi: 10.1038/s41598-019-53482-x.
The fact that 20-40% of all breast cancer (BC) patients develop recurrence when 5 year survival is 90% strongly suggests that late recurrence, i.e. more than 5 years after diagnosis, is the remaining challenge to decrease the absolute number of BC deaths. Better understanding late recurrence is an essential first step to address this issue. We hypothesized that primary tumors with a distinctive tumor immune microenvironment will develop late recurrence. Accordingly, we evaluated the relationship between the timing of cancer recurrence, clinical factors, gene expression profiles, and immune status utilizing two published large cohorts. 308 primary BCs in TCGA were analyzed and categorized as: recurrence ≤2 years (Early, n = 49), between 2-5 years (Mid, n = 54), recurrence >5 years (Late, n = 20), and no recurrence >5 years (Survivors, n = 185). 1,727 primary BCs in METABRIC were analyzed and categorized similarly: Early, n = 170; distant (D), n = 19; local (L), Mid, n = 213; D, n = 21; L, Late, n = 199; D, n = 57, L, and Survivors, n = 1048. Utilizing pre-ranked GSEA, we showed that primary tumors with Survivors were associated with anti-cancer signaling such as INF-α/-γ response and TNF-α signaling, compared with all recurrence groups in pre-ranked GSEA. Furtherrmore, we found that host defense immunity (leukocyte fraction, lymphocyte infiltration, and macrophage fractions) was decreased in primary tumors with Late recurrence compared with Survivors. Utilizing the CIBERSORT algorithm, we showed anti-cancer lymphocytes, memory CD4+ T cells and γδT cells, were significantly lower, and pro-cancerous regulatory T cells were significantly higher in Late tumors compared with Survivors. In agreement, cytolytic activity score that assesses immune cell cytolytic activity was significantly lower in Late compared with Survivors. We demonstrated that not only host defense immunity, but also pro-cancerous immune cells and immune cell cytolytic activity in primary BC was associated with late recurrence.
事实上，20-40%的乳腺癌（BC）患者在 5 年生存率达到 90%时会出现复发，这强烈表明，晚期复发（即诊断后超过 5 年）仍然是降低绝对 BC 死亡人数的挑战。更好地了解晚期复发是解决这一问题的重要第一步。我们假设具有独特肿瘤免疫微环境的原发性肿瘤将发生晚期复发。因此，我们利用两个已发表的大型队列评估了癌症复发的时间、临床因素、基因表达谱和免疫状态之间的关系。TCGA 中的 308 例原发性 BC 进行了分析，并分为：复发≤2 年（早期，n=49）、2-5 年（中期，n=54）、复发>5 年（晚期，n=20）和>5 年无复发（幸存者，n=185）。METABRIC 中的 1727 例原发性 BC 进行了类似的分析和分类：早期，n=170；远处（D），n=19；局部（L），中期，n=213；D，n=21；L，晚期，n=199；D，n=57，L 和幸存者，n=1048。利用预排序 GSEA，我们发现与所有复发组相比，幸存者的原发性肿瘤与抗癌信号相关，如 INF-α/-γ 反应和 TNF-α 信号。此外，我们发现与幸存者相比，晚期复发的原发性肿瘤中宿主防御免疫（白细胞分数、淋巴细胞浸润和巨噬细胞分数）减少。利用 CIBERSORT 算法，我们发现抗癌淋巴细胞、记忆 CD4+T 细胞和γδT 细胞显著减少，而促癌性调节性 T 细胞显著增加。一致地，评估免疫细胞细胞毒性活性的细胞毒性活性评分在晚期肿瘤中明显低于幸存者。我们证明，不仅宿主防御免疫，而且原发性 BC 中的促癌性免疫细胞和免疫细胞细胞毒性活性与晚期复发有关。
