Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Department of Surgery, Yokohama City University, Yokohama, Japan.
Ann Surg Oncol. 2020 Oct;27(11):4475-4485. doi: 10.1245/s10434-020-08608-1. Epub 2020 May 20.
Cancer biology dominates the behavior and prognosis of a tumor. Although Nottingham histological grade is a subjective pathological determination, it has been accepted as a surrogate model for cancer biology. As such, histologic grade was incorporated into the latest 8th edition of the American Joint Committee on Cancer breast cancer staging system. In this study, we hypothesized that grade 3 breast cancers demonstrate aggressive molecular biological profiles, reflecting worse biology and possible underlying immunogenicity.
Transcriptomic and clinical data were obtained from the Molecular Taxonomy of Breast Cancer International Consortium, and the findings were validated by The Cancer Genome Atlas breast cancer cohort and GSE25066.
Overall, 2876 patients were analyzed in this study. Grade 3 tumors were more common in estrogen receptor (ER)-negative, advanced-stage patients, and were associated with human epidermal growth factor receptor 2 and basal subtypes by the PAM50 classifier, as well as with increased MKI67 expression (all p <0.001). Disease-free survival was significantly worse in grade 3 tumors (all cohorts). Gene set enrichment analysis demonstrated that grade 3 tumors were significantly enriched with not only cell proliferation and cell cycle-related gene sets but also immune activity-related gene sets. CIBERSORT confirmed that grade 3 tumors were infiltrated with macrophage M1, follicular helper T cells, and activated natural killer cells (all p <0.001). Furthermore, grade 3 tumors were associated with more diverse T cell receptors (p =0.001) and increased cytolytic activity (p <0.001). Lastly, major T-cell exhaustion markers were significantly elevated in grade 3 breast cancers (p <0.001).
Grade 3 breast cancers demonstrated aggressive transcriptomic features with enhanced immunogenicity and elevated T-cell exhaustion markers.
癌症生物学主导着肿瘤的行为和预后。虽然 Nottingham 组织学分级是一种主观的病理判断，但它已被接受为癌症生物学的替代模型。因此，组织学分级被纳入了最新的第 8 版美国癌症联合委员会乳腺癌分期系统。在这项研究中，我们假设 3 级乳腺癌表现出侵袭性的分子生物学特征，反映了更差的生物学和可能潜在的免疫原性。
从乳腺癌国际分子分类联盟获得转录组和临床数据，并通过癌症基因组图谱乳腺癌队列和 GSE25066 进行验证。
总体而言，本研究分析了 2876 例患者。3 级肿瘤在雌激素受体（ER）阴性、晚期患者中更为常见，并且通过 PAM50 分类器与人类表皮生长因子受体 2 和基底亚型相关，以及与 MKI67 表达增加相关（均 p<0.001）。无病生存率在 3 级肿瘤中明显较差（所有队列）。基因集富集分析表明，3 级肿瘤不仅显著富集了与细胞增殖和细胞周期相关的基因集，而且还与免疫活性相关的基因集相关。CIBERSORT 证实 3 级肿瘤浸润了巨噬细胞 M1、滤泡辅助 T 细胞和活化的自然杀伤细胞（均 p<0.001）。此外，3 级肿瘤与更多样的 T 细胞受体相关（p=0.001），并具有更高的细胞毒性活性（p<0.001）。最后，3 级乳腺癌中主要的 T 细胞耗竭标志物显著升高（p<0.001）。
3 级乳腺癌表现出侵袭性转录组特征，具有增强的免疫原性和升高的 T 细胞耗竭标志物。
