School of Medicine, University College Cork, Cork, Ireland.
Cork Breast Research Centre, Cork University Hospital, Cork, Ireland.
Exp Mol Pathol. 2020 Jun;114:104404. doi: 10.1016/j.yexmp.2020.104404. Epub 2020 Feb 14.
de novo metastatic breast cancer (dnMBC) is responsible for 6-10% of breast cancer presentations with increasing incidence and has remained resistant to detection by mammography screening. Recent publications hypothesized that in addition to poor screening uptake, the presentation of dnMBC may be due to its unfavourable biology which remains unknown at the molecular level. Here we investigated the tumour biology of dnMBC in the form of clinicopathology, genomic alterations and differential gene expression to create a comparative landscape of de novo versus relapsed metastatic breast cancer (rMBC). Additionally, to address the current screening limitations, we conducted a preliminary biomarker investigation for early dnMBC detection.
In this retrospective case-control study, gene expression and clinical data were accessed from the Cancer Genome Atlas (TCGA) for primary tumours of treatment-naïve patients with dnMBC (n = 17), rMBC (n = 49), and normal tissue (n = 113). The clinical and histological data were assessed categorically using Fisher's Exact-Test for significance (p < .05), or continuously using the Mann-Whitney Test (p < .05) where appropriate. The differential gene expression analysis was performed using EdgeR's negative binomial distribution model with a false discovery rate (FDR) <0.05. The resulting gene list was analysed manually for roles in metastasis as well as ontologically using STRING-DB with FDR <0.05.
dnMBCs showed improved median survival vs rMBC (36 vs. 12 months). dnMBCs were more likely to be hormone receptor positive, less likely to be triple negative with lower histological lymphocytic infiltrate. In terms of genome alterations, dnMBCs had 4-fold increased PTEN mutations and poor survival with ABL2 and GATA3 alterations. Expression-wise, dnMBCs down-regulated TNFa, IL-17 signalling, and chemotaxis, while up-regulating steroid biosynthesis, cell migration, and cell adhesion. Biomarker analysis detected pre-existing and novel breast cancer biomarkers.
The comparative tumour landscape revealed significant clinical, pathological and molecular differences between dnMBC and rMBC, indicating that dnMBC may be a separate biological entity to rMBC at the primary level with differing paths to metastasis. Additionally, we provided a list of potential serum biomarkers that may be useful in detecting dnMBC in its pre-metastatic window if such a window exists.
新发转移性乳腺癌（dnMBC）占乳腺癌就诊病例的 6-10%，发病率不断上升，并且仍然难以通过乳房 X 线筛查检测到。最近的研究假设，除了筛查参与度低之外，dnMBC 的表现可能与其分子水平上未知的不良生物学特性有关。在这里，我们通过临床病理、基因组改变和差异基因表达来研究 dnMBC 的肿瘤生物学，以创建新发转移性乳腺癌与复发性转移性乳腺癌（rMBC）的对比图谱。此外，为了解决当前的筛查局限性，我们对早期 dnMBC 的检测进行了初步的生物标志物研究。
在这项回顾性病例对照研究中，我们从癌症基因组图谱（TCGA）中获取了治疗初治 dnMBC（n=17）、rMBC（n=49）和正常组织（n=113）患者的基因表达和临床数据。使用 Fisher 精确检验评估临床和组织学数据的显著性（p<0.05），或使用 Mann-Whitney 检验（p<0.05）进行连续分析。差异基因表达分析使用 EdgeR 的负二项分布模型进行，假发现率（FDR）<0.05。使用 STRING-DB 对所得基因列表进行手动分析，以确定其在转移中的作用，并使用 FDR<0.05 进行本体论分析。
dnMBC 的中位生存期优于 rMBC（36 个月 vs. 12 个月）。dnMBC 更可能为激素受体阳性，三阴性更少，组织学淋巴细胞浸润程度更低。在基因组改变方面，dnMBC 中 PTEN 突变增加了 4 倍，ABL2 和 GATA3 改变与生存率差有关。在表达方面，dnMBC 下调了 TNFa、IL-17 信号和趋化作用，而上调了类固醇生物合成、细胞迁移和细胞黏附。生物标志物分析检测到了现有的和新的乳腺癌生物标志物。
肿瘤对比图谱揭示了 dnMBC 和 rMBC 之间在临床、病理和分子方面的显著差异，这表明 dnMBC 可能是原发性水平上与 rMBC 不同的生物学实体，具有不同的转移途径。此外，如果存在这种转移前窗口，我们提供了一个潜在的血清生物标志物列表，这些标志物可能有助于在其转移前窗口检测 dnMBC。
