SUPERTAM_HGU133A Gene Set Enrichment Analysis (GSEA) in term of lymph node and distant metastasis

Background
Lymph node status is generally considered as one of the best prognostic factors in breast cancer. However, association between nodal and distant metastasis is not straightforward. Here we analyze differences between molecular mechanisms responsible for nodal and distant metastasis, and the impact of molecular subtype on this association.
Methods
We use SUPERTAM_HGU133A cohort of 836 patients with full microarray data available. Logistic regression evaluates distant metastasis risk, and Gene Set Enrichment Analysis (GSEA) is used to identify molecular mechanisms targetable in the key clinical scenarios.
Results
GSEA shows different molecular background for lymph node and distant metastasis and unique patterns of deregulated molecular processes in tumors of four breast cancer subtypes. Risk of distant metastasis in node positive luminal A patients is strong in SUPERTAM_HGU133A (OR: 2.401, CI: 1.316-4.380) dataset. For luminal A tumors, nodal positivity is associated with enrichment of NF-κB and Src, while distant metastasis is associated with strong mechanisms of cell cycle regulation, thrombolysis, DNA-repair, and immune response. Based on GSEA results, we select panels of promising inhibitors applicable for the key clinical scenarios depending on lymph node status that are currently being tested in vitro, in vivo, or in clinical trials.
Conclusions
Potential molecular targets are different for nodal and distant metastasis in breast cancer and are highly variable among different molecular subtypes. Panels of inhibitors have potential to improve the outcome of luminal A breast cancer patients based on lymph node status. We hope that further clinical trials have potential to translate the current knowledge from the laboratory to an improved treatment of breast cancer patients.

# 背景
淋巴结状态通常被认为是乳腺癌最佳预后因素之一。然而，淋巴结转移与远处转移之间的关联并非简单直接。本研究旨在分析介导淋巴结转移与远处转移的分子机制差异，以及分子亚型对该关联的影响。

# 方法
本研究使用包含836例患者的SUPERTAM_HGU133A队列，该队列带有完整的微阵列数据。采用逻辑回归评估远处转移风险，并使用基因集富集分析（Gene Set Enrichment Analysis, GSEA）识别关键临床场景下可靶向的分子机制。

# 结果
基因集富集分析结果显示，淋巴结转移与远处转移具有不同的分子背景，且四种乳腺癌分子亚型的肿瘤中存在独特的异常调控分子过程模式。在SUPERTAM_HGU133A数据集中，淋巴结阳性的腔A型（luminal A）患者远处转移风险显著升高（比值比（Odds Ratio, OR）: 2.401，置信区间（Confidence Interval, CI）: 1.316-4.380）。对于腔A型肿瘤，淋巴结阳性与NF-κB及Src通路的富集相关，而远处转移则与细胞周期调控、溶栓过程、DNA修复及免疫应答等强效分子机制相关。基于基因集富集分析结果，我们筛选出可根据淋巴结状态应用于关键临床场景的候选抑制剂组合，这些抑制剂目前正在体外、体内及临床试验中开展测试。

# 结论
乳腺癌中介导淋巴结转移与远处转移的潜在分子靶点存在差异，且在不同分子亚型间具有高度异质性。根据淋巴结状态匹配的抑制剂组合有望改善腔A型乳腺癌患者的预后。我们期望后续临床试验能够将当前实验室研究成果转化为更优化的乳腺癌患者治疗方案。