Supplementary Material for: Identifying High-Risk Triple-Negative Breast Cancer Patients by Molecular Subtyping

<b><i>Introduction:</i></b> Triple-negative breast cancer (TNBC) is considered the most aggressive type of breast cancer (BC) with limited options for therapy. TNBC is a heterogeneous disease and tumors have been classified into TNBC subtypes using gene expression profiling to distinguish basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor (LAR), and one nonclassifiable group (called unstable). <b><i>Objectives:</i></b> The aim of this study was to verify the clinical relevance of molecular subtyping of TNBCs to improve the individual indication of systemic therapy. <b><i>Patients and Methods:</i></b> Molecular subtyping was performed in 124 (82%) of 152 TNBC tumors that were obtained from a prospective, multicenter cohort including 1,270 histopathologically confirmed invasive, nonmetastatic BCs (NCT 01592825). Treatment was guideline-based. TNBC subtypes were correlated with recurrence-free interval (RFI) and overall survival (OS) after 5 years of observation. <b><i>Results:</i></b> Using PAM50 analysis, 87% of the tumors were typed as basal with an inferior clinical outcome compared to patients with nonbasal tumors. Using the TNBCtype-6 classifier, we identified 23 (15%) of TNBCs as LAR subtype. After standard adjuvant or neoadjuvant chemotherapy, patients with LAR subtype showed the most events for 5-year RFI (66.7 vs. 80.6%) and the poorest probability of 5-year OS (60.0 vs. 84.4%) compared to patients with non-LAR disease (RFI: adjusted hazard ratio [aHR] = 1.87, 95% confidence interval [CI] 0.69–5.05, <i>p</i> = 0.211; OS: aHR = 2.74, 95% CI 1.06–7.10, <i>p</i> = 0.037). <b><i>Conclusion:</i></b> Molecular analysis and subtyping of TNBC may be relevant to identify patients with LAR subtype. These cancers seem to be less sensitive to conventional chemotherapy, and new treatment options, including androgen receptor-blocking agents and immune checkpoint inhibitors, have to be explored.

<b><i>引言：</i></b> 三阴性乳腺癌（Triple-negative breast cancer, TNBC）被认为是最具侵袭性的乳腺癌亚型，治疗选择极为有限。三阴性乳腺癌属于异质性疾病，目前已通过基因表达谱分析将其分为多个亚型：基底样1型、基底样2型、免疫调节型、间质型、间质干细胞样型、腔面雄激素受体型（LAR），以及一类无法分类的组别（unstable，即不稳定型）。<b><i>研究目标：</i></b> 本研究旨在验证三阴性乳腺癌分子分型的临床相关性，以优化全身治疗的个体化适应症选择。<b><i>患者与研究方法：</i></b> 本研究从一项前瞻性多中心队列研究中选取124例三阴性乳腺癌肿瘤样本（占总样本量的82%）完成分子分型，该队列共纳入1270例经组织病理学确认的浸润性非转移性乳腺癌（临床试验编号：NCT 01592825）。所有患者均接受基于临床指南的治疗方案。随后将三阴性乳腺癌亚型与无复发生存间期（recurrence-free interval, RFI）及5年随访后的总生存期（overall survival, OS）进行相关性分析。<b><i>研究结果：</i></b> 通过PAM50分析，87%的肿瘤被归类为基底样型，该亚型患者的临床结局劣于非基底样型患者。采用TNBCtype-6分类器，我们将23例（15%）三阴性乳腺癌鉴定为LAR亚型。在接受标准辅助或新辅助化疗后，与非LAR亚型患者相比，LAR亚型患者的5年无复发生存间期事件发生率更高（66.7% vs. 80.6%），且5年总生存率更低（60.0% vs. 84.4%）（无复发生存间期：校正风险比[adjusted hazard ratio, aHR] = 1.87，95%置信区间[confidence interval, CI] 0.69–5.05，<i>p</i> = 0.211；总生存期：aHR = 2.74，95%CI 1.06–7.10，<i>p</i> = 0.037）。<b><i>研究结论：</i></b> 三阴性乳腺癌的分子分析与分型有助于识别LAR亚型患者。此类癌症对常规化疗的敏感性相对较低，因此亟需探索包括雄激素受体阻断剂与免疫检查点抑制剂在内的新型治疗方案。