Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
Cancer. 2020 Jul 15;126(14):3209-3218. doi: 10.1002/cncr.32922. Epub 2020 May 8.
Age at the time of breast cancer diagnosis not only predicts clinical outcome but also indicates distinct molecular characteristics that provide the rationale for appropriate treatment strategies. However, to the authors' knowledge, little is known regarding the molecular profile and biological basis of triple-negative breast cancers (TNBCs) occurring in young and elderly patients.
Using the study institution's largest, single-center, multiomics TNBC data set, the authors analyzed the clinical and genomic features of young (aged ≤39 years) and elderly (aged ≥65 years) patients with TNBC.
In the current study, a total of 50 patients, 354 patients, and 69 patients, respectively, were grouped as young, intermediate, and elderly patients with TNBC. Young patients with TNBC had worse short-term survival, upregulation of DNA repair, cell cycle and RNA metabolism gene sets, frequent pathogenic germline variants, and predominant homologous recombination deficiency-related mutational signatures. Several copy number alterations also were found to be enriched in young patients with TNBC. Nearly one-half of the TNBC cases in elderly patients were of the luminal androgen receptor subtype. TNBC in elderly patients was identified as being associated with severe fibrosis; a lower Ki-67 index; and somatic mutations in PIK3CA, KMT2D, ERBB2, ERBB3, and their corresponding pathways. Elderly patients with TNBC also were more likely to harbor targetable mutations.
The findings of the current study indicated that young patients with TNBC had an enhanced cell cycle, which may have helped to explain their inferior short-term survival, whereas the homologous recombination deficiency and enriched pathogenic germline variants observed among young patients with TNBC suggested the need for genetic counseling and testing, as well as the potential use of DNA damage agents and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. Molecular characteristics of elderly patients with TNBC, although suggesting less response to chemotherapy, provided a rationale for the routine detection of actionable somatic mutations.
乳腺癌诊断时的年龄不仅预测临床结局，而且还提示了独特的分子特征，为制定适当的治疗策略提供了依据。然而，据作者所知，对于年轻和老年患者中发生的三阴性乳腺癌（TNBC）的分子谱和生物学基础知之甚少。
作者使用研究机构最大的、单中心的、多组学 TNBC 数据集，分析了年轻（≤39 岁）和老年（≥65 岁）TNBC 患者的临床和基因组特征。
在本研究中，分别将 50 例、354 例和 69 例 TNBC 患者分为年轻、中年和老年患者组。年轻的 TNBC 患者短期生存率较差，DNA 修复、细胞周期和 RNA 代谢基因集上调，频繁发生致病性种系变异，且以同源重组缺陷相关突变特征为主。还发现一些拷贝数改变在年轻的 TNBC 患者中富集。老年患者中几乎有一半的 TNBC 病例为腔面雄激素受体亚型。老年患者的 TNBC 被认为与严重纤维化、较低的 Ki-67 指数、PIK3CA、KMT2D、ERBB2、ERBB3 及其相应通路的体细胞突变有关。老年 TNBC 患者也更有可能携带可靶向的突变。
本研究的结果表明，年轻的 TNBC 患者具有增强的细胞周期，这可能有助于解释其短期生存率较差的情况，而年轻的 TNBC 患者中观察到的同源重组缺陷和丰富的致病性种系变异表明需要进行遗传咨询和检测，以及潜在地使用 DNA 损伤剂和聚（腺苷二磷酸核糖）聚合酶（PARP）抑制剂。尽管老年 TNBC 患者的分子特征提示对化疗的反应性较低，但为常规检测可操作的体细胞突变提供了依据。
