Integrated molecular profiling of young and elderly patients with triple-negative breast cancer indicates different biological bases and clinical management strategies
Integrated molecular profiling of young and elderly patients with triple-negative breast cancer indicates different biological bases and clinical management strategies
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年轻和老年三阴性乳腺癌患者的综合分子谱表明不同的生物学基础和临床管理策略
DOI：
10.1002/cncr.32922
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发表时间：
2020-05-08
期刊：
影响因子：
6.2
通讯作者：
Shao, Zhi-Ming
中科院分区：
文献类型：
--
作者：
Ma, Ding;Jiang, Yi-Zhou;Shao, Zhi-Ming
背景：乳腺癌诊断时的年龄不仅可以预测临床结果，还可以显示不同的分子特征，为适当的治疗策略提供依据。然而，据作者所知，关于年轻和老年患者发生的三阴性乳腺癌（TNBC）的分子特征和生物学基础知之甚少。方法使用研究机构最大的，单中心，多组学TNBC数据集，作者分析了年轻患者的临床和基因组学特征。结果在本研究中，分别将总共50名患者、354名患者和69名患者分组为年轻、中等和老年TNBC患者。年轻TNBC患者的短期生存率更差，DNA修复、细胞周期和RNA代谢基因组上调，常见的致病性种系变异，以及主要的同源重组缺陷相关突变特征。还发现几种拷贝数改变在年轻TNBC患者中富集。老年患者中近一半的TNBC病例为管腔雄激素受体亚型。老年患者中的TNBC被确定为与重度纤维化、较低的Ki-67指数以及PIK 3CA、KMT 2D、ERBB 2、ERBB 3及其相应通路的体细胞突变相关。老年TNBC患者也更容易携带靶向突变。结论本研究的结果表明，年轻TNBC患者具有增强的细胞周期，这可能有助于解释他们较差的短期生存率，而在年轻TNBC患者中观察到的同源重组缺陷和丰富的致病性生殖系变异表明需要进行遗传咨询和检测，以及DNA损伤剂和聚（腺苷二磷酸核糖）聚合酶（PARP）抑制剂的潜在用途。老年TNBC患者的分子特征，虽然表明对化疗的反应较低，但为常规检测可操作的体细胞突变提供了依据。
Background 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.Methods Using the study institution's largest, single-center, multiomics TNBC data set, the authors analyzed the clinical and genomic features of young (aged = 65 years) patients with TNBC.Results 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.Conclusions 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.