青年与老年女性三阴性乳腺癌分子特征
根据乳腺癌确诊时的年龄，不仅可以预测临床结局，而且可以预示不同的分子特征，从而为采取适当的治疗策略提供依据。不过，青年与老年患者三阴性乳腺癌分子特征和生物学基础的区别尚不明确。
2020年5月8日，美国癌症学会官方期刊《癌症》在线发表复旦大学附属肿瘤医院马丁、江一舟、肖毅、谢梦丹、赵珅、金希、徐晓恩、邵志敏等学者的研究报告，首次对青年与老年患者三阴性乳腺癌的分子特征、生物学基础和临床治疗策略进行了比较。
该单中心回顾研究对目前全球最大的单中心多组学三阴性乳腺癌数据库进行回顾分析，比较了青年（≤39岁）与老年（≥65岁）三阴性乳腺癌患者临床和基因组学特征。
结果，三阴性乳腺癌患者共计473例，青年、中年、老年分别为50例、354例、69例。
青年与老年三阴性乳腺癌患者相比：
早期转移较多
疾病复发较多
短期生存较差
DNA修复、细胞周期、RNA代谢基因表达水平较高
生殖细胞致病变异比例较高
同源重组缺陷相关突变比例较高
基因拷贝数量变化比例较高
老年与青年三阴性乳腺癌患者相比：
雄激素受体阳性比例较高（49%）
重度纤维化比例较高
增殖指数Ki-67较低
体细胞PIK3CA、KMT2D、ERBB2、ERBB3基因及其相关通路突变比例较高
可靶向突变比例较高
因此，该研究结果表明，青年三阴性乳腺癌患者细胞分裂增殖较快，可能有助于解释其短期生存较差，同源重组缺陷和生殖细胞致病变异比例较高，故有必要进行遗传咨询和检测，可能需要采用破坏DNA的化疗药物和多腺苷二磷酸核糖聚合酶（PARP）抑制剂。老年三阴性乳腺癌患者分子特征表明，虽然对化疗效果可能较差，但是为常规检测体细胞可靶向突变提供了理论依据。
相关链接
Cancer. 2020 May 8. [Epub ahead of print]
Integrated molecular profiling of young and elderly patients with triple-negative breast cancer indicates different biological bases and clinical management strategies.
Ma D, Jiang YZ, Xiao Y, Xie MD, Zhao S, Jin X, Xu XE, Shao ZM.
Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China.
Triple-negative breast cancer (TNBC) diagnosed in young women is characterized by a higher incidence of early metastasis or disease recurrence, upregulated DNA repair, cell cycle and RNA metabolism gene sets, frequent pathogenic germline variants, a homologous recombination deficiency-related mutational signature, and several focal copy number alterations. TNBC diagnosed among elderly women is associated with the luminal androgen receptor subtype; severe fibrosis; a lower Ki-67 index; and somatic mutations in PIK3CA, KMT2D, ERBB2, and ERBB3 and their corresponding pathways as well as more frequent actionable mutations. These findings provide clues regarding the unique biology of and potential therapeutic strategies for TNBCs arising in young and elderly women.
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 ≤39 years) and elderly (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.
KEYWORDS: age of onset, DNA copy number variations, gene expression, mutation, triple-negative breast neoplasms
DOI: 10.1002/cncr.32922