尽管乳腺癌（BC）的风险随着年龄增长而增加，但较年轻女性的BC比较年长女性更具侵袭性，死亡率更高。我们对年轻女性的BC的基因组景观进行了表征。在两个大型队列[AACR-GENIE8.1（n = 11,594）和METABRIC（n = 2509）]中研究了女性BC患者在不同年龄组（<40岁，40-60岁，> 60岁）之间的临床病理学、分子和基因组差异。Cox比例回归分析METABRIC队列中年龄组对疾病特异性生存（DSS）和无复发生存（RFS）以及GENIE队列中进展无病生存（PFS）的预后影响。使用卡方检验评估基因组改变与年龄组之间的统计关联。 生存分析显示40岁以下的女性DSS（风险比（HR）：1.52，p = 0.005），RFS（HR：1.4，p = 0.006）和PFS（HR：1.82，p = 0.0003）较40-60岁的女性更短，且RFS（HR：1.5，p = 0.001）和PFS（HR：2.95，p < 0.0001）较60岁以上女性更短。METABRIC队列中的分子亚型显示，40岁以下的女性以基底样和HER2阳性亚型为主，并且较不富集于伏露A和B亚型（p < 0.0001）。两个队列中基因组改变的表征表明，40岁以下女性的BC较富集于TP53突变（FDR < 0.0001），BRCA1突变（FDR = 0.01），ERBB2扩增（FDR < 0.001），CDK12扩增（FDR < 0.001）和PPM1D扩增（FDR < 0.001）。相反，年龄较大的女性（> 60岁）的BC较富集于PIK3CA，KMT2C和CDH1突变（FDR < 0.0001）。 年轻女性的BC与较短的生存和更具侵袭性的基因组特征相关，包括TP53和BRCA1的突变以及ERBB2和CDK12的扩增。这些发现有潜力影响临床试验设计和治疗。©2023。外科肿瘤学学会。

Although breast cancer (BC) risk increases with age, BC in younger women is more aggressive with higher mortality compared with older women. We characterize the genomic landscape of BCs in younger women.Clinicopathologic, molecular, and genomic differences across age groups (< 40 years, 40-60 years, > 60 years) in female BC patients were investigated in two large cohorts [AACR-GENIE8.1 (n = 11,594) and METABRIC (n = 2509)]. Cox-proportional regression analyzed the prognostic impact of age groups for disease-specific survival (DSS) and recurrence-free survival (RFS) in METABRIC and progression-free survival (PFS) in GENIE cohorts. Chi-squared test was used to assess statistical associations between genomic alterations and age groups.Survival analysis showed that women < 40 years had shorter DSS [hazard ratio (HR): 1.52, p = 0.005], RFS (HR: 1.4, p = 0.006), and PFS (HR: 1.82, p = 0.0003) compared with women 40-60 years, and shorter RFS (HR: 1.5, p = 0.001) and PFS (HR: 2.95, p < 0.0001) compared with women > 60 years. Molecular subtypes in the METABRIC cohort showed women < 40 years were enriched with basal, and HER2+ subtypes, and less enriched with luminal A and B subtype (p < 0.0001). Characterization of genomic alterations in both cohorts demonstrated that BCs in women < 40 years were more enriched with TP53 mutations (FDR < 0.0001), BRCA1 mutations (FDR = 0.01), ERBB2 amplifications (FDR < 0.001), CDK12 amplifications (FDR < 0.001), and PPM1D amplifications (FDR < 0.001). In contrast, BCs in older women (> 60 years) were more enriched with PIK3CA, KMT2C, and CDH1 mutations (FDR < 0.0001).BCs in young women are associated with shorter survival and more aggressive genomic features, including mutations in TP53 and BRCA1, and amplifications in ERBB2 and CDK12. These findings have the potential to impact clinical trial design and treatment.© 2023. Society of Surgical Oncology.