Tumor genomics in patients younger than 40 years of age with metastatic breast cancer.

Unique disease characteristics of younger patients warrants investigation of tumor genomics in young-onset metastatic breast cancer (MBC). Targeted DNA sequencing was completed for tumors of MBC patients diagnosed between 2009-2020. Multivariable logistic regression tested associations between single nucleotide variants (SNVs) and copy number variants and age at MBC diagnosis. Multivariable Cox regression estimated hazard ratios for overall survival (OS) by somatic alterations. Among 2,357 MBC patients, tumors of those ≤40 years at diagnosis (vs. >55) were more likely to harbor amplifications in ERBB2 and MYC (p < 0.01) and mutations in TP53 (odds ratio [OR] = 1.83, p < 0.001), and less likely to harbor mutations in CDH1 and PIK3CA (p < 0.001). OS was shorter among younger recurrent MBC patients [median: 2.8 (≤ 40) vs. 3.6 years ( > 55), p = 0.04], with SNVs in TP53 and PTEN associated with shorter OS. Distinct tumor genomics of young-onset MBC patients suggest differences in tumor biology that should guide investigation of targetable pathways.