Genomic Landscape in Early Onset Breast Cancer: A Comprehensive Analysis from the Tempus Database
ESMO 2026
Nerea Lopetegui-Lia, Sinead Cullina, Alexus LeVee, Unnati Jariwala, Stamatina Fragkogianni, Kayla Layng, Jacob Mercer, Himanshu Savardekar, Emily Teslow, James Rae, Erin Cobain, Maryam Lustberg, Sara Myers, Irene Kang, Daniel Stover
Background
Early onset breast cancer (EOBC; ≤ 45 years) is a growing public health challenge and the leading cause of cancer-death in young women. While next-generation sequencing (NGS) has expanded genomically targeted therapy approvals, outcomes in EOBC remain worse than non-EOBC. This study characterized the genomic landscape of EOBC.
Methods
Women with invasive BC and Tempus xT NGS (DNA; 648 genes) were retrospectively identified from the Tempus Lens database. Age groups:15-29, 30-44, 45-59, and 60+ years. Somatic single nucleotide variants (SNVs)/indels and copy number variations (CNVs) were compared across age groups using Fisher’s exact test or Pearson’s Chi-squared Test (q-value <0.05 statistically significant).
Results
Of 17,129 patients included, 3,560 (20.6%) were EOBC (282 aged 15–29; 3,278 aged 30–44) and 7,401 were non-EOBC (aged 60+). EOBC were enriched for HER2+ compared to non-EOBC (p<0.001). Advanced stage at diagnosis was more common in EOBC, 33% were stage III in 15–29 vs 15% in 60+, whereas stage I was less common in EOBC (5.8% vs. 14%); all p<0.001. Among somatic SNV/indels, EOBC harbored higher frequencies of TP53 (51–52% vs. 46%), BRCA1 (2.8–5.7% vs. 1.4%), BRCA2 (3.2–3.7% vs. 2.1%), and GATA3 (14–15% vs. 7.1%) compared to aged 60+ (all q<0.001). Conversely, PIK3CA (16–25% vs. 39%) and CDH1 (0.7–4.3% vs. 15%), were less prevalent in EOBC (both q<0.001). CNV analysis demonstrated EOBC enrichment for ERBB2 amplifications (10–11% vs. 5.9%), MDM2, PPM1D, RPS6KB1, CDK12, PTEN, ZNF217, FGFR pathway genes, and MYC (all q< 0.05).
Conclusions
EOBC is characterized by a distinct clinical and genomic profile, including more advanced stage at presentation, HER2+ subtype enrichment, and higher frequencies of TP53, BRCA1/2, and GATA3 mutations alongside widespread oncogene amplifications. The lower prevalence of PIK3CA, an actionable therapeutic target, coupled with enrichment for ERBB2, FGFR pathway, and cell cycle gene amplifications suggests that EOBC may derive differential benefit from targeted therapies. These findings underscore the need for age-specific trials and precision oncology to improve EOBC outcomes.
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