Exploring tumor genomics and clinical outcomes in in adolescent and young adult (AYA) breast cancer.

Abstract

567 Background: Breast cancer in adolescents and young adults (AYAs, defined as individuals aged 39 or younger) often exhibits aggressive biological behavior and distinct clinical patterns compared to older patients. This research investigates the somatic mutations and clinical features that distinguish AYA breast cancer, aiming to uncover unique genomic and prognostic characteristics. Methods: We analyzed data from the METABRIC cohort using cBioPortal, focusing on 173 genes sequenced from 2,509 breast cancer cases. The dataset included information on copy number variations, gene expression, and long-term clinical outcomes. Tumor characteristics, mutation frequencies, and relapse-free survival (RFS) outcomes were compared between AYAs and older patients. Statistical methods employed included Chi-square tests for categorical data, Wilcoxon Rank-Sum tests for medians, and Cox regression for survival analysis. The 10 most commonly altered genes across the dataset were examined. Results: Of 2,498 patients included in the analysis, 143 were AYAs (5.7%) and 2,355 were older patients (94.3%). Compared to older patients, AYAs demonstrated: Lower ER-positive rates (37.8% vs. 74.9%), Higher ER-/HER2- subtype prevalence (25.2% vs. 11.6%), Greater lymph node positivity (52.4% vs. 41.3%), and Worse Nottingham Prognostic Index scores (median 5.04 vs. 4.04). Genomic analysis revealed significantly higher TP53 mutation frequencies in AYAs (58.9% vs. 33.2%, p < 0.01) and lower PIK3CA alterations (28.1% vs. 42.1%, p < 0.01). Other significantly altered genes in AYAs included TG, TRPS1, CASC8, POU5F1B, MYC, CASC11, NDRG1, and LINC02912. However, stratification by receptor subtypes (ER-/HER2-, ER+/HER2-, HER2+) showed no significant differences in TP53 or PIK3CA alterations between AYAs and older patients. AYA status ( < 40 years) was associated with worse recurrence-free survival (RFS) in univariable analysis and remained a significant predictor in multivariable analysis, adjusting for ER status, HER2 status, and nodal involvement (HR: 1.33, 95% CI: 1.00–1.77, p = 0.048). Conclusions: AYA breast cancer is marked by distinct genomic and clinical features, including higher TP53 mutation rates, lower PIK3CA mutation rates, more aggressive subtypes such as ER-/HER2-. While some genomic differences are less pronounced within biomarker-matched subgroups, AYAs remain at higher risk for recurrence. These findings highlight the urgent need for age-specific therapeutic strategies to improve outcomes in this population. Gene alteration event frequency by age group (AYA versus >39 years). Gene AYA >39 p-Value q-Value TP53 58.90% (86/146) 33.16% (780/2352) <0.001 <0.001 PIK3CA 28.08% (41/146) 42.05% (989/2352) <0.001 0.0442 TG 35.62% (52/146) 23.72% (558/2352) <0.01 0.0645 NDRG1 29.45% (43/146) 19.56% (460/2352) <0.01 0.126 TRPS1 30.82% (45/146) 23.04% (542/2352) 0.0347 0.340 CASC8 30.14% (44/146) 21.51% (506/2352) 0.0178 0.231 LINC02912 29.45% (43/146) 20.88% (491/2352) 0.0167 0.229 CASC11 30.14% (44/146) 21.73% (511/2352) 0.0235 0.268 MYC 30.14% (44/146) 21.68% (510/2352) 0.0234 0.268