Breast cancer in adolescents and young adults has a specific biology and poor patient outcome compared with older patients.

Background: We aimed to clarify the features of adolescents and young adults (AYA: younger than 40 years old) breast cancer (BC) compared with other age groups in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC, given the effects of age-related hormonal status.

Methods: The cohorts analyzed were divided into AYA (15-39 years old), perimenopausal (40-54 years old), menopausal (55-64 years old), and old (65+ years old). Clinicopathological and biological features were analyzed using gene set variation analysis and xCell algorithm using transcriptome profiles from large public databases of ER-positive/HER2-negative BC (METABRIC; n = 1353, SCAN-B; n = 2381).

Results: In the ER-positive/HER2-negative subtype, pathological lymph node positivity, and Nottingham grade 3 were higher among AYA (all P < 0.001). AYA patients had a trend toward worse disease-specific and overall survival, particularly compared with the perimenopausal group. Estrogen response late signaling decreased with age (all P ≤ 0.001 in both METABRIC and SCAN-B cohorts). AYA was associated with significantly higher BRCAness and DNA repair than the other groups (all P < 0.05 in both cohorts). AYA significantly enriched cell proliferation-related and procancerous gene sets [mTORC1, unfolded protein response, and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling] when compared with the others (all P < 0.03 in both cohorts). Interestingly, these features have also been observed in tumors <2 cm. Infiltration of CD8, regulatory, T helper type 2 cells, and M1 macrophages was higher, while M2 macrophages were lower in AYA (all P < 0.03 in both cohorts). Finally, ER-positive/HER2-negative BC in AYA patients has different features of gene mutations, including AHNAK2, GATA3, HERC2, and TG, which were observed at a higher rate in AYA, and KMT2C, which was observed at a lower rate in AYA, compared with other age groups.

Conclusions: ER-positive/HER2-negative BC in AYA was highly proliferative with high immune cell infiltration compared with the other age groups.