Abstract PO3-13-12: ER-positive/HER2-negative breast cancer in Adolescent & Young Adult (AYA) age group has a specific biological feature and worse outcome compared to other generations
Authors: Oshi Masanori , Yamada Akimitsu , Sasamoto Mahato , Kawashima Kei , Fujiwara Yoshie , Adachi Shoko , Yamamoto Shinya , Narui Kazutaka , Ishikawa Takashi , Endo Itaru , Takabe Kazuaki 
Published: May 2024

Abstract
Background: Adolescents & Young Adults (AYA) is commonly defined as patients younger than 40 years old. Breast cancer patients in AYA has been reported to have poor outcome compared to other generation, however, the clinicopathological and biological features of AYA breast cancer remains controversial partly because many previous studies did not consider the difference in subtypes by age. We aim to clarify the features of AYA compared with the other age group in ER-positive/HER2-negative breast cancer, assuming the effects of age-related hormonal status.
Material and Methods: Each analyzed cohort were divided into four age groups; AYA (15-39yo), perimenopausal (40-55yo), menopausal (55-65yo), and old (65+yo). Clinicopathological and biological features were analyzed using gene set variation analysis and the xCell algorithm using mRNA expression profiles of large independent public databases (METABRIC; n = 1,903, GSE96058; n = 3,273).
Results: We found that both clinical and pathological T-category of AJCC staging were larger in AYA and Old compared from the other groups. Pathological N-category as well as pathological Stage were higher in AYA. Nottingham histological grade 3 was significantly higher in the AYA compared with the other older groups. Among the subtypes, AYA breast cancer was significantly associated with higher rate of triple-negative breast cancer compared to the others, as expected. Considering the whole cohort, ER and PgR positivity trended to be lower, but HER2-positivity trended to be higher in AYA. Within the ER-positive/HER2-negative subtype, PgR positivity was higher in the AYA and Perimenopausal groups compared to others. AYA had poorer disease-specific survival than other groups (p = 0.010 and p = 0.002, respectively), as well as overall survival, especially compared to perimenopausal group. The survival difference was more pronounced in ER-positive/HER2-negative breast cancer patients. In biological analysis in ER-positive/HER2-negative subtype, we found that estrogen response late signaling level decreased as the age group gets older. AYA breast cancer had significant enrichment in cell proliferation-related gene sets (G2M checkpoint, E2F targets, and MYC target v1), other pro-cancerous gene sets (MTORC1, unfolded protein response, and PI3K/ACT/MTOR signaling), consistently in two cohorts (all p ≦ 0.028), when compared to the other age groups. Interestingly, the features were observed even in the small tumor size (T1/T2) subgroup. Furthermore, AYA breast cancer showed significantly high BRCAness (all p≦0.002) and DNA repair (all p≦0.023) compared to other age groups. The infiltration fraction of several immune cells: CD8+ T cells, M1 macrophages, regulatory T cells, helper type 2 T cells, were significantly higher, and M2 macrophages were significantly lower in AYA, consistently in two cohorts.
Conclusion: ER-positive/HER2-negative breast cancer in AYA was highly proliferative with high immune cell infiltrations compared to other generations. This may be related to the difference in outcomes in each age group. Considering these unique features may enable us to fine tune treatment strategies for AYA.
Citation Format: Masanori Oshi, Akimitsu Yamada, Mahato Sasamoto, Kei Kawashima, Yoshie Fujiwara, Shoko Adachi, Shinya Yamamoto, Kazutaka Narui, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe. ER-positive/HER2-negative breast cancer in Adolescent & Young Adult (AYA) age group has a specific biological feature and worse outcome compared to other generations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-12.