Abstract Background and objective: Breast cancer seriously damages the physical and mental health of women, and patients with different ages present different clinical characteristics. The purpose of this study was to investigate the molecular characteristics of patients in different ages and their correlation with drugs and survival. Methods: 417 breast cancer patients were collected, and 85.61% of them were invasive breast cancer. Based on the age distribution, they were divided into young (≤35 years, n=54), middle aged (35-65 years, n=325), and old (≥65 years, n=38) groups. Deep sequencing targeting 450 cancer genes were performed in a laboratory with both CAP and CLIA accreditation. Homologous recombination repair (HRR) genes and differential mutation genes were analyzed among different age groups. Furthermore, 739 old and 46 young patients from TCGA database were used for survival comparison. Results: Collectively, 51.8% (216/417) of breast cancer patients carried at least one HRR gene mutation with 64.8% (35/54) in young group, 50.2% (163/325) in middle aged group and 47.4% (18/38) in old group. In young patients, the top 3 mutated genes were NBN (25.9%), BRCA1 (16.7%) and RAD54B (16.7%). Moreover, there were 27 significantly different mutations among three groups, including NBN, IRS2, KMT2A and GATA3 (P < 0.005). Interestingly, the frequency of top 3 mutated HRR genes NBN (3.69% middle age, 10.53% in old), RAD54B (3.08% middle age, 7.89% in old) and BRCA1 (3.69% middle age, 10.53% in old) in young group were statistically different among three groups. The different mutation genes of MDM2 (P=0.0185), MDM4 (P = 0.00087) and JAK2 (P=0.0314) were reported to be associated with immune hyperprogression, and concurrently JAK2 (P=0.0314) was reported to involved in immunotherapy resistance. Last but not least, AKT1 mutation was associated with a poor survival in young patients (mutation patients vs wild patients: mOS 29.7 vs 195.4 months, P=0.0053), but it was a longer survival factor in old group (mutation patients vs wild patients: mOS 171 vs 112 months, P=0.026). ATK1 has been well studied to play a role in the recurrence and metastasis of breast cancer, and it relates to poor prognosis and increased mortality. Here, we found that the relationship between ATK1 and OS was affected by age. Conclusion: Breast cancer patients with the same gene mutation have different performance in different age groups, which may lead to different response rates of different age patients to the same PAPR inhibitor and immune drug, as well as OS. Citation Format: Hong Liu, Jinpu Yu, Zanmei Xu, Fei Wang, Yang Li, Siyue Zhang, Bin Wang, Beibei Yang, Weifeng Wang. Genomic mutation characteristics and clinical implications of breast cancer in different age groups [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2173.