Breast cancers arising in high mammographic density tissue harbor tumor-promoting immune profiles.

Epidemiological studies have shown that high mammographic density (HMD) is a strong risk factor for breast cancer (BC) and is associated with poor prognosis. Although tumors from women with low (LMD) and HMD are genetically similar, HMD has a worse prognosis. We explored whether differences in the immune tumor microenvironment could explain the poorer outcomes. BC data were predominantly obtained from Lifepool, a population-based cohort of over 55,000 Australian women within the screening program. We identified 670 cases of invasive BC with pathology reports, family cancer history, and matched MD data to evaluate the clinico-pathological features of BC across MD quintiles. Tumour tissue was retrieved from 122 cases and we performed multiplexed immunohistochemistry to assess the infiltration of immune cells. Whole-genome sequencing (WGS) was performed on twelve luminal BCs of ductal origin, which included 4 LMD, and 5 HMD cases. Additional cases for WGS were obtained from the MAGIC study. BCs in women with HMD were linked to older age at diagnosis, higher rates of interval cancers, distinct histological subtypes, and a stronger family history of BC. Mutational signatures showed increased homologous recombination deficiency. APOBEC-associated mutations were unique to LMD. HMD also exhibited a significant rise in adaptive immune cells, including T cell B cells. Our findings suggest that HMD is associated with distinct somatic genetic events and an immune microenvironment that favors tumor-promoting immune cells within BC.