mTOR activation and racial disparity in early breast cancer survival.

569 Background: Black women have lower survival rates following a diagnosis of estrogen receptor-positive (ER+) early breast cancer (EBC) compared with White women, with 80% higher mortality and more frequent genomically high-risk tumors (Hoskins et al, JAMA Oncol, 2021). A whole-transcriptome comparison of 412 luminal tumors from Black women with EBC and age-matched White women showed increased mTOR signaling in tumors from Black patients (Hoskins et al. J Clin Oncol 2021, 39:15_suppl, 1009-1009), suggesting a molecular driver of the survival disparity. This study aimed to confirm increased mTOR pathway activation at the protein level in Black patients with an independent cohort, and to explore factors responsible for racial differences in luminal tumor biology. Methods: A breast tumor tissue microarray (TMA) comprising primary tumor cores from diverse patients with EBC was analyzed with multiplex immunofluorescence staining to quantify protein markers of mTOR pathway activation (pS6K and pAkt). Image segmentation was performed with pan-cytokeratin staining to delineate tumor cells from stromal cells. Halo HighPlex image analysis software was used for automated digital image analysis to calculate an H-score for each tumor core. Ancestry admixture analysis was performed with ancestry informative markers that are located within coding regions of genes using RNAseq data generated from tumors represented on the TMA. Data on contextual factors was obtained by geocoding patients’ residential address at the time of diagnosis and linking to a census tract-level measure of neighborhood disadvantage (Area Deprivation Index-ADI). mTOR pathway activation levels were compared by self-identified race, proportion of African ancestry, body mass index (BMI), insurance status, and ADI. One-sided t-tests evaluated mean H-scores for pS6K and pAkt in tumor cells for various comparisons. Results: Analysis of 70 ER+ primary tumors from Black patients and 43 tumors from White patients showed mean pS6K staining in pan-cytokeratin-positive cells was significantly higher in tumor cores from Black compared with White patients (p-value = .05). Ancestry admixture analysis (dichotomized by the proportion of African ancestry > 0.4 vs. < 0.4) showed significantly increased pS6K staining in patients with greater proportion of African ancestry (p-value = .04). There was no association with ADI (p-value = .30). Analyses of association with insurance status and BMI, multivariable analyses, and survival analyses are ongoing and results will be presented, along with data on pAkt staining. Conclusions: This study demonstrated increased mTOR pathway activation at the protein level in Black women with ER+ EBC, confirming the result of a prior gene expression analysis. The underlying cause of this racial difference is unknown, but findings support development of clinical trials targeting the mTOR signaling pathway to mitigate racial disparity in EBC survival.