Racial disparity in pro-metastatic tumor microenvironment in treatment naïve breast cancer

Black women with estrogen receptor-positive, HER2-negative (ER + /HER2-) breast cancer experience higher rates of distant recurrence and worse survival outcomes compared to White women. This may be due not only to disparities in social determinants of health, but also differences in the tumor microenvironment (TME), including TMEM (Tumor Microenvironment of Metastasis) doorway score. TMEM doorways serve as portals for cancer cell hematogenous dissemination to distant sites. While higher TMEM doorway scores have been observed in Black (compared to White) patients with residual ER + /HER2- breast cancer after neoadjuvant chemotherapy, this has not been evaluated in treatment-naïve primary breast cancers. Here, we report on a multi-institutional study to evaluate TMEM doorway score in 418 treatment-naïve archived human breast cancer samples, including 265 patients with ER + /HER2-, 102 with triple negative (TNBC), and 51 with HER2-positive breast cancer. In addition to analyzing TMEM doorway scores by race across breast cancer subtypes, we examined their association with distant recurrence and assessed whether the effect of TMEM doorway scores on recurrence differed by race. Black patients had significantly higher TMEM doorway score than White patients in the overall study population (median 29.9 vs 17.9, p < 0.001), in the ER + /HER2- (median 25.0 vs 16.8, p < 0.001) and the HER2-positive subset (median 37.2 vs 12.9, p = 0.003), but not in TNBC (median 36.2 vs 36.3, p = 0.86). Racial differences in macrophage density mirrored racial differences in the TMEM doorway score. In multivariate models including age, body mass index, tumor size, grade, lymph node status, and chemotherapy treatment, neither Black race nor TMEM doorway density was associated with a higher distant recurrence risk alone. However, there was a statistically significant interaction between race and high TMEM doorway score with respect to distant recurrence risk in ER + /HER2- patients; Black patients with high TMEM doorway score were 4.6-fold (95% CI 1.28-22.82, p = 0.03) and 4.2-fold (95% CI 1.17 - 18.23, p = 0.04) more likely to have a distant recurrence at 5-years and 10-years, respectively, while White patients with high TMEM doorway scores did not (p = 0.21, p = 0.11). Our study reveals racial disparities in the TME of women with ER + /HER2- breast cancer, which may play a critical role in driving disparities in breast cancer outcomes.