Study Shows Racial Disparity in Prometastatic Tumor Microenvironment


Tumor microenvironment differences in Black women may explain disparities in outcomes for those with residual tumors after chemotherapy treatment for ER–positive/HER2-negative breast cancer.

Residual tumors from Black patients with estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer treated with neoadjuvant chemotherapy had a higher score of a biomarker of distant metastatic recurrence than tumors from White patients, according to data presented at the San Antonio Breast Cancer Symposium (SABCS) in Texas on December 6, 2022.1

“Black women with breast cancer are more likely to be diagnosed with advanced-stage disease, have lower access to care, and have triple-negative disease, all of which contribute to higher mortality rates compared with White women,” Maja H. Oktay, MD, PhD, professor and co-leader of the Tumor Microenvironment and Metastasis Program at the NCI-designated Montefiore Einstein Cancer Center, professor of pathology at Albert Einstein College of Medicine, and senior author of the study, said in a statement. “The results from our study demonstrate differences in the tumor microenvironment [TME] of Black women that may partly explain the racial disparities in the outcomes of ER–positive/HER2-negative breast cancer, the most common breast cancer subtype in both White and Black women.”1

Previous research by the investigators led to the identification of 3-cell structures in primary breast tumors in which an invasive tumor cell partially inserted into a blood vessel wall is bound to an endothelial cell and a macrophage, and all 3 are in direct and stable contact.1

“We have used the term tumor microenvironment of metastasis (TMEM) doorways, because these structures serve as portals for tumor cells to enter the blood circulation,” Oktay said.1

Investigators showed that the density of TMEM doorways in the primary untreated tumors, as measured by the TMEM doorway score, is a prognostic biomarker for the development of distant metastatic recurrence in patients with ER–positive/HER2-negative breast cancer.1

“We have also shown that [neoadjuvant chemotherapy] increases the TMEM doorway score and produces prometastatic changes in the tumor microenvironment in some women, uncovering a previously unrecognized mechanism of resistance to chemotherapy,” Oktay said.1

Investigators conducted a multi-institutional, retrospective study of TMEM doorway score and macrophage density in patients with unilateral, invasive breast cancer who received neoadjuvant chemotherapy to determine whether the TMEM doorway score can provide prognostic information about the residual disease after the neoadjuvant chemotherapy and whether there were racial differences in the TMEM doorway score in the residual disease.1

In the study, 96 patients self-identified as Black and 87 as White. The TMEM doorway score was determined in the residual breast cancer tissues after pre-operative chemotherapy using previously validated multiplex staining and automated scoring method. Investigators analyzed the relationship among distance recurrence-free survival (DRFS), macrophage density, and TMEM scores.1

Study results showed that 49% of Black patients developed distant recurrence compared with 34.5% of White patients, and that Black women were more likely to have mastectomies than White women, at 69.8% and 54%, respectively, and have higher-grade tumors.1

Tumors from Black patients had more macrophages and higher TMEM doorway scores than tumors from White patients in the entire cohort and in the ER–positive/HER2-negative subset, but not in the triple-negative subset.1

Adjusting for age, lymph node status, race, surgery type, and tumor grade, size, and subtype, the researchers found that high TMEM doorway scores were associated with worse DRFS. Further, the risk of distant recurrence approximately doubled in patients with high TMEM scores compared with those with intermediate or low TMEM scores in the entire cohort.

A similar trend was seen in the ER–positive/HER2-negative subgroup, though not statistically significant. There was no association between high TMEM scores and an increased risk of distant recurrence in women with triple-negative breast cancer.1

One study limitation relates to the fact that the team did not evaluate the TMEM doorway density in the tumors before neoadjavant chemotherapy, according to Oktay.1

In addition, the study did not demonstrate that chemotherapy increases the number of TMEM doorways in Black women more than in White women.1

During a presentation at SABCS where she presented these data, Oktay said that the racial disparity seen in this study could be the result of differences in body mass index and also “may relate to geographic ancestry” and an enhanced response to injury.2

“We are scratching the surface, but this may show use where the differences lie,” she said.2


1. Study finds racial disparity in pro-metastatic tumor microenvironment among women with residual breast cancer after neoadjuvant chemotherapy. December 6, 2022. Accessed December 6, 2022.

2. Press conference I. San Antonio Breast Cancer Symposium. December 6, 2022.

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