Study Finds Racial Disparity in Prometastatic Tumor Microenvironment Among Patients With Residual Breast Cancer After Neoadjuvant Chemotherapy

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Residual tumors from Black patients with estrogen receptor–positive/HER2-negative primary breast cancer treated with neoadjuvant chemotherapy had a higher risk score associated with a biomarker of distant metastatic recurrence compared with tumors from White patients, according to new findings presented by Oktay et al at the San Antonio Breast Cancer Symposium (SABCS) 2022 (Abstract GS1-02).


“Black [patients] 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 [patients],” explained senior study author Maja H. Oktay, MD, PhD, Professor of Pathology and Surgery at the Albert Einstein College of Medicine and Co-Leader of the Tumor Microenvironment and Metastasis program at Montefiore Medical Center. “The results from our study demonstrate differences in the tumor microenvironment of Black [patients] that may partly explain the racial disparities in the outcomes of [estrogen receptor]–positive/HER2-negative breast cancer, the most common breast cancer subtype in both White and Black [patients].”

Previous research by Dr. Oktay and her colleagues led to the identification of three-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 three are in direct and stable contact. “We have used the term 'tumor microenvironment of metastasis doorways' (TMEM) because these structures serve as portals for tumor cells to enter the blood circulation,” noted Dr. Oktay.

She and her colleagues 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 estrogen receptor–positive/HER2-negative patients.

“We have also shown that [neoadjuvant chemotherapy] increases the TMEM doorway score and produces pro-metastatic changes in the tumor microenvironment in some [patients], uncovering a previously unrecognized mechanism of resistance to chemotherapy,” Dr. Oktay highlighted. “Although numerous prospective clinical trials and population-based studies have shown that chemotherapy reduces the risk of recurrence and death when given before or after surgery to patients with locally advanced breast cancer, and prolongs survival for patients with metastatic breast cancer, we suspect that in some patients, [neoadjuvant chemotherapy] may prime the tumor to more efficiently disseminate tumor cells into the bloodstream. Identifying this mechanism of resistance may allow us to develop new treatment strategies to reverse it.”

Research Methods and Results

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

In the study cohort, 96 patients self-identified as Black and 87 identified as White. The TMEM doorway score was determined in the residual breast cancer tissues after preoperative chemotherapy using the previously validated multiplex staining and automated scoring method. The researchers analyzed the relationship between the TMEM doorway score, macrophage density, and distant recurrence–free survival.

The results showed that 49% of Black patients developed distant recurrence, compared to 34.5% of White patients—and that Black female patients were more likely to receive a mastectomy than White female patients (69.8% and 54%, respectively), and have higher-grade tumors.

Additionally, researchers detected more macrophages and calculated higher TMEM doorway scores in the tumors of Black patients than in the tumors of White patients in the entire cohort and in the estrogen receptor–positive/HER2-negative subset, but not in the triple-negative subset.

Adjusting for race, age, surgery type, tumor size, lymph node status, tumor grade, and tumor subtype, a high TMEM doorway score was associated with worse distant recurrence–free survival. The risk of distant recurrence approximately doubled in patients with high TMEM scores compared with patients who had either intermediate or low TMEM scores in the entire cohort. A similar trend was observed in the estrogen receptor–positive/HER2-negative subgroup, although not statistically significant. There was no association between high TMEM scores and an increased risk of distant recurrence in patients with triple-negative breast cancer.


“Our study provides a potential explanation for the persistent racial disparities in [estrogen receptor]-positive/HER2-negative breast cancer outcomes that are not fully explained by disparities in social determinants of health, including access to care or treatment,” concluded Dr. Oktay.

The researchers deduced that the racial disparities in patient outcomes may have been the result of a more pronounced pro-metastatic response to chemotherapy in Black patients compared with White patients; therefore, a higher prevalence of triple-negative breast cancer in Black patients was potentially not to blame for the disparity.

Disclosure: The research in this study was funded by the National Institutes of Health, New York State Department of Health Peter T. Rowley Breast Cancer Scientific Research Projects, Helen & Irving Spatz Family Foundation, Evelyn Gruss Lipper Charitable Foundation, and the Gruss-Lipper Biophotonics Center and the Integrated Imaging Program at the Albert Einstein College of Medicine.

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