Suboptimal treatment, which often underlies worse outcomes for cancer in racial minorities, did not explain a recent finding from the landmark RxPONDER study: non-Hispanic Black women with hormone receptor–positive, HER2-negative, lymph node–positive breast cancer had worse outcomes compared with non-Hispanic White patients regardless of treatment, recurrence score, age, and tumor grade, investigators reported at the 2022 San Antonio Breast Cancer Symposium.¹

“We continue to note worse outcomes for Black patients, suggesting race is independently prognostic,” said Yara Abdou, MD, Assistant Professor at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill. To illustrate the persisting racial disparities in breast cancer, she noted that Black women have a 4% lower incidence but 40% higher breast cancer mortality than White women.

“These data definitely highlight that we need to do more in regard to diversity and inclusion in clinical trials, and the only way to overcome this is to build out racial cohorts in our clinical trials prospectively.”

— Yara Abdou, MD

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Other researchers may have found a reason for racial disparities in outcomes. Investigators from Montefiore Einstein Cancer Center in the Bronx, New York, reported in San Antonio that residual estrogen receptor (ER)-positive, HER2-negative breast cancer after neoadjuvant chemotherapy from Black women shows enhanced prometastatic tumor microenvironment compared to the same type of residual cancer from White women.²

Cancer cells disseminate to distant sites through a tumor microenvironment of metastasis (TMEM) “doorways.” A high TMEM doorway score was previously found to be an independent prognostic risk factor for inferior survival in patients with ER-positive, HER2-negative breast cancer treated with adjuvant chemotherapy. New data show that the TMEM doorway score is an independent prognostic indicator for patients with residual ER-positive, HER2-negative disease after neoadjuvant chemotherapy, and Black patients had higher scores, according to the study’s senior investigator, Maja H. Oktay, MD, PhD, of Montefiore.

Maja H. Oktay, MD, PhD

Burcu Karadal, MD

“Racial disparity in outcome may be due to a more pronounced prometastatic tumor microenvironment—indicated by increased TMEM doorway density—in Black, compared with White, patients with residual ER-positive, HER2-negative tumors. We’re just scratching the surface, but I think this is a pretty good indication that racial disparity in outcome of ER-positive, HER2-negative breast cancer may be mechanistically linked to racial differences in dissemination of cancer cells,” Dr. Oktay said in a press briefing. The study was presented during a general session at the San Antonio meeting by Burcu Karadal, MD, a postdoctoral fellow at Montefiore Einstein Cancer Center.

RxPONDER Findings by Race

RxPONDER investigated the role of recurrence score in determining which patients with early breast cancer benefit from adjuvant chemotherapy. The current analysis of clinicopathologic characteristics, outcomes, and race included 4,048 hormone receptor–positive, HER2-negative women with one to three positive lymph nodes and Oncotype DX recurrence scores ≤ 25. Of these patients, 70% were non-Hispanic White, 6% non-Hispanic Black, 15% Hispanic, 8% Asian, and 0.8% Native American or Pacific Islander.

The racial subsets were largely similar in terms of clinicopathologic characteristics except for a greater percentage of premenopausal women in the Asian subset, more high-grade tumors among non-Hispanic Black patients, and higher body mass index among non-Hispanic Black patients; body mass index was lowest among Asian patients.

Differences in Outcomes

The 5-year invasive disease–free survival rate was 87.2% for Black patients compared with 91.5% for White patients, 93.9% for Asian patients, and 91.4% for Hispanic patients. In the multivariable analysis that adjusted for recurrence score, treatment arm, menopausal status, age, and tumor grade, the hazard ratios (HRs) were 1.37 (P = .05) for non-Hispanic Black vs non-Hispanic White patients, 0.67 for Asian vs non-Hispanic White patients (P = .05), and 0.92 for Hispanic vs non-Hispanic White patients (P = .55).When the analysis also adjusted for body mass index, the relative higher risk in Black patients was attenuated, and the P values lost significance. The 5-year distant relapse–free survival rate was 90.1% in Black patients and 94.7% in White patients (unadjusted HR = 1.39; P = .004), Dr. Abdou reported.

Interestingly, treatment exposure may have been better in the subset of Black women, as 93% of Black patients accepted their treatment assignment compared with 86% of White patients; 98% of Black patients remained on endocrine therapy at 6 months and 96% were still on it at 12 months, compared with 97% and 95%, respectively, for White patients. Dr. Abdou believes, therefore, that the differences in outcome are not likely attributable to differences in treatment compliance within the first year.

There was no significant interaction between race and treatment arm in either the postmenopausal or premenopausal cohorts, although definitive conclusions about racial differences in treatment benefit cannot be drawn due to the small cohorts of minority patients and the small number of events in the non-Hispanic Black cohort, Dr. Abdou said.

“These data definitely highlight that we need to do more in regard to diversity and inclusion in clinical trials, and the only way to overcome this is to build out racial cohorts in our clinical trials prospectively,” she said.

TMEM Doorways Denser in Black Women

“A prometastatic tumor microenvironment allows cancer cells to disseminate from the primary site to distant sites, and they do that through the blood vasculature. They have to somehow gain access to blood vessels, and they do that through portals in blood vessels that we call TMEM doorways. Each TMEM doorway consists of three distinct cells in close and stable physical contact: an immune cell called a macrophage, an invasive tumor cell, and an endothelial cell. Due to specific mediators released during the interaction of these three cell types, the endothelial cells pull apart and create an opening through which the content of blood vessels adjacent to the TMEM doorway can leak out, and other non-TMEM–associated cancer cells in the microenvironment can move it,” Dr. Oktay explained. Her team has been conducting work on TMEM doorways for more than 10 years.

The TMEM doorway density was already shown to be a prognostic marker of metastasis in patients with breast cancer treated with adjuvant chemotherapy. The current study asked whether it is also prognostic after neoadjuvant chemotherapy and looked at differences by race.

The TMEM doorway score was determined in the postchemotherapy residual tumors using a previously validated multiplex staining and automated scoring method that allows visualization of macrophages, tumor cells, and endothelial cells. The researchers analyzed the relationship between TMEM doorway score, macrophage density, and distant recurrence–free survival in a multi-institutional study of 96 Black and 87 White women with primary breast cancer.

TMEM Density Linked to Recurrence

Ultimately, distant recurrences were documented for 49.0% of Black women vs 34.5% of White women (P = .07), with the effect driven by the ER-positive, HER2-negative subtype. Black women had a higher TMEM doorway score in the entire cohort (P = .002) and in the ER-positive, HER2-negative subtype (P = .01), but not in the triple-negative subtype. Macrophage density followed a similar trend by race.

After adjustments 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 doorway scores vs those with intermediate or low TMEM doorway scores for the entire cohort (P = .01); a similar but nonsignificant trend was seen in the ER-positive, HER2-negative subset (P = .06). Along with the well-established factors of tumor size and lymph node status, TMEM doorway score was prognostic for distant recurrence.

No association was seen between TMEM doorway score and outcome in triple-negative breast cancer. Dr. Oktay speculated, “the TMEM doorway density in triple-negative breast cancer is already so high that it’s not a limiting factor in triple-negative disease.”

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

Dr. Oktay acknowledged two study limitations: lack of evaluation of the TMEM doorway density before neoadjuvant chemotherapy (for comparison with residual tumor), and an inability to determine whether chemotherapy increased the number of TMEM doorways in Black women more than White women. She and her team are working on finding TMEM doorway inhibitors, with several candidates under evaluation now. 

DISCLOSURE: Dr. Abdou has served as a consultant to AstraZeneca and Exact Sciences; and has received honoraria from MJH holdings, MDEdge, and Clinical Care Oncology. Dr. Oktay reported no conflicts of interest.

REFERENCES

1. Abdou Y, Barlow WE, Gralow JR, et al: Race and clinical outcomes in the RxPONDER trial (SWOG S1007). 2022 San Antonio Breast Cancer Symposium. Abstract GS1-01. Presented December 6, 2022.

2. Karadal B, Kim G, Sharma V, et al: Racial disparity in tumor microenvironment and outcomes in residual breast cancer treated with neoadjuvant chemotherapy. 2022 San Antonio Breast Cancer Symposium. Abstract GS1-02. Presented December 6, 2022.