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SAN ANTONIO -- Black patients with certain types of breast cancer treated with chemotherapy had increased concentrations of a cellular complex that facilitates metastasis in residual tissue, offering a possible biological explanation for worse outcomes, according to a study reported here.

A post-treatment analysis of Black and white patients showed that residual triple-negative (TNBC) and estrogen receptor-positive/HER2-negative (ER+/HER2-) breast cancer was associated with increased tumor microenvironment of metastasis (TMEM) doorway density and macrophage density. In Black patients, however, only ER+/HER2- cancers were associated with higher TMEM density, whereas residual TNBC was associated with higher macrophage density.

The results might explain Black patients' worse outcomes in ER+/HER2- breast cancer as compared with white patients, reported Maja H. Oktay, MD, PhD, of Montefiore Einstein Cancer Center, in New York City, at the San Antonio Breast Cancer Symposium (SABCS).

"We are just scratching the surface, but I think this is a pretty good introduction to what the differences [associated with disparate outcomes] might be and where they might lie with respect to the dissemination of cancer," Oktay said during an SABCS press briefing.

One working hypothesis is that the origin of the outcome disparity revolves around geographic ancestry, going back thousands of years, she added. At some point, differences in response to injury emerged, which was carried forward by people of African ancestry. The hypothesis has some supporting scientific evidence, including observations that Black patients have more adverse effects when treated with paclitaxel.

Potential Therapeutic Target

The findings further suggest that giving patients TMEM inhibitors along with neoadjuvant chemotherapy might improve outcomes in Black patients and help eliminate the outcome disparity in ER+/HER2- breast cancer. Inhibitory agents already exist, such as VEGF inhibitors and the multitargeted tyrosine kinase inhibitor rebastinib. Oktay and colleagues that administration of rebastinib reversed TMEM activity and cancer cell dissemination.

"We are not encouraging [use of VEGF inhibitors]," she added. "We are talking about very localized increases in VEGF, as we know that VEGF inhibitors do not work very well [in breast cancer] and cause ischemia and other side effects that may actually make matters worse."

In response to a question, Oktay acknowledged that intratumor injection of VEGF inhibitors or other drugs that inhibit TMEM doorways are being considered.

The findings represent an important first step toward better understanding of the biological differences between Black and white patients but also differences in cancer biology, said press briefing moderator Virginia Kaklamani, MD, of UT Health San Antonio.

"If we have a specific type of cancer that has more density and is resistant to our chemotherapy, we have drugs available, we have drugs that are going to be developed," she said. "That would be wonderful to try to use them in our patients to improve their outcomes."

Distant metastasis continues to be the primary driver of cancer-related mortality. Among patients with breast cancer, the is 99% for localized disease and 86% for nodal involvement, before declining dramatically to 29% for distant-metastatic breast cancer. In the subgroup of patients with distant metastasis, 5-year survival is more than 30% lower among Black patients.

Multiple studies have documented social factors that play a role in the racial disparity, but disease heterogeneity also contributes, said Oktay. Black patients have a higher prevalence of TNBC and an increased risk of distant recurrent in ER+/HER2- disease. Earlier this year, Oktay and colleagues worse distant recurrence-free survival (DRFS) in Black patients with residual ER+/HER2- disease after neoadjuvant chemotherapy in eight large randomized clinical trials.

"Based on these data, we formulated the hypothesis that racial disparity in distant recurrence-free survival among patients with residual ER-positive/HER2-negative disease is due to enhanced prometastatic response to chemotherapy in Black women compared to white women," said Oktay.

Objectives, Key Findings

The study had two primary research objectives: To determine whether a prometastatic tumor environment (TME) in residual disease was associated with inferior outcomes and whether a racial disparity existed in TME in residual disease.

A TME facilitates cancer cells' migration from the primary tumor to distant sites. The facilitation occurs by means of portals into blood vessels, known as TMEM doorways. The doorways consist of three types of cells that remain in stable contact with one another: immune cell macrophages, invasive tumor cells, and endothelial cells.

Over the past 10-15 years, an accumulation of research has shown that TMEM doorway density is predictive for distant metastasis after neoadjuvant chemotherapy, said Oktay. The research led to development of a that has proven to be predictive for distant metastasis for ER+/HER2- disease treated with neoadjuvant chemotherapy. The score is derived from histopathologic analysis of staining for separate markers of tumor cells, endothelial cells, and macrophages.

Investigators performed a multicenter case-control study to investigate TMEM doorway density in TNBC and ER+/HER2- breast cancer. The study involved 183 patients who received neoadjuvant chemotherapy for early breast cancer. The cohort comprised 96 Black patients (43 with ER+/HER2-, 37 with TNBC) and 87 white patients (50 with ER+/HER2-, 22 with TNBC). Subsequently, 47 (49%) Black patients and 30 (34.5%) had distant recurrence (P=0.07).

The laboratory results showed that TNBC had a significantly higher TMEM doorway score (P=0.0080) and macrophage density (P=0.0003) but not microvascular density (endothelial cells), as compared with ER+/HER2- breast cancer. The finding suggests a possible mechanism of early recurrence in TNBC.

Black patients had a higher TMEM score versus white patients in an overall comparison (P=0.0018) and in those with the ER+/HER2- subtype (P=0.0102). Macrophage density also was higher among blacks in a comparison of all patients (P=0.0017) and those with ER+/HER2- disease (P=0.0128). Microvascular density did not have a significant association in any of the analyses.

For the entire cohort, irrespective of cancer subtype or race, TMEM doorway score was associated with significantly worse DRFS (P=0.008). A trend toward worse DRFS was observed in the ER+/HER2- subgroup (P=0.059), but not in the TNBC subgroup (P=0.77).

By multivariable analysis, a high or mid-range TMEM doorway score was an independent risk factor (HR 2.01, 95% C 1.17-3.44, P=0.01) in the overall cohort and exhibited a trend toward significance for the ER+/HER2- subgroup (HR 2.33, 95% CI 0.96-5.67, P=0.06).

The findings could have implications that extend beyond breast cancer, according to Oktay.

"We found TMEM doorways in human pancreatic ductal adenocarcinoma [PDAC], lung adenocarcinoma, and sarcomas," she told MedPage Today via email. "We have preclinical evidence that TMEM doorways are also active in PDAC and can be blocked by rebastinib. There is ongoing investigation to explore the hypothesis that TMEM doorways may be therapeutic targets across multiple cancers."

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