A new study suggests that chemotherapy before surgery (neoadjuvant therapy) in Black patients with the most common form of breast cancer increases the number of microscopic "doorways" in blood vessels through which cancer cells can spread to distant parts of the body. What's more, the researchers showed that the density of tumor microenvironment of metastasis (TMEM) doorways in excised breast tissue from Black patients with ER+/HER2- disease was significantly greater when compared to White patients, but not in triple-negative disease.
The results, presented during the 2022 San Antonio Breast Cancer Symposium (SABCS) may explain, along with social determinants of health, why Black women with breast cancer generally experience worse treatment outcomes than White patients (Abstract GS1-02).
"The take-home message is racial disparity in outcomes may be due to higher TMEM doorway density in Black patients compared to White patients," said Maja H. Oktay, MD, PhD, Professor and Co-Leader of the Tumor Microenvironment and Metastasis Program at the Montefiore Einstein Cancer Center, Professor of Pathology at Albert Einstein College of Medicine, and senior author of the study. Previous research by Oktay and colleagues provided some of the first insights into the metastasis of breast cancer to distant parts of the body, including the role of TMEM.
These studies found that TMEM is composed of three different types of cells that are in close physical contact with one another on a blood vessel wall: 1) an endothelial cell that lines blood vessels, 2) an immune cell called a macrophage, and 3) an invasive tumor cell bound to the epithelial wall.
In previous research, Einstein researchers showed that macrophages in a TMEM loosen the normally tight connection that exists between endothelial cells, creating a temporary opening or portal in the wall of the blood vessel. Tumor cells then squeeze through this doorway and enter the bloodstream, where they travel to destinations far removed from their original home in the breast.
In several related studies, Oktay and colleagues created visualizations of TMEM doorways from thin slices of excised breast cancer tissues, using triple immunochemistry to identify macrophages, tumor cells, and endothelial cells. With the aid of automated image analysis, their evaluation concluded that the density of TMEM doorways, referred to as a TMEM score, was a prognostic biomarker of metastatic recurrence in patients who were treated with adjuvant chemotherapy (after surgery) in patients with ER+/HER- disease.
The team also demonstrated that chemotherapy before surgery (neoadjuvant) increases the TMEM doorway score and produces pro-metastatic changes in the tumor microenvironment of some women, uncovering a previously unrecognized mechanism of resistance to chemotherapy.
"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," Oktay noted.
Study Details
For the current study, the Einstein team performed a prospective-retrospective multi-institutional, multi-race case-control study of TMEM doorway score and macrophage density in patients with unilateral, invasive breast cancer who received neoadjuvant chemotherapy. Their goals were to determine if the TMEM doorway score could provide prognostic information about residual disease after neoadjuvant chemotherapy and if there were racial differences in the TMEM doorway score in the residual disease.
The research cohort consisted of 96 self-identified Black patients and 87 White patients diagnosed between 2004 and 2014 with unilateral invasive ductal cancer of the breast. Tumor characteristics and patient survival were compared between Black and White patients, with patients matched according to race and estrogen receptor status.
Study results showed that 49 percent of Black patients developed distant metastatic recurrence, compared to 34.5 percent of White patients. Black women were more likely to receive mastectomy than White women (69.8% and 54%, respectively) and have higher grade tumors.
"In addition, we found that Black patients compared to White patients had higher TMEM doorway densities, specifically in ER+/HER2- disease, but not in triple-negative disease...and macrophage density followed the same pattern," said Oktay. "This finding may explain the racial disparity in ER+/HER2- disease."
The risk of distant recurrence approximately doubled in patients with a high TMEM score compared to patients with low to intermediate scores. A similar trend was observed in the ER+/HER2- subgroup, although not statistically significant. And there was no association between a high TMEM score and an increased risk of distant recurrence in women with triple-negative breast cancer.
Asked why a high TMEM score was not a predictive marker for triple-negative breast cancer, Okay said the score for triple-negative breast cancer was already so high that "it was not a limiting factor any longer. Because triple-negative is such an aggressive disease, it really doesn't matter. In ER+, where tumor density is less, then it matters if there is an increase."
One limiting factor to the study relates to the fact that the team did not evaluate the TMEM doorway density in tumors before neoadjuvant therapy. The study also did not demonstrate determinants of health, including access to care or treatment.
"Looking forward in future directions, we propose to use TMEM doorway density as a prognostic marker on distant recurrence-free survival as a marker of dissemination and also as a predictive marker of response to drugs that can block TMEM doorway activity," Oktay said. Several trials are underway to test agents that may block TMEM doorway activity in patients.
Warren Froelich is a contributing writer.