Posted on December 22, 2022

By Krystal Redman (KR), DrPH, MHA, (they/she), Executive Director

Changes in Tumor Microenvironment May Not Fully Explain Disparities in Breast Cancer Outcomes of Black Women

In the oral presentation focusing on tumor microenvironment in Black patients, Dr. Burcu Karadal-Ferrena, MD (with Montefiore Einstein Cancer Center), presented findings of a study titled Racial disparity in tumor microenvironment and outcomes in residual breast cancer treated with neoadjuvant chemotherapy. According to the presenter, the majority of breast cancer-related deaths are caused by distant metastases. [Distant metastases are tumors that have developed from tumor cells that spread to areas of the body distant or remote from the primary tumor. They are comprised of tumor cells that have broken away from the primary tumor and have traveled to other parts of the body. Tumor metastases are also called remote, disseminated, diffuse, or metastatic tumors (National Cancer Institute, Dec 2022)].

Black patients with breast cancer have 40% higher death rates compared to white patients (DeSantis et al., Breast Cancer Statistics 2019, CA Cancer J Clin, 2019). Further, it was reported that Black women with estrogen receptor positive (ER+) disease have a higher risk of recurrence. [ER+ or estrogen receptor (ER) positive means that the cells of this type of breast cancer have receptors that allow them to use the hormone estrogen to grow. Treatment with anti-estrogen hormone (endocrine) therapy can block the growth of such cancer cells.]

SURPRISINGLY, the Black race is associated with distant recurrence in ER+/HER2-, but not in triple-negative or HER2+ disease [triple-negative breast cancer is a kind of breast cancer that does not have any of the receptors that are commonly found in breast cancer. Breast cancer cells with higher than normal levels of HER2 hormones are called HER2-positive. These cancers tend to grow and spread faster than breast cancers that are HER2-negative, but are much more likely to respond to treatment with drugs that target the HER2 protein]. The study also showed that racial disparities in distant recurrence–free survival (DRFS) have been observed in patients with residual ER+ cancer after neoadjuvant chemotherapy. 

The presenter raised the question: What could cause racial disparity in residual ER+/HER2- disease? In addressing that question, the authors hypothesized that: racial disparity in DRFS among patients with residual ER+/HER2- disease is due to an enhanced pro-metastatic response after neoadjuvant chemotherapy (NAC) in Black women compared to white women. [DRFS is defined as the time from surgery to the first distant recurrence, and the cases of death without distant recurrence were censored at the time of the death. Neoadjuvant chemotherapy is treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery, is given. Examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy. It is a type of induction therapy.]

In the study, researchers found that the tumor microenvironment of metastasis (TMEM) doorway density is a prognostic marker of metastasis in breast cancer patients and a higher? TMEM doorway score is associated with increased risk of metastasis, especially in ER+/HER2- disease. Also, that TMEM doorway score trends towards being an independent prognostic factor in ER+/HER2- subtype. [Tumor microenvironment of metastasis (TMEM) doorways are portals for cancer cell dissemination.] 

The findings further demonstrated that:

  1. High-TMEM doorway score is an independent prognostic risk factor of inferior survival in patients with residual cancer after NAC.
  2. Racial disparity in outcomes may be due to a more pronounced pro-metastatic tumor microenvironment (increased TMEM doorway density) in Black, compared to white, patients with residual ER+/HER2- breast cancer.
  3. Prognostic factors may include tumor size (established), lymph node status (local spread – established), and TMEM doorway score (distant spread – proposed).

Finally, the researchers found that triple-negative breast cancer (TNBC) has higher TMEM doorway and macrophage density compared to ER+/HER2- subtype. The presenter asserted that the above findings “may explain racial disparity in ER+/HER2- disease.” [Macrophages are tissue-resident or infiltrated immune cells critical for innate immunity, normal tissue development, homeostasis, and repair of damaged tissue. Macrophage function is a sum of their development, the local environment in which they reside, and the type of injuries or pathogen to which they are exposed.] Hmmm… this assertion seems too simple and nondescript. How can the pronounced pro-metastatic tumor microenvironment in patients explain something so complex as “racial disparities.” Showing disparities in tumor microenvironments does NOT explain how those disparities came to be, and whether or not the causes of those disparities are “biological” or environmental. The presenter suggests that disparities in breast cancer outcomes observed in Black women compared to white women could be attributed, in part, to greater changes in the tumor microenvironment in Black women. And, that racial disparities in outcomes may be due to a more pronounced pro-metastatic response to chemotherapy in Black patients with ER+/HER2- disease. Maybe, but why is this so?

As session commentator, Dr.  Lori Pierce, MD stated “What is there about Black people (the Black race) that would lead to this result?” The study failed to examine education, community, social context, neighborhood, food, weathering, environment, built-environment, etc., which all impact the health outcomes of patients. Dr. Pierce raised the issue of heterogeneity within races, and the arbitrariness of race. For example, based on the blood quantum rule, having one drop of blood of African ancestry is enough to be considered Black. This is not the same in other race groups. Further, it is important to remember that race is a construct influenced by power and greed, and we ought to question how we consider race in the interpretation of scientific studies. Biology is necessary but not sufficient. We must dig deeper to discover and discuss the hidden factors that contribute to disparities in race, such as racism.

The bigger clinical question is whether these disparities in tumor microenvironments may be due to neoadjuvant chemotherapy. Could observed disparities be due to access to or timing of administering neoadjuvant chemotherapy? Dr. Pierce also questioned if the data suggests that a pro-metastatic effect of NAC may be more pronounced in Black women, and highlighted that there was no baseline TMEM data from the Montefiore Einstein Cancer Center, so it is unclear whether there was a change in neoadjuvant chemotherapy. If we think that NAC promotes metastasis, then there should be an inferior outcome compared to that of adjuvant chemotherapy. This is not what we see in the research presented during the session. 

Overall, while I think the data is interesting, I wouldn’t want Black women to be discouraged by learning that researchers observed a more pronounced pro-metastatic tumor microenvironment in Black participants, compared to white participants. There is much more to be investigated here before firmly settling on the results. Additional studies are needed to further test the hypothesis.