EZH2 Biomarker Predicts Metastatic Disease in Patients With Triple-Negative Breast Cancer Treated With Neoadjuvant Chemotherapy

Susan Fineberg, MD, Montefiore Medical Center, Bronx, NY, overviews EZH2 expression in the neoadjuvant setting to predict metastatic recurrence for patients with triple-negative breast cancer (TNBC).

Transcript
I'm Dr. Susan Fineberg. I am a pathologist. I'm an associate professor of pathology at Montefiore Medical Center and the Albert Einstein College of Medicine. I am the section head of breast pathology at Montefiore Medical Center.

Triple-negative breast cancer (TNBC) accounts for about 15% of all breast cancers, and it's a very aggressive type of breast cancer.

The standard of care for localized high-risk TNBC is neoadjuvant chemotherapy, which is chemotherapy prior to surgery. Patients who achieve pathologic complete response after neoadjuvant chemotherapy have an excellent prognosis. Whereas, patients with poor response to neoadjuvant chemotherapy have reduced survival.

Currently, there are no good biomarkers to differentiate those patients with TNBC, who will respond to neoadjuvant chemo from those who won't.

EZH2 is a targetable oncogenic protein. An overexpression of EZH2 in breast cancer is linked to prognosis. In TNBC, EZH2 contributes to stem cell maintenance and expansion. Now we know that stem cells contribute to chemo resistance and metastatic tumor spread. Hence, we ask the following questions: first, can EZH2 overexpression in TNBC be used as a biomarker for resistance to neoadjuvant chemo? Second, do high EZH2 levels predict development of metastatic disease in patients with TNBC treated with neoadjuvant chemotherapy?

Our study included 63 patients with TNBC, treated with neoadjuvant chemotherapy. We looked at EZH2 protein expression levels in cancer cells, using immunohistochemistry and quantify EZH2 expression, using a combination of the percentage of cell staining and the intensity of the stain.

We used logistic regression analysis to determine first, if there was an association between EZH2 expression levels in pre-therapy tumor, and response to neoadjuvant chemo. Second, to determine if there was an association between EZH2 expression levels in pre-therapy tumor, and overall disease-free survival (DFS). Surprisingly, we found no association between EZH2 expression and tumor response to neoadjuvant chemotherapy.

Regarding the question of EZH2 expression and DFS. First, we would like to note that 19 patients in our study developed metastatic disease and of these 19, one-third had an excellent response to neoadjuvant chemotherapy. Again, suggesting that tumor response to neoadjuvant chemotherapy, which is currently the gold standard for determining prognosis, is an imperfect marker of DFS.

What we found is that there was a significant association between high EZH2 levels in TNBC pre-therapy and development of metastatic disease. More importantly, in multivariable analysis, adjusting for tumor response to neoadjuvant chemotherapy, we found a significant association between high EZH2 expression and development of metastatic disease.

Thus, our study suggests that EZH2 may be a useful biomarker, which can predict metastatic recurrence in patients with TNBC treated with neoadjuvant chemotherapy, independent of tumor response to neoadjuvant chemotherapy. 

Our results require confirmation with a larger study. However, if confirmed, EZH2 may turn out to be a useful tool to better stratify patient outcomes in cases of TNBC after neoadjuvant chemotherapy, and potentially be used then to guide the need for additional adjuvant therapies or alternative therapies in this setting.

How or why do patients with TNBC, who have a complete pathologic response to neoadjuvant chemo—that is when you remove where the tumor was, there's no tumor left in the breast axilla—how do they go on to develop metastatic disease?

One possibility, is that metastatic spread can and does actually occur in a small number of patients during their course of neoadjuvant chemotherapy.

We hypothesize that high EZH2 expression in TNBC may identify patients at highest risk for tumor dissemination during neoadjuvant chemotherapy. Hence, these patients with high EZH2 may benefit from an upfront surgical approach, rather than neoadjuvant chemotherapy, which has kind of now become the standard of care.

To support or further investigate this, we would like to look at circulating tumor cells (CTCs) during neoadjuvant chemotherapy, to see if high EZH2 expression is associated with increased CTCs during neoadjuvant chemotherapy.

If we find an association between high EZH2 and increased CTCs during neoadjuvant chemo, one could design a trial where you would use EZH2 levels to triage patients with resectable TNBC to upfront surgery prior to chemotherapy, if EZH2 is high. If EZH2 is low, then just give them neoadjuvant chemotherapy to see if this triage improves DFS in TNBC.

EZH2 expression is easy to measure by immunohistochemistry, pathologists can do it in their lab. It's extremely accessible. It doesn't require any very high expense or unusual techniques. EZH2 inhibitors are currently in use for treating lymphomas and are in clinical trials for treatment of many solid tumors, including TNBC.

Hence, studies such as ours are clinically relevant and timely.

Finally, we are looking at EZH2 expression in the neoadjuvant setting, in other types of invasive breast cancer and hope to report on this soon.

Source:
Fineberg S, Tian X, Makower D, Harigopal M, Lo Y. EZH2 Protein Expression in Triple-negative Breast Cancer Treated With Neoadjuvant Chemotherapy: An Exploratory Study of Association With Tumor Response and Prognosis. Appl Immunohistochem Mol Morphol. 2022;30(3):157-164.