At the 2022 San Antonio Breast Cancer Symposium in San Antonio, Texas, Clinton Yam, MD, MD Anderson Cancer Center, Houston, TX discussed the clinical and molecular characteristics of HER2-low early-stage triple-negative breast cancer compared to HER2-zero early-stage triple-negative breast cancer.

Dr Yam focused on the findings from his recent research trial, investigating differences not just in the characteristics of the disease states, but differences in patient outcomes and biomarkers of response and resistance in the context of HER2 expression as well.

Transcript

Hi, I'm Dr. Clinton Yam from the University of Texas MD Anderson Cancer Center. I'm a breast medical oncologist and I'm at the 2022 San Antonio Breast Cancer Symposium.

Today I would like to discuss my abstract titled ‘Clinical and molecular characteristics of HER2-zero versus HER2- low early-stage triple-negative breast cancer.”

As we know, trastuzumab deruxtecan was shown to be highly effective in patients with HER2-low metastatic breast cancer. However, the significance of HER2-low expression is unclear in triple-negative breast cancer in the early-stage setting. As such, we conducted a study to evaluate the differences between HER2-low and HER2-zero tumors that were also triple negative.

We conducted a study within our prospective clinical trial at MD Anderson Cancer Center where we enrolled patients with early-stage triple negative breast cancer. We had 367 patients that had available HER2 immunohistochemistry results, and we categorized these patients to HER2-low versus HER2-zero based on the definitions given by the DESTINY-Breast04 study.

We then compared the molecular and clinical characteristics between patients with HER2-zero triple-negative breast cancer and those with HER2-low triple-negative breast cancer. We found that patients with HER2-low triple-negative breast cancer had tumors that had lower Ki-67 scores, and they also had a higher proportion of androgen receptor expression.

We also performed RNA sequencing on the pre-treatment tumor samples and found that HER2-low tumors had higher expression of genes associated with steroid metabolism as well as fatty acid metabolism.

We then further investigated the differences between outcomes in patients with HER2-zero tumors versus those with HER2-low tumors. We found that there was not a significant difference in the rates of pathological complete response after neoadjuvant chemotherapy between patients with HER2-low triple-negative breast cancer versus those with HER2-zero triple-negative breast cancer.

We then decided to further interrogate biomarkers of response and resistance in the context of HER2 expression. We divided the patients with triple-negative breast cancer into those with HER2-low triple-negative breast cancer and those with HER2-zero triple negative breast cancer within the subgroup of patients with HER2-low triple-negative breast cancer. We then looked at the RNA-sequenced data to figure out if there was a difference in patients who experienced a pathological complete response versus those who didn't.

Within the subset of patients with HER2-low triple-negative breast cancer, we found resistance to chemotherapy. Namely, patients who did not experience a pathological complete response, they had tumors that had higher expression of EREG, which is an EGFR ligand. Within the subset of patients with HER2-zero triple-negative breast cancer, resistance to chemotherapy seemed to be associated with lower expression of immune related genes, suggesting that the immune response plays a greater role in patients with HER2-zero triple-negative breast cancer.

However, all these findings are very preliminary, and although our data suggests that there are some biologic differences between patients with HER2-zero triple-negative breast cancer versus those with HER2-low triple-negative breast cancer, I think in the context of all the studies that were presented in San Antonio, we have found that approximately half of the studies concluded that there was a biologic difference, whereas the other half concluded that there was no biologic difference between patients with HER2-zero versus HER2-low triple-negative breast cancer.

I think the jury's still out, and further studies need to be done to further solidify this question as to whether there is truly a biologic difference between patients with HER2-low triple-negative breast cancer versus those with HER2-zero tumors. I think one of the confounding factors is that we do not have a good assay to assess and clearly separate HER2-zero tumors from HER2-low tumors.

The DESTINY-Breast04 study relied on immunohistochemistry, but as was presented during some of the talks, HER2 immunohistochemistry has been known to be a very subjective test and there's a lot of discordance both within the same pathologists as well as between different pathologists.

Groups like Dr. David Grimm's group are working on trying to figure out if there's a better way to assess HER2 expression with newer quantitative assays. I think with a more standardized approach to assess HER2 expression, some of these questions about whether there's truly a biologic difference between HER2-zero and HER2-ow tumors will be clearer in the future.

For now, it's still an open question. A lot of research teams are doing great work trying to figure this out to determine if there's truly a biologic difference or is HER2 expression simply a biomarker for response to HER2 antibody drug conjugates.

Source:

Yam C, Li Z, Korkut A, Ma W, et al. “Clinical and molecular characteristics of HER2-low/zero early stage triple-negative breast cancer” Presented at San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, Texas. Abstract HER2-01