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SABCS 2022 | Clinical and molecular characteristics of HER2-low/zero early stage triple-negative breast cancer

Clinton Yam, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, discusses an investigation into the clinical and molecular characteristics of HER2-low/zero early stage triple-negative breast cancer (TNBC). HER2-low is defined by an immunohistochemistry score of 1+ or 2+ and ISH-negative. Approximately 50% of patients with TNBC have HER2-low breast cancer. However, it is unclear if HER2-low is a distinct biological entity within TNBC. 367 patients with stage I-III TNBC, who were enrolled on the prospective ARTEMIS trial (NCT02276443), with available HER2 immunohistochemistry (IHC) results were separated into HRE2-low and HER2-zero breast cancer. Compared to HER2-zero tumors, HER2-low tumors were less likely of metaplastic histology, associated with lower Ki67 and were more likely to be androgen receptor (AR)-positive. An upregulation of genes involved in fatty acid metabolism (ACSM1) and steroid hormone metabolism (DHRS2, UGT2B28) was observed in HER2-low tumors versus HER2-zero tumors. This data suggested there may be some biological differences between HER2-low and HER2-zero TNBCs. Although rates of patholic response (pCR) were not significantly different between patients with HER2-zero and HER2-low tumors, non-pCR in patients with HER2-low tumors was associated with increased expression of a gene encoding an EGFR ligand, while non-pCR in patients with HER2-zero tumors was associated with downregulation in genes involved in immune response pathways. This interview took place at the San Antonio Breast Cancer Symposium (SABCS) 2022 in San Antonio, TX.

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Transcript (edited for clarity)

As we all know, based on the DESTINY-Breast04 study, trastuzumab deruxtecan was approved as a treatment for HER2-low metastatic breast cancer earlier this year. Now, HER2-low is defined by immunohistochemistry score of HER2 of 1+ or 2+ and ISH negative. And so, about 50% of patients with triple-negative breast cancer have HER2-low breast cancer. And so, it is unclear if HER2-low forms a distinct biologic entity within triple-negative breast cancer...

As we all know, based on the DESTINY-Breast04 study, trastuzumab deruxtecan was approved as a treatment for HER2-low metastatic breast cancer earlier this year. Now, HER2-low is defined by immunohistochemistry score of HER2 of 1+ or 2+ and ISH negative. And so, about 50% of patients with triple-negative breast cancer have HER2-low breast cancer. And so, it is unclear if HER2-low forms a distinct biologic entity within triple-negative breast cancer.

And so, we designed a study based on a cohort of patients who are enrolled on a prospective clinical trial for triple-negative breast cancer where they received neoadjuvant chemotherapy. And so, we had about 367 patients with triple-negative breast cancer in this cohort, and we separated them into patients with HER2-zero breast cancer versus HER2-low breast cancer based on the definitions from the DESTINY-Breast04 study.

And so, we interrogated the differences between HER2-low and HER2-zero tumors and found that HER2-low tumors were more likely to have a lower Ki-67 score, which is a marker of cell proliferation, and they were more likely to be androgen receptor positive. And then we asked the question, are there molecular differences in the HER2-zero tumors versus the HER2-low tumors? And we found that HER2-low tumors tend to have upregulation of genes involved in fatty acid metabolism, as well as steroid hormone metabolism.

And so, these data together suggest that there may be some biologic differences between HER2-low and HER2- zero tumors within the triple-negative breast cancer subset. And so, then we went on to further interrogate whether there were differences between responders and non-responders separately within the HER2-low cohort as well as the HER2-zero cohort.

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