Findings suggest that the HER2 L755S mutation plays a role in the aggressiveness of lobular breast cancer observed in the clinic.
New research has found that the drug poziotinib, which is already approved for other cancer types, reduced tumor growth and multi-organ metastasis in laboratory tests and animal models assessing human epidermal growth factor receptor 2 (HER2)-mutant driven metastatic breast cancer.
Neratinib is frequently used for patients with HER2 mutations, but these responses are variable and often not durable. To further understand this variation, researchers investigated whether different HER2 mutations drove therapy responses, which led to the identification of a mutation that conferred therapeutic resistance and promoted metastatic behavior.
These findings, published in Cancer Research, in addition to the findings about poziotinib, support future clinical trials assessing the value of poziotinib to treat HER2-mutant driven breast cancer, according to the study authors.
“In this study we focused on 2 types of breast cancer—ductal breast cancer and lobular breast cancer—which is understudied when compared to ductal breast cancer,” said leading author Shyam M. Kavuri, PhD, assistant professor at Baylor’s Lester and Sue Smith Breast Cencer and the Department of Medicine, in a press release. “More than 20% of patients with these types of breast cancer develop a metastatic or invasive form of the disease, for which there is no current treatment.”
The investigators examined studies that sequenced the genes of human lobular and ductal breast cancers, specifically analyzing mutations in the HER2 gene. They found that the HER2 L755S mutation was more common among patients with metastatic lobular breast cancer than in patients with ductal breast cancer. Patients with these alterations also had significantly reduced overall survival (OS) compared to those carrying the natural or non-mutated form of HER2, suggesting that recurrent L755 alterations are associated with the more aggressive form of lobular breast cancer, according to the study.
The researchers did not detect any difference in OS among patients with ductal breast cancer and HER2 mutations. Kavuri said this suggests a significant difference between the lobular and the ductal forms of cancer and could have important clinical implications.
To further examine how this HER2 mutation influenced cancer behavior, the researchers conducted laboratory experiments in which the HER2 L755S gene was introduced into cells. Then they treated the modified cells with drugs approved to treat the human cancer.
“We found that having the HER2 L755S mutation conferred the cells resistance to treatments, including neratinib—the cells continued to grow,” said first author Rashi Kalra, MD, in the press release. “When human tumor cells carrying this mutation were grown in animal models, they developed metastasis more often than cells not carrying this mutation.”
These findings therefore suggest that the HER2 L755S mutation plays a role in the aggressiveness of lobular breast cancer observed in the clinic.
The team also searched for drugs that could better treat cancer carrying the HER2 L755S mutation. Of the drugs they tested, Kavuri said poziotinib was able to completely inhibit both tumor growth and metastasis in experimental models.
“We are excited by our findings,” said co-author Bora Lim, MD, in the press release. “Poziotinib offers the possibility of a more effective treatment option for HER2 mutant metastatic breast cancer. We are actively working on the development of a phase 2 clinical trial to determine the value of this drug in the treatment of patients with this devastating condition.”
REFERENCE
A potentially more effective treatment for HER2 mutant metastatic breast cancer. News release. Baylor College of Medicine; June 24, 2022. Accessed July 1, 2022. https://www.bcm.edu/news/a-potentially-more-effective-treatment-for-her2-mutant-metastatic-breast-cancer
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