HER2阴性乳腺癌 z-bo 2020-09-21 355

　　A recent study published in the Proceedings of the National Academy of Sciences showed that HER2 missense mutations do not cause gene amplification or protein overexpression, so they are often classified as HER2 negative. Currently, studies on whether HER2 targeted drugs can act on such mutations are underway.

　　According to a recent article published in the Proceedings of the National Academy of Sciences, not all HER2 genes cause the proliferation and spread of cancer cells, so this mutation cannot be used to predict whether HER2 targeted drugs can produce relief.

　　About 5% of breast cancer patients carry HER2 missense mutations, and missense mutations generally occur in the absence of HER2 gene amplification. Unlike most HER2 genes, missense mutations do not cause protein overexpression, and will therefore be classified as HER2 negative by FISH or immunohistochemical analysis.

　　In order to determine whether HER2 missense mutations can be targeted by drugs currently approved to treat HER2-amplified breast cancer, researchers from Johns Hopkins University's Sidney Kimmel Cancer Comprehensive Treatment Center identified 7 species in human breast cancer The missense mutations were introduced into normal and cancerous human breast cells for research. These cells cannot overexpress the HER2 protein or have underlying HER2 mutations.

　　Through the application of genome editing technology, researchers have found that most of the HER2 missense mutations do not produce currently detectable tumor mutations. But there is one missense mutation-HER2 V777L can increase the activation of biochemical pathways, and in the case of PIK3CA mutations, it can enhance cell migration in vitro.

　　"V777L mutation does not change the tumorigenicity of cells in vivo, nor can it increase the sensitivity of HER2 targeted therapy in cell proliferation testing. All missense mutations cannot increase tumorigenicity and migration of tumor cells in mice.

　　According to the study authors, the results show that HER2 missense mutations have unique functionality and require additional oncogenes to affect the phenotype of tumor cells. Only HER2 missense mutations may not be a reliable predictor of HER2 targeted therapy. This hypothesis is currently being verified by a genome-guided clinical trial. According to the study author, Dr. Ben Ho Park, a scientist at the Sidney Kimmel Comprehensive Cancer Treatment Center.

　　"Compared with HER2 amplification or overexpression, the understanding of HER2 missense mutations is relatively new." Park pointed out, "Currently, studies on whether targeted therapies like Herceptin are effective against such mutations are ongoing. But this is not a standard treatment plan."

　　HER2-positive patients often receive targeted drug therapy, such as trastuzumab, pertuzumab, T-DM1, lapatinib, etc. However, because HER2 missense mutations often exist in HER2-negative breast cancer patients, it is not clear whether these targeted drugs can act on such rare mutations.

　　It is estimated that 1/5 of breast cancer patients carry the HER2 amplified gene. Abnormal copy number increase and genome-wide overexpression result in excessive HER2 protein in cancer cells. Missense mutations are different from standard HER2 mutations, except that one nucleotide is replaced by another nucleotide. This mutation is relatively rare, but it is estimated that 10,000 of the 21,000 new breast cancer cases in the United States each year may carry a HER2 missense mutation.

　　Past studies have shown that overexpression of a HER2 missense mutation (L755S) can cause lapatinib resistance. But the Park team found that in their experimental cell line, there was no lapatinib resistance when the mutation activity was at a normal level. The researchers pointed out that the results of the study are of great significance to clinical practice, because breast cancer patients with these normally expressed mutations may still be sensitive to lapatinib.

　　Research on the efficacy of HER2 targeted drugs on HER2 missense mutations is still ongoing, Park said, paying attention to whether tumor genes respond to targeted therapy "will help us understand how to better target mutations for targeted therapy. "