CHEK2 Mutations Linked to Hormone Receptor-Positive Breast Cancer Treatment Resistance in Younger Women

In pre-menopausal women diagnosed with hormone receptor-positive, HER2-negative breast cancer, a CHEK2 genetic mutation is associated with the cancer’s resistance to hormonal therapy medicines, according to a study. The mutation doesn’t seem to affect hormonal therapy resistance in post-menopausal women.

The research was published online on June 30, 2023, by the journal Science Advances. Read “Molecular portraits of cell cycles checkpoint kinases in cancer evolution, progression, and treatment responsiveness.”

The CHEK2 gene helps repair DNA damage in cells by making a protein called CHK2. When it works properly, the CHEK2 gene can help suppress the development of cancer.

Everyone has two copies of the CHEK2 gene, one from each parent. If you inherit a CHEK2 gene that is not working properly due to a genetic mutation, you have a higher risk of developing certain cancers if too much DNA damage occurs within a cell.

Researchers are continuing to study the types of cancers thought to be related to the CHEK2 gene. The cancers currently associated with CHEK2 mutations are:

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  breast cancer

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  colorectal cancer

Emerging evidence suggests that a CHEK2 mutation also increases the risk of other cancers, such as prostate cancer.

Research suggests that a CHEK2 mutation can nearly double the risk of breast cancer. Although not as common as a BRCA1 or BRCA2 mutation, CHEK2 mutations have been found in up to 1.6% of the general population and in 2% to 3% of women diagnosed with breast cancer.

Because the CHEK2 gene is linked to breast cancer development, the researchers wanted to see if a CHECK2 mutation affected outcomes of the disease.

The study was made up of three parts.

In the first part, the researchers looked at the records of 5,480 women diagnosed with hormone receptor-positive, HER2-negative breast cancer. The researchers wanted to know the breast cancer outcomes in women with a CHEK2 mutation. The results showed that the cancer in pre-menopausal women with a CHEK2 mutation was more likely to be resistant to hormonal therapy and grow than cancer in pre-menopausal women without a CHEK2 mutation.

The researchers also found that a CHEK2 mutation was linked to an earlier age at diagnosis. In other words, women with a CHEK2 mutation were more likely to be diagnosed with hormone receptor-positive, HER2-negative breast cancer when they were pre-menopausal. The average age at diagnosis of women with a CHEK2 mutation was 46. The average age at diagnosis of women without a CHEK2 mutation was 58.

In the second part of the study, the researchers looked at two breast cancer cell lines, doing experiments in petri dishes. They reduced levels of the CHK2 protein in the cells and found it caused resistance to hormonal therapy.

In the third part of the study, the researchers used both pre-menopausal and post-menopausal mice that had cells from women’s breast cancer tumors implanted in them. The mice had a CHEK2 mutation. The researchers found that lower levels of the CHK2 protein was linked to resistance to hormonal therapy in pre-menopausal mice, but not in post-menopausal mice.

“This paper is not an easy one to understand because I think it’s at the leading edge of how cancer research will be done in the very near future,” said senior author Svasti Haricharan, PhD, assistant professor and co-director of the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys. “Readers have to process information acquired through multiple, parallel lines of investigation, which means even the average biologist, for instance, might struggle if they don’t understand bioinformatics, and vice versa for informaticians who may not understand the complex experimental systems we use. But, on the plus side, the results are likely to be real and meaningful since they are supported by so many different lines of investigation.”

If you’re a pre-menopausal woman who has been diagnosed with hormone receptor-positive, HER2-negative breast cancer, the results of this study suggest that talking to your doctor about genetic testing for a CHEK2 mutation may be a good idea. If you learn you have this mutation, you and your doctor can discuss treatment options other than hormonal therapy that might be a good fit for your situation.

“It’s certainly worthwhile for any younger woman diagnosed with breast cancer to have genetic testing,” explained Dr. Haricharan. “And in this case especially so, as there might be potential for different treatment options or increased care based on our findings.”