Researchers have pinpointed variations in 2 genes that can help predict which women at high risk of breast cancer will respond to preventive treatment. The findings represent a major step toward personalized breast cancer prevention therapy, the study authors said.
In today’s Cancer Discovery, investigators in the United States and Japan report on DNA analyses from women at high risk of breast cancer who were taking the preventive drugs tamoxifen and raloxifene, including 592 who developed breast cancer and 1171 matched controls. All were selected from the 33 000 women in the National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 breast cancer prevention trials.
The analysis showed that certain single nucleotide polymorphisms (SNPs) in the ZNF423 gene and near the CTSO gene were more common in women who developed breast cancer during the trials than in women who remained disease free. Neither these 2 genes nor any SNPs related to them had ever been implicated in breast cancer risk or response to the preventive drugs. Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs) that block estrogen’s ability to signal breast cancer cells to multiply.
Additional analyses using breast cancer cell lines showed that in cells with certain variants of the ZNF423 and CTSO SNPs, estrogen increased the expression not only of ZNF423 and CTSO but also of BRCA1, an important breast cancer risk gene. In cells with other variants of the ZNF423 and CTSO SNPs, estrogen didn’t increase expression of the 3 genes. A healthy BRCA1 gene protects against breast cancer by repairing genetic damage, but mutated versions of the gene increase the risk of breast cancer.
When tamoxifen and raloxifene were added to the cells, those with protective variants of the ZNF423 and CTSO SNPs had expression of these genes and BRCA1, offering a possible explanation for why fewer cancers developed in women with these variations. With risky variants, the cells’ BRCA1 expression increased even in the presence of tamoxifen or raloxifene. Depending on which versions of the SNPs a woman had, her breast cancer risk while taking a SERM could vary by nearly 6-fold.
“For the first time, we discovered genetic factors that could be used to select women who should be offered the drugs for prevention,” lead author James Ingle, MD, of the Mayo Clinic in Rochester, Minnesota, said in a statement. “Also of substantial importance is that we have discovered new information on how tamoxifen and raloxifene work to prevent breast cancer.”