Gene Variations May Predict Response to Breast Cancer Prevention Therapies

Five years of either prophylactic tamoxifen or raloxifene therapy is approved by the US Food and Drug Administration for prevention of breast cancer in women at high-risk for the disease. Still, not many women opt for this type of therapy, even though results from two large preventive trials of more than 33,000 show that the drug regimen can reduce the risk of developing breast cancer in these high-risk women by as much as 50%. The major reason is the slew of side effects that these therapies induce, and the higher risk for developing blood clots and endometrial cancer.

A major reason for the underutilization of the preventive therapy is that although there is a risk reduction in the population, we didn’t have a way to identify individual women who would benefit,” said Angela DeMichele, MD, associate professor of medicine at the University of Pennsylvania, Philadelphia. “Women perceive their own benefits to be quite low relative to the risk of side effects and worsening of quality of life.”

“The women who decide to take tamoxifen or raloxifene are those with relatively higher levels of risk,” said James N. Ingle, MD, professor of oncology at the Mayo Clinic in Rochester, Minnesota. “This is a very personal decision with the vast majority electing not to take either drug.”

Now, researchers from the Mayo Clinic in Minnesota have identified variants in two genes that result in a higher chance that tamoxifen or raloxifene will actually prevent breast cancer. More studies are needed, but if confirmed, women with these variants may be more likely to undergo the 5 year preventive regimen. The results are published in Cancer Discovery.

Ingle and colleagues identified single-nucleotide polymorphisms (SNPs) in two genes-ZNF423 and CTSO-that were associated with a decreased risk of breast cancer occurrence among women taking selective estrogen receptor modulators (SERM) therapy, such as tamoxifen or raloxifene. Those women with other types of variations in these two genes, so-called unfavorable SNPs, may not benefit from preventive therapy with tamoxifen or raloxifene. Within this high-risk population of women, those with the unfavorable mutations had a five-fold higher risk of developing breast cancer compared to the women with the favorable mutations.

These genes were isolated from a genome-wide association study of 592 participants who had developed breast cancer while on SERM therapy and 1,171 matched control participants who did not develop breast cancer. All participants were part of one of two large preventive trials-the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and NSABP P-2.

The researchers also tested the role of these SNPs in estrogen production. Tamoxifen and raloxifene both inhibit the estrogen receptor in breast tissue and are thus anti-estrogen therapies that are used to prevent recurrence or first diagnosis of estrogen receptor positive breast cancer.

Using breast cancer cell lines, Ingle and colleagues showed that estrogen induced the expression of ZNF423 and CTSO. They also found a link of expression of these genes and the DNA repair gene, BRCA1, that when mutated, results in an increased risk of breast cancer. BRCA1 is known to be upregulated in the presence of estrogen. When these same cells were also exposed to either tamoxifen or raloxifene, induction of these genes was reversed. Cells with wild type ZNF423 or CTSO genes were not upregulated in the presence of estrogen and one of the two SERMs. But in cells with one of the SNP variants from those with lowered breast cancer risk on SERM therapy, SERM treatment induced expression of these genes.

The discovery of these novel mechanisms for the estrogen-dependent induction of BRCA1 and for SNP-dependent variation in SERM effect has obvious implications for the individualization of SERM-dependent breast cancer prevention.

“The ability to identify women most likely to benefit really would be a major step toward increasing the benefit-to-risk ratio, which would likely increase uptake of this prevention strategy,” said DeMichele, who was not involved in the current study.

The results suggest the need for more research on personalized prevention strategies for women at risk for breast cancer. Ingle told Cancer Network that more laboratory research and clinical studies are underway, as well as discussions about new prospective clinical trials.