Genetic Markers Could Focus Breast Cancer Chemoprevention

Kate Johnson

June 13, 2013

Two newly described genetic variations have the potential to individualize breast cancer chemoprevention with selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene.

The findings, which were published online June 13 in Cancer Discovery, "are important because, for the first time, we discovered genetic factors that could be used to select women who should be offered the drugs for prevention," say the researchers, headed by James Ingle, MD, from the Mayo Clinic in Rochester, Minnesota.

"If validated, this approach to personalizing prevention holds great promise because it could simultaneously reduce overall drug usage and maximize the gains for the group of patients most likely to benefit," Clifford Hudis, MD, president of the American Society of Clinical Oncology and chief of the breast cancer medicine service at the Memorial Sloan-Kettering Cancer Center in New York City, told Medscape Medical News.

SERM Effective But Little Used

Recent guidelines from the US Preventive Services Taskforce note that 5 years of SERM therapy can reduce the risk for breast cancer by half in high-risk women, Dr. Ingle and colleagues write.

However, despite evidence of their benefit, SERMs are not often used, they point out.

"This is true both because of the large number (about 51) of patients who must be exposed to 5 years of SERM therapy to prevent a single case of breast cancer and because of the occurrence of rare, but serious, SERM-related adverse drug responses," they explain.

"If we could develop a more highly individualized approach to SERM-based breast cancer prevention, thus resulting in a more favorable benefit/risk ratio," it is likely that the use of SERMs for prevention would increase, the researchers note.

First Study to Show Genes Involved

In an attempt to do just that, Dr. Ingle and colleagues conducted a genome-wide association study involving patients from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 breast cancer prevention trials.

Using DNA samples from 592 patients who developed breast cancer while on SERM therapy and from 1171 matched controls, the researchers found a single-nucleotide polymorphism (SNP) in the ZNF423 gene on chromosome 16 that was associated with a decreased risk for breast cancer during SERM therapy.

Another SNP found near the CTSO gene on chromosome 4 was associated with a 5-fold increased risk for breast cancer.

The researchers used several breast cancer cell lines to show that, in cells with the most common SNPs, estradiol induced the expression of both the ZNF423 and CTSO genes, which in turn induced the expression of the BRCA1 gene. This process did not occur in cells with less common SNPs.

In the presence of tamoxifen or raloxifene, this estrogen-induced pattern of ZNF423 and BRCA1 expression was reversed; in cells with less common SNPs, gene expression rose, they note. "The presence of SERMs reversed the expression responses for both ZNF423 and BRCA1 in an SNP-dependent manner."

"There had been no [previous] reports that either of these genes might be related to SERM effect, to estrogens, or to breast cancer risk," they write.

Dr. Ingle and colleagues say that their findings have "potential implications for the selection of women for SERM breast cancer prevention therapy and for the possible reduction of exposure to these drugs of women who have less likelihood of benefit."

Dr. Hudis noted that "because the overall use of SERMs as chemoprevention is relatively low, a predictive test that would improve the risk/benefit ratio for patients, if validated, would be useful."

However, he noted that many average-risk women already use a SERM (raloxifene) for the treatment of osteopenia.

The authors have disclosed no relevant financial relationships.

Cancer Discov. Published online June 13, 2013. Abstract



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