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Study: Gene Variants May Predict Who Will Respond to Breast Cancer Prevention Drugs

Discovery advances individualized care of high-risk women (June 13)

In women at high risk for breast cancer, long-term treatment with tamoxifen or raloxifene can cut the risk of developing the disease in half. Research supported by the National Institutes of Health (NIH) have identified two gene variants that may predict which women are most likely to benefit from this therapy — and who should avoid it.

The work represents a major step toward individualized breast cancer prevention in women at high risk for the disease based on their age, family history of breast cancer, and medical history.

“Our study reveals the first known genetic factors that can help predict which high-risk women should be offered breast cancer prevention treatment and which women should be spared any unnecessary expense and risk from taking these medications,” said lead scientist James N. Ingle, MD. “We also discovered new information about how the drugs tamoxifen and raloxifene work to prevent breast cancer.”

The research, which shows nearly a six-fold difference in disease risk depending on a woman’s genetic makeup, was published in the June 13 issue of Cancer Discovery.

Women undergoing breast cancer preventive treatment take tamoxifen or raloxifene for 5 years. In rare cases, the drugs can cause dangerous side effects, including blood clots, strokes, and endometrial cancer. Many women never try the therapy because the chance of success seems small compared with the perceived risk of adverse effects.

In the new study, investigators analyzed data related to genetic variations called single nucleotide polymorphisms (SNPs) obtained from more than 33,000 high-risk women who had participated in the National Surgical Adjuvant Breast and Bowel Project (NSABP).

The researchers looked for SNPs that occurred more commonly in women who developed breast cancer during the trial than in women who remained free of the disease. The analysis identified two such SNPs — one in a gene called ZNF423 and the other near a gene called CTSO.

The scientists’ work revealed that women with the beneficial version of the two SNPs were 5.71 times less likely to develop breast cancer while taking preventive drugs than were women with neither advantageous SNP.

Further, the scientists learned that ZNF423 and CTSO act by affecting the activity of BRCA1, a known breast cancer risk gene. Healthy versions of BRCA1 reduce disease by repairing a serious form of genetic damage, whereas harmful versions of BRCA1 dramatically increase a woman’s chance of developing breast cancer.

Source: NIH; June 13, 2013.

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