June 13, 2013
Genetic Markers May Signify Response To Breast Cancer Therapy
Brett Smith for redOrbit.com — Your Universe Online
New research from the Mayo Clinic has identified favorable genetic variations that increase the chances of a positive response to preventive breast cancer therapy with the drugs tamoxifen and raloxifene, according to a new report in the journal Cancer Discovery.
"Our findings are important because we identified genetic factors that could eventually be used to select women who should be offered the drugs for prevention," said study co-author Dr. James Ingle, an oncologist at the clinic.
Referred to as selective estrogen receptor modulator (SERM) therapy, tamoxifen or raloxifene are often prescribed to prevent breast cancer in women who have a high risk for the disease. Occasionally, the drugs can cause hazardous side effects, such as blood clots, strokes and uterine cancer. These risks can be a deterrent for women who would otherwise benefit from the treatments.
In an effort to better predict whether the therapy will work, researchers at the Mayo Clinic, the National Surgical Adjuvant Breast and Bowel Project (NSABP) in Pittsburgh, and the RIKEN Center for Genomic Medicine in Tokyo conducted a genetic analysis involving over 590 patients who developed breast cancer while on SERM therapy and 1,200 women in a control group. They were chosen from 33,000 women enrolled in two NSABP breast cancer prevention trials.
In their analysis, the scientists focused on over 500,000 genetic variations in the DNA called single nucleotide polymorphisms (SNP). These SNPs were compared between women who developed breast cancer during the trial and those who remained free of the disease.
The analysis identified two genes associated with a higher risk for cancer: ZNF423 and CTSO. Neither of these genes had been linked with breast cancer or any response to the preventive drugs. Women with the beneficial variations of the two SNPs were 5.7 times less likely to develop breast cancer while on the preventive drugs than were women with neither advantageous SNP.
A biochemical analysis of the SNPs showed they affect the activity of BRCA1, a known breast cancer risk gene. Desirable versions of BRCA1 reduce disease by repairing genetic damage, while harmful versions of BRCA1 dramatically increase breast cancer risk.
"Our discovery is a major step toward truly individualized prevention of breast cancer,” Ingle said. “Findings from our study provide clear direction as to which women are likely and which are unlikely to benefit from tamoxifen or raloxifene.
"The best chance we have of decreasing the burden of breast cancer is to prevent it in the first place,” he added.”Our findings provide the basis for a reinvigoration of research efforts in breast cancer prevention."
The origins of SERM therapy actually lie in efforts to produce a contraceptive drug. After being developed in the United Kingdom during the late 1950s, tamoxifen eventually received marketing approval in the US as a fertility treatment, but never proved particularly valuable with respect to contraception.
After subsequent connections between estrogen and cancer were made, clinical trials on breast cancer patients showed promise during the 1970s and the treatment was definitively demonstrated as effective in the late 1990s.