May 14, 2001 Researchers at Jefferson Medical College may be close to developing a simple, inexpensive and rapid test to help identify those women with breast cancer who are at greatest risk of carrying a damaged version of BRCA1 or BRCA2, genes predisposing them to the hereditary form of the disease. The genes put women with breast cancer at a much greater risk of developing other cancers in the same or other breast, in addition to ovarian cancer.
If the scientists, led by Bruce C. Turner, M.D., Ph.D., assistant professor of radiation oncology at Jefferson Medical College and the Kimmel Cancer Center of Thomas Jefferson University in Philadelphia, are right, the test will help identify those patients with breast cancer who need to be tested for alterations in these genes. He presents his group’s work May 13 at the annual meeting of the American Society of Clinical Oncology in San Francisco.
“This is important because patients with breast cancer who have mutations in BRCA1 or BRCA2 may be better candidates for certain types of therapy,” Dr. Turner says. “For example, they may be better candidates for mastectomy than lumpectomy and radiation therapy – also known as breast-conserving therapy. Those patients electing breast conserving therapy need to have constant monitoring not only of their treated breast but also their other breast if they don’t have a mastectomy on that side, and also of their ovaries.”
Dr. Turner and his colleagues may have an easy way for patients with breast cancer to determine whether they should be tested for alterations in the cancer genes. His team, along with help from scientists at Coulter Pharmaceuticals in San Diego, has devised a test using a special protein called a monoclonal antibody to determine if BRCA1 is damaged.
The antibody serves as a guided missile aimed directly at the protein made by BRCA1. If the antibody fails to find the normal protein, then this suggests that the gene is damaged or missing, and sequencing should be done.
“The thinking is, if we can develop a screening test for women with a diagnosis of breast cancer – a screening test to determine if they have a high probability of harboring an alteration in BRCA1, then we could identify those patients at high risk for inheriting the damaged gene,” explains Dr. Turner. “These women would then be counseled to go on to sequencing to find the exact mutation that is causing the cancer.”
Currently, women with a family history of breast cancer or ovarian cancer must undergo genetic sequencing to determine if they carry damaged versions of BRCA1 or BRCA2, which raises their risk of cancer to as much as 80 percent over their lifetime. But the testing takes several weeks to complete and can be expensive. Most patients with breast cancer who are at risk for mutations in the genes – about 5 to 10 percent or 10,000 to 20,000 women annually have such mutations – do not undergo sequencing.
The researchers stained samples of breast cancer cells that were obtained at the time of biopsy when the initial diagnosis of breast cancer was made with a specially designed antibody to BRCA1. “A breast cancer that carries an altered BRCA1 gene will be negative for the antibody staining because the alteration would prevent the gene from making its protein – you can’t pick it up immunohistochemically,” Dr. Turner says.
The scientists wanted to find out if those breast cancer samples that did not have stains for BRCA1 also turned out to have BRCA1 mutations when sequenced. They found that of 118 patients with breast cancer, 22 had the mutation. Of those 22, only one had any “immunoreactivity” to the monoclonal antibody and the other 21 breast cancer samples showed no evidence of BRCA1 protein.
In contrast, the majority of breast cancers with normal versions of the BRCA1 gene had high levels of the BRCA1 protein as detected by the antibody test.
“This study suggests that a simple, rapid immunohistochemical test, which is inexpensive, is a reliable screening test to identify patients who are then optimal candidates for sequencing,” he says.
Dr. Turner and his group have begun working with Coulter to design a larger, prospective study to examine the effectiveness of such a screening tool and also to design an antibody that is effective in identifying those breast cancer patients with damaged versions of the other breast cancer gene, BRCA2.
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