Researchers call for studies on role of BRCA1 mutations in chemotherapy response

11/10/04

Loss of BRCA1 function is associated with sensitivity to DNA-damaging chemotherapy and may also be associated with resistance to taxane-based chemotherapy. However, prospective clinical studies are needed to evaluate the role of BRCA1 in chemotherapy response, concludes a new review in the November 17 issue of the Journal of the National Cancer Institute.

BRCA1 mutations account for only 5% of breast and ovarian cancers, but loss-of-function mutations in the BRCA1 gene confer up to an 82% risk of breast cancer and up to a 54% risk of ovarian cancer. Because BRCA1 is involved in DNA repair, loss of a functioning BRCA1 gene may make a cell more vulnerable to chemotherapy agents that damage DNA, such as platinum-based compounds. In addition, BRCA1 has also been shown to be involved in the regulation of cell division, and loss of the gene has been proposed to protect a cell against spindle poisons, a group of chemotherapy agents, such as taxanes and vinca alkaloids, that disrupt cell division.

To determine whether the level of BRCA1 function in a patient could be used to predict response to chemotherapy for breast and ovarian cancers, D. Paul Harkin, B.Sc., Ph.D., and Richard D. Kennedy, M.D., Ph.D., of The Queen's University of Belfast in Northern Ireland, and colleagues reviewed published preclinical and clinical evidence. Preclinical studies included research in both animal models and cell lines. Clinical studies were all retrospective in nature, because no prospective trials have been designed to study the role of BRCA1 in chemotherapy response.

The researchers found that BRCA1 inactivation through mutation appears to confer sensitivity to DNA-damaging chemotherapeutic drugs commonly used to treat breast and ovarian cancers. However, preclinical evidence suggests that BRCA1 function is necessary for spindle poisons to work. The authors recommend that prospective studies be conducted to evaluate BRCA1 expression and chemotherapeutic response and discuss several issues that should be considered when designing appropriate clinical trials.

"By these approaches, it may be possible to determine whether the BRCA1 gene is a useful predictive marker for chemotherapeutic choice in breast or ovarian cancer," the authors write. "These studies may also point the way to new chemotherapeutic strategies targeting BRCA1-mediated pathways that participate in cancer cell death or an improved response to conventional treatments."

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