The risk reductions suggested by studies examining the value of prophylactic surgery for the prevention of breast and ovarian cancer in high-risk women may be either exaggerated or underestimated because of potentially unrecognized biases in study design, according to a commentary in the July 2 issue of the Journal of the National Cancer Institute. Understanding these biases might help researchers better evaluate past studies and improve the design of future studies.

Women who carry germline mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 are at increased risk of breast and ovarian cancer. In studies, prophylactic bilateral mastectomy has been associated with an 85% to 100% reduction of breast cancer risk. Prophylactic oophorectomy (surgery to remove the ovaries) has been associated with a similar risk reduction in ovarian cancer and in breast cancer.

Hester M. Klaren, M.D., Matti A. Rookus, Ph.D., and their colleagues from the Netherlands Cancer Institute in Amsterdam, caution that such studies contain a number of potential biases. One such bias is "confounding by indication," which occurs when comparing surgery and nonsurgery patients who are from families with a different baseline risk of breast and ovarian cancer. This form of bias may lead to an underestimation of risk reduction after prophylactic oophorectomy.

"Familial-event bias" may occur when a woman's decision to undergo prophylactic surgery for a certain cancer is influenced by events involving a family member who was recently diagnosed with that cancer or died from that cancer. If this familial event is also included in the study, this may result in bias. As a consequence, cancer risk among women in the nonsurgery group may be overestimated, and this will result in an overestimation of the risk reduction after prophylactic surgery.

Other potential biases include survival bias, detection bias, testing bias, and confounding by other risk factors for breast and ovarian cancer.

The authors say that such biases need to be considered seriously, particularly because most biases seem to result in an incorrect estimation of the benefit from prophylactic surgery. They say that a more critical discussion about potential biases, including an estimation of their direction and quantitative impact, is needed.

"Only in this way can BRCA1/2 mutation carriers, clinical geneticists, and treating physicians obtain more accurate information about the true extent of cancer risk reduction from prophylactic surgery," they say. "This valid estimate of risk reduction may become even more crucial in the future when data become available regarding the efficacy of new surveillance methods, such as magnetic resonance imaging, and new chemoprevention agents, such as raloxifene."

SOURCES:
Journal of the National Cancer Institute, July 2, 2003
Netherlands Cancer Institute (http://www.nki.ni)