Prophylactic surgery greatly reduces cancer risk, but by how much is unclear

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 over- 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 a misestimation 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."

Contact: Netherlands Cancer Institute
Department of Communications
31-20-5122999
l.kuipers@nki.nl.

Klaren HM, van't Veer LJ, van Leeuwen FE, Rookus MA. Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst 2003;95:941–7.

Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage.

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