Prophylactic Mastectomy Substantially Reduces Cancer in BRCA 1/2 Carriers

March 02, 2004

March 2, 2004 — A study by University of Pennsylvania researchers in the March 15 issue of the Journal of Clinical Oncology and published online Feb. 24 adds to a growing body of evidence that prophylactic double mastectomy can reduce breast cancer incidence, especially in high-risk carriers of the BRCA 1 and BRCA 2 mutations.

But the decision to have the procedure is still complex and difficult, say the authors and breast oncologists.

In the Prevention and Observation of Surgical Endpoints (PROSE) study, 483 women with BRCA 1 and 2 mutations who underwent bilateral mastectomy at 11 sites in the U.S., Canada, U.K., and the Netherlands were followed for six years. They were compared with control patients matched for mutation, treatment center, and age (within five years of the case birth year).

The women had one of four procedures: total (simple) mastectomy; subcutaneous mastectomy; modified radical mastectomy; or radical mastectomy.

In four separate analyses, Timothy Rebbeck, MD, and colleagues determined that having bilateral mastectomy substantially reduced the risk of developing cancer. Overall, 1.9% of the case patients developed invasive breast cancer or ductal carcinoma in-situ compared with 48.7% of control patients, a 90% risk reduction.

Each analysis attempted to eliminate selection bias because the women who came to the treatment centers knew they were mutation carriers. Control patients had to be free of cancer when their matched cases had surgery, but they could have had cancer before coming to the center, and some had had an oophorectomy or bilateral mastectomy previously.

In an accompanying editorial, Lynn Hartmann, MD, and colleagues, from the Mayo Clinic Cancer Center in Rochester, Minnesota, said some of these women who developed or had a recurrence of cancer would be motivated to seek care at a cancer center, which could lead to selection bias. "This selection bias could artificially increase the number of breast cancers in the control group and thus, overestimate the benefit of the procedure," but they concluded that "there are considerable strengths to the work."

Dr. Hartmann was the lead author on a 1999 New England Journal of Medicine article that showed a similar 90% risk reduction, but in women with unknown carrier status.

Dr. Rebbeck agreed that the background baseline risk for the control patients was higher than has been seen in other studies, but he told Medscape that he believes the sample is representative of women with mutations who do come into a clinic.

"It's possible this article may overstate the benefits to some degree, given the limitations," said Christopher E. Desch, MD, a breast oncologist and research director of the Virginia Cancer Institute in Richmond, in an interview with Medscape. "But the magnitude appears very large in the high-risk population," he added.

The PROSE study could not determine which type of mastectomy was the most effective, but the two women who did develop cancer had less aggressive procedures, said Dr. Rebbeck.

With several other studies pointing to reduced risk, prophylactic mastectomy seems like an effective option for high-risk women, said Dr. Desch. But, he added, "at the practicing physician level, it still is a very difficult discussion, and I think it's difficult for women to face issues like this."

Henry T. Lynch, MD, from Creighton University School of Medicine in Omaha, Nebraska, who first described hereditary breast-ovarian cancer syndrome in the early 1970s, told Medscape that the PROSE study "definitely adds considerably to the evidence favoring prophylactic mastectomy in high-risk women."

But, Dr. Lynch added in an email, women who decide to have the procedure must be sure of their risk status, and consult with a genetic counselor, a general surgeon, and a plasticor reconstructive surgeon before going ahead. "She must appreciate fully how this might impact upon her psychologically as well as physically," Dr. Lynch said.

High-risk women could instead opt for intensive screening, either through mammography or magnetic resonance imaging, Dr. Lynch and Dr. Desch agreed. Tamoxifen is another option, but prevention data in high-risk women are minimal, Dr. Desch said. Oophorectomy is another possibility, but he said he does not recommend it to women until they finish having children.

"This is one of the most complicated decisions in terms of trade-offs," said Dr. Desch.

J Clin Oncol. Published online Feb. 24, 2004.

Reviewed by Gary D. Vogin, MD

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