Impact of Risk-Reducing Strategies in BRCA Mutation Carriers Outlined

Zosia Chustecka

January 28, 2010

January 28, 2009 – Women who find that they are carriers of BRCA mutations, and therefore at a significantly increased risk of developing breast and ovarian cancer, have a variety of options that they can pursue to reduce that risk.

But choosing which option to pursue can be daunting task, especially because some can appear rather drastic, such as surgery in still-healthy women to remove the ovaries and/or breasts.

Advising women on which option to choose is a difficult task because there are no data from randomized trials that compare the various approaches, and it is unlikely that such trials will ever be carried out.

However, there are data on each strategy alone, and by combining all of these data, a group of researchers has come up with a computer-simulation model that quantifies the impact of each decision.

"Our analysis aims to enhance patient care by bridging the evidence gap," say the researchers, Allison Kurian, MD, and colleagues, from Stanford University School of Medicine in California. "We provide a computer model that integrates the best available data."

Details are outlined in a paper published in the January 10 issue of the Journal of Clinical Oncology.

This decision analysis will prove to be an important reference for physicians.

"This decision analysis will prove to be an important reference for physicians, other genetic professionals, and most importantly, patients with BRCA mutations," according to an accompanying editorial.

"The results of this study have the potential to markedly facilitate decision making," write the editorialists, Zsofia Stadler, MD, and Noah Kauff, MD, both from the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in New York City.

Decision-Analysis Model

The computer-simulation model integrates empiric data from the literature to estimate the survival probability for women with BRCA1 and BRCA2 mutations.

The model simulates the life histories of a 1980 birth cohort of 1 million women with BRCA1 or BRCA2 mutations from the ages of 25 to 100 or death, whichever comes first, the researchers explain. The key findings are outlined below.

Women With BRCA1 Mutation

Women who carry the BRCA1 mutation have a 53% chance of reaching the age of 70, as does 84% of the general population in the United States. They have an equal chance of dying from breast or ovarian cancer (41% vs 36%, conditional on death by age 70).

The most effective combination strategy is a prophylactic mastectomy at age 25 plus a prophylactic oophorectomy at age 40; together, this strategy increases the chance of reaching the age of 70 to 79%. This represents a survival gain of 26% by age 70, compared with no intervention (79% vs 53%).

Postponing the mastectomy until age 40, but in the meantime undergoing breast screening, and having an oophorectomy at age 40 reduces this survival gain only slightly (by 2%), to 24%. Similarly, opting not to have a mastectomy and instead undergoing breast screening from the ages of 25 to 69 and having an oophorectomy at age 40 also reduces the survival gain only slightly (by 3%), to 23%.

The most effective single intervention is an oophorectomy at age 40, which increases the chance of reaching the age of 70 to 68%, and represents a 15% absolute gain over no intervention (68% vs 53%).

Delaying the oophorectomy until age 50 cuts this absolute gain by half (8% vs 15% at age 40).

Opting for mastectomy alone at age 25 reduces the absolute gain slightly (by 2%), and yields a 13% absolute gain, compared with no intervention. Delaying the mastectomy until age 40 reduces it even further (by 4%), to an 11% absolute gain.

Opting for breast screening alone from the ages of 25 to 69 yields the lowest absolute gain (6%) of the single-intervention options.

 

Women With BRCA2 Mutation

Women with the BRCA2 mutation have a 71% chance of reaching the age of 70, as does 84% of the general population in the United States. These women have a greater chance of dying from breast than from ovarian cancer (36% vs 20%, conditional on death by age 70), but noncancer deaths are more frequent (44%) than deaths from either cancer among these women.

The most effective combination strategy is mastectomy at age 25 plus oophorectomy at age 40, which together provide a 12% survival gain by age 70, compared with no intervention (83% vs 71%).

Postponing mastectomy until age 40, but in the meantime undergoing breast screening, and having an oophorectomy at age 40 reduces the survival gain slightly (by 1%), to 11%. Similarly, opting not to have a mastectomy but instead to undergo breast screening from the ages of 25 to 69 and having an oophorectomy at age 40 reduces the survival gain slightly (2%), to 10%.

The most effective single strategy is mastectomy at age 25, yielding a 8% gain, compared with no intervention (79% vs 71%).

Postponing mastectomy until age 40 reduces this only slightly (by 1%), to a 7% absolute gain.

Opting for an oophorectomy at age 40 yields a 6% survival gain, relative to no intervention (77% vs 71%). Delaying oophorectomy until age 50 reduces this slightly (by 2%), to a 4% gain.

Breast screening alone, with annual magnetic resonance imaging and mammography, provides a 4% absolute gain.

Better-Informed Choices

The authors hope that their computer model will "facilitate shared decision making, guiding women with BRCA1/2 mutations toward better-informed choices between prophylactic surgery and screening alternatives."

"Individual women make widely disparate choices about how to manage their cancer risks, depending on their family history, healthcare access, reproductive concerns, and concurrent diagnoses," Dr. Kurian and colleagues explain.

Our results can anchor such choices quantitatively.

"Our results can anchor such choices quantitatively, helping a woman weigh strategies that yield small differences in survival, yet potentially larger differences in physical and emotional effects, according to her preferences," they add.

Both the researchers and the editorialists point out limitations to the model, and note that there are many questions that have not been addressed, which could alter judgments about the efficacy and tolerability of the different strategies. For example, one issue is the affect of menopausal hormone therapy in women who opt to have an oophorectomy at an early age, and another is the impact of partial rather than complete mastectomies.

"Future updates will be needed," the editorialists write.

The study authors have disclosed no relevant financial relationships. Editorialist Dr. Kauff reports having served as a consultant and having provided expert testimony for Wyeth.

J Clin Oncol. 2010;28:222-231. Abstract

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