Helping Breast Cancer Gene Mutation Carriers Weigh Prevention Choices
More than 300,000 women in the United States have defects in one of two DNA repair genes known as breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2). Since the mid-1990s, when work by Dr. Mary-Claire King and others helped to uncover the significance of harmful mutations in genes located on chromosomes 17 and 13, dozens of studies in the United States and abroad have confirmed that women who carry specific BRCA1 and BRCA2 mutations face a much higher risk of some cancers, including an approximately 60 percent lifetime risk of breast cancer and a 15 to 40 percent lifetime risk of ovarian cancer.
“The real question becomes: What can women do about it, and how can we best help them understand and cope with their elevated risk?” said Dr. Beth Karlan, director of the Women’s Cancer Research Institute and Division of Gynecologic Oncology at Cedars-Sinai Medical Center and professor of obstetrics and gynecology at UCLA’s David Geffen School of Medicine. “In many cases, women feel as if they have to act, but they may not fully understand the potential impact of the preventive measures that we know will lower that risk.”
It has generally been shown that prophylactic mastectomy reduces breast cancer risk in mutation carriers by 90 percent. Prophylactic salpingo-oophorectomy reduces the risk of ovarian cancer by approximately 80 percent and also cuts breast cancer risk in half. And, in a study led by Drs. Sylvia K. Plevritis, Allison W. Kurian, and Bronislava M. Sigal of Stanford University, supplementing mammography with annual magnetic resonance imaging (MRI) of the breast in this high-risk population helped women manage their risk even further, at an acceptable cost relative to the benefit. (The American Cancer Society revised its screening guidelines in 2007 to include annual MRI for BRCA mutation carriers, citing this study.)
Despite having these risk-reducing and surveillance options, women who carry BRCA mutations are still faced with difficult decisions about the timing and acceptance of what amounts to highly invasive strategies that do not completely eliminate cancer risks and that carry long-term physical consequences. And because it is not possible to randomly assign women to drastic interventions like prophylactic mastectomy or prophylactic oophorectomy, no definitive evidence exists to help them decide whether to have either procedure.
Modeling Earns Its Place
One approach is to develop decision aids based on computer simulations that are firmly rooted in evidence from a range of sources, such as clinical trials, observational studies, and clinical expertise. “The goal is to bridge the evidence gap by using models to integrate the best available data,” said Dr. Plevritis.
In December 2009, she and Drs. Kurian and Sigal built on their previous study by analyzing the outcomes of prophylactic mastectomy and prophylactic oophorectomy in combination with intensive screening, reporting their results in the Journal of Clinical Oncology. Their earlier MRI study provided a tool for policy-level decision making, whereas the current model was designed to support individual-level decision making.
Among the general population, 84 percent of 25-year-old women will survive to age 70. Risk of death from any cause is greater for women with BRCA2 mutations, however; 71 percent will survive to age 70 with no risk-reducing intervention, and only 53 percent of women with BRCA1 mutations will survive to that age.
The model shows how specific risk-reducing strategies used alone or in combination improve the chances of survival to age 70. The most aggressive combination of risk-reducing strategies—prophylactic BRCA2 mastectomy at age 25 plus prophylactic oophorectomy at age 40—can increase survival for a BRCA2 mutation carrier to 83 percent, only 1 percentage point less than estimates for the general population. Those same strategies, the model predicts, will bring the survival probability to 79 percent for BRCA1 mutation carriers.
Probability of Survival to Age 70 among BRCA1/2 Mutation Carriers
Interventions used singly:
Interventions used in combination:
PM at age 25 + PO at age 40
Helping Women Make Tough Choices
Weighing the projections from a computer model is only part of the equation for women who carry BRCA mutations and want to reduce their cancer risk. “Discussing cancer risk with BRCA1/2 mutation carriers can be complicated for all sorts of individual, cultural, and emotional reasons,” explained Dr. Karlan.
“Individual women make widely disparate choices about how to manage their cancer risks, depending on their family history, access to health care, reproductive concerns, and concurrent diagnoses and personal preferences,” agreed Dr. Kurian. “These preventive choices show small differences in survival but potentially large differences in physical and emotional effects.”
Memorial Sloan-Kettering Cancer Center in New York City is one of the few hospitals offering genetic testing services for BRCA mutations that refers women having difficulty with these decisions—those who are either highly stressed or very ambivalent—to an on-staff clinical psychologist, Dr. Karen Hurley.
“People are hungry for data, and decision aids like the one in this model can be very helpful,” she explained. “On the other hand, there are things that can’t be captured in numbers.”
Dr. Hurley sometimes sees patients who use risk numbers to obsess about small differences in survival. “As professionals, we deal with survival numbers all the time in pragmatic and matter-of-fact terms. But we have to be sensitive to the fact that these numbers put mortality on the table, with all the feelings that entails.” Not many people in their 20s, 30s, and 40s find it easy to grapple with their mortality, she said, but “the BRCA mutation can fast-forward them in time in relation to their peers.
“I tell people that their decisions about these dramatic risk-reducing strategies should make both medical and emotional sense,” Dr. Hurley continued. “Most people are resilient. They may need help in understanding the numbers, and they may have unresolved issues to deal with that affect their decision making, such as past bereavements or other life stressors. We try to work through those things together. As a clinician, I’m listening for one clear statement to emerge: What they expect the specific risk-reducing intervention to do specifically for them.”
Ultimately, each woman must make her own personal decision about the best strategy for managing the high cancer risks conveyed by a BRCA1 or BRCA2 mutation. “Our model aims to anchor women’s choices quantitatively,” said Dr. Kurian, “guiding women with BRCA1/2 mutations toward better-informed decisions between prophylactic surgery and screening alternatives.”