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Are SERMs an effective alternative to prophylactic mastectomy in women at high risk for breast cancer without BRCA mutations?
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Tamoxifen undervalued, underused.
If a woman doesn’t carry a BRCA1 or BRCA2 mutation, there are only a few ways that she can find herself to be at high risk for breast cancer. There are other genes that raise the risk to BRCA-like levels, such as p53 and PALB2, but mutation carriers are very few. A high dose of radiation in early adulthood can lead to lifetime risks in the neighborhood of 50%, but in 2010, very few women face these exposure levels (the possible exception is chest radiation for Hodgkin’s disease). Other groups at moderate risk include women with a history of benign breast disease with atypia, or with very high mammographic density or with a strong family history of cancer without a known BRCA mutation. For some women in the latter group, we have estimated the lifetime risk to be as high as 40%.
Prophylactic mastectomy should be an option for women at moderate risk, but few women will be willing to undergo an operation for this level of risk. We have had no success in identifying a vitamin or a micronutrient or a ‘healthy’ lifestyle that can reduce the risk to an acceptable level.
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The risk of familial breast cancer starts at ages younger than 50 — and the only drug that is currently available for the prevention of breast cancer in premenopausal women is tamoxifen. It is rarely used in this setting; women are afraid of the side effects, and physicians are unsure of the benefits and side effects. As a result, to my mind, tamoxifen is undervalued and is underused.
We should take pains to ensure that women have access to it, and that concerns about side effects are evaluated formally and dealt with. The current recommended duration of tamoxifen in the preventive setting is 5 years, which is based on treatment studies. There are no clear data to support that this is the optimal schedule for tamoxifen in the preventive setting, and shorter durations should be explored. Tamoxifen is the best we have, and we should try to understand its mechanism of action, the optimal length of treatment in the preventive setting and the duration of the protective effect.
Steven Narod, MD, FRCPC, is director of the Familial Breast Cancer Research Unit at the Women’s College Research Institute, Toronto, Ontario.
Prophylactic mastectomy offers effective prevention.
Several management strategies are available for women at high risk for breast cancer: surveillance with frequent clinical examinations and imaging studies, chemoprevention with drugs such as tamoxifen, and risk-reducing surgery. The Society of Surgical Oncology issued a position statement in 2007 regarding indications for prophylactic mastectomy among healthy women without breast cancer. In this statement, potential indications for bilateral prophylactic mastectomy include BRCA mutation or other susceptibility genes, strong family history without genetic mutation, and histologic risk factors (atypical ductal hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in situ).
Several studies have demonstrated that bilateral prophylactic mastectomy reduces the risk of breast cancer in women at moderate to high risk, including those with BRCA mutations. Hartmann and colleagues conducted a retrospective review of all women with a family history of breast cancer who underwent bilateral prophylactic mastectomy at the Mayo Clinic between 1963 and 1990. Using the Gail model and sisters of patients as controls, the authors determined that the relative risk reduction was about 90%. With improved mastectomy (skin-sparing, nipple-sparing) and reconstruction techniques, bilateral prophylactic mastectomy is becoming a more attractive option for many high-risk women today.
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Nevertheless, bilateral prophylactic mastectomy is irreversible and not risk-free. The overall complication rate after bilateral mastectomy and reconstruction is about 15% to 20%. Even without complications, these operations are long (often 5 to 6 hours) and require 2 to 3 days of inpatient hospital care, drainage catheters, and a 3- to 4-week overall recovery. Despite the potential complications, most women are generally satisfied with the decision to undergo bilateral prophylactic mastectomy. In a Cochrane Database of Systematic Reviews, the vast majority of women reported positive psychosocial and emotional outcomes after prophylactic surgery.
Since many women highly overestimate their risk of developing breast cancer, physicians need to provide women with accurate and easily understood information on their actual risk. Although bilateral prophylactic mastectomy is an effective means of reducing breast cancer, alternative strategies such as tamoxifen or surveillance should be thoroughly discussed before considering major risk-reduction surgery.
Todd M. Tuttle, MD, MPH, is Owen H. and Sarah Wangensteen Chair in Experimental Surgery and chief of the division of surgical oncology at the Masonic Cancer Center, University of Minnesota.