Study Expands on Breast Cancer Risk Prediction for Atypia, Contradicts Some Previous Findings
Margot Joan Fromer · Oncology Times · 2007
Women with three or more sites of cellular atypia in breast tissue are almost eight times more likely than average to develop breast cancer, according to a study from the Mayo Clinic. The study, led by Amy C. Degnim, MD, Assistant Professor of Surgery, and published in the July 1st issue of the Journal of Clinical Oncology, found that women with atypical hyperplasia (atypia) have a much higher absolute risk for breast cancer than previously estimated: 25% over 25 years—which is even higher in women with multiple areas of atypia and calcification. Several previous studies have had similar findings, but this one differed in important ways, especially in family history, in how long the increased risk for atypia lasts from the time it was diagnosed, and in the usefulness of the Gail model. Reliable estimates are important for risk-benefit analysis and decision making for women who are at increased risk for breast cancer, and atypia is well known to cause about a four-fold increase. Although published literature has shown that the risk abates considerably 10 years after a diagnosis of atypia, more recent evidence indicates that this may not be true. Moreover, no one knows whether breast cancer risk is higher in atypical ductal hyperplasia (ADH) or atypical lobular hypoplasia (ALH). The Gail model predicts risk by using age at onset of menses, age at birth of first child, the number of previous breast biopsies, and the number of close relatives with breast cancer. Dr. Degnim and her colleagues thought that this might prove inaccurate, and it did. The risk of breast cancer associated with atypia is independent of family history. Dr. Degnim and her colleagues looked at 331 women with atypia out of 9,376 in the Mayo Benign Breast Disease Cohort, paying attention to the effect of family history, the time since biopsy, the age at diagnosis, the influence of ADH vs ALH, the presence of calcification, and multifocality. The women were 18 to 85 years old and had a benign breast biopsy some time between 1967 and 1991. Of the 331 women, 56% were older than 55 at diagnosis, and 43% had a family history of breast cancer (23.5% with a strong history). The majority (almost 69%) had calcification, and 60% had only one focus of atypia.Figure: Amy C. Degnim, MD: “With the ability to stratify the risk of breast cancer in women with atypia, we can have more informed discussions with our patients regarding their personal risk. This will help us to have individualized discussions regarding how aggressively to pursue risk-reduction treatments.”Main Results The major results were the following: ▪ There were no significant differences in relative risk among subgroups with a family history. This counters the commonly held view that a positive family history increases breast cancer risk. ▪ Atypia diagnosed at a younger age conferred a higher risk than expected: The relative risk was 6.76 for patients younger than 45, 5.1 at age 45 to 55, and 2.87 for those over age 55. The increased risk in younger women was not due to family history, Dr. Degnim noted. “Perhaps atypical hyperplasia at a young age is the result of previous oncogenic events. Or breast tissue with atypia may be unusually susceptible to oncogenic estrogen metabolites associated with the premenopausal hormonal environment.” ▪ As the number of foci increases, so does the degree of risk. The relative risk is 2.33 with a single focus, 5.26 for two foci, and 7.97 for three or more. The increased risk seen with multiple foci was not due to the predominance of young women in those groups, Dr. Degnim reported. Women with three or more foci of atypia are at a risk level approaching that reported for carriers of BRCA1 and BRCA2 mutations. ▪ The risk increased dramatically in women with calcification and three or more foci, but women with calcification and fewer than three foci had a risk similar to those with three or fewer and no calcification. ▪ The histologic type of atypia did not affect risk. ▪ The relative risk for the entire group of women with atypia was elevated beyond 15 years. At 20 years, the cumulative risk was 21%, and at 25 years it was 29%. Caution about Relatively Small Study Still, the number of patients in the study is small. “There's absolutely no doubt that's there's a four- to fivefold increase in risk of breast cancer in women with atypical hyperplasia, but this was a study of only 331 patients, so it's impossible to say that three foci plus calcification is a particularly dire scenario,” noted Monica Morrow, MD, Chairman of the Department of Surgical Oncology and the G. Willing Pepper Chair in Cancer Research at Fox Chase Cancer Center, when asked for her opinion for this article. “We need to look at many more patients.” Dr. Degnim observed that the ability to stratify risk in atypia makes for more informed discussions with patients. “This will help patients decide how aggressively to pursue risk-reduction treatments.” In fact, she added, there is an ongoing effort at Mayo to create a model that will make predictions for individual women. “The Gail model works for risk in groups, but it cannot individualize it.” The Nurses Health Study (Cancer 2006;107:1240–1247) confirms Dr. Degnim's findings about family history. “To explain these findings, we postulate that atypical hyperplasia is a phenotype reflecting increased risk; this phenotype derives from both inherited risk and lifetime exposures. Thus, the histologic presence of atypia already reflects the increased breast cancer risk inherent in a positive family history,” concluded the authors, led by Laura Collins, MBBS, of Dana-Farber Cancer Institute and Harvard Medical School. Dr. Degnim added that there could be a question of whether multiple atypias are actually subtle in situ carcinoma. But she says that is not the case: If individual foci arise in separate and distinct terminal duct lobular units, none of which are more than 2 mm, then they are not DCIS. However, the more widespread the distribution of atypical foci within breast tissue, the larger the burden of risk and the more likely it is that the tissue has progressed along the continuum toward cancer, she said. “The evidence of this study shows that the extent of premalignant breast change is related to subsequent cancer risk.” Clinical & Counseling Ramifications The length of time for atypia is a key element in planning risk-reduction strategies, Dr. Degnim continued. It had been previously believed that the greatest risk of breast cancer after diagnosis came in the first 10 years. After that, it was reduced by half. But the Nurses Health Study found that risk does not decrease over time and in fact is slightly higher after 10 years. Given that data on long-term absolute risk are more useful than relative risk when counseling patients, Dr. Degnim recommends chemoprevention: tamoxifen or raloxifene. She noted that the National Adjuvant Breast and Bowel Project found an 86% reduction in risk with tamoxifen, and in a head-to-head comparison, the Study of Tamoxifen and Raloxifene (STAR) showed about equal risk reduction for both drugs. Dr. Morrow agreed, but added that for postmenopausal women, raloxifene has a better side effect profile. Raloxifene also decreases the risk of osteoporosis. “It does not seem to reduce the risk of DCIS as well as tamoxifen, although there's not enough data to say for sure,” she said. “Beyond chemoprevention, we recommend closer surveillance,” Dr. Degnim said. “This means a mammogram coupled with a clinical exam once a year. MRI has been used, but it is controversial as a screening technique because it's so expensive and because it has not been proven cost effective as a screening technique.” What about prophylactic mastectomy? “I don't recommend it,” Dr. Degnim replied. “First of all, it reduces risk only by 90 or 95 percent. It's not totally effective—and it's irreversible. Moreover, even though reconstructive surgery is very good, women have no way of knowing how they're going to feel about it until they have it—and then it's too late to change their minds.” Dr. Morrow said that although she would never specifically recommend prophylactic mastectomy, some women, of course, do seek preventive surgery, especially those who carry the BRCA1 or BRCA2 gene, a status that confers a 30% to 80% risk of breast cancer. “But for atypical hyperplasia, I don't think mastectomy is appropriate,” she said. The study was supported in part by a Department of Defense Center of Excellence Grant, the Susan G. Komen for the Cure Foundation, the Breast Cancer Research Foundation, and the Fred C. and Katherine B. Andersen Foundation.