Two premalignant abnormalities on breast biopsies that for decades have been viewed as having very different behaviors appear to have the same long-term cancer potential and progression risk, according to new data from researchers at the Mayo Clinic.
It is generally believed that atypical ductal hyperplasia (ADH) is a direct precursor of breast cancer and therefore portends breast cancer in the same breast, while atypical lobular hyperplasia (ALH) has an equal risk of cancer in both breasts and may not be a direct precursor of breast cancer. In the study, however, published in Cancer Prevention Research (2014;7;211-217) and led by Lynn C. Hartmann, MD, Professor of Oncology, cancer was twice as likely to occur in the breast having the biopsy, and this was true for both ADH and ALH.
Moreover, the findings run counter to current understanding that ALH primarily leads to lobular cancer. Instead, the researchers discovered that ALH was associated predominantly with later ductal cancers of the breast—also similar to cancers after ADH.
Both types resulted in invasive ductal cancers, and 69 percent were of intermediate or high grade. Further, about 25 percent had spread to the lymph nodes. Although the numbers were not statistically significant, the study also found that more ductal cancer in situ occurred following ADH than after ALH—25 percent versus 13 percent. In addition, women with ADH were more likely to have an ipsilateral breast cancer in the first five years after diagnosis than in later years.
The study included 698 women with biopsies showing atypical hyperplasia: 330 with ADH, 327 with ALH, and 32 with both types. Over an average follow-up of 12.5 years, 143 women developed breast cancer, but at the same rates regardless of the type of atypia. And in confirmation of the high-risk nature of atypia, 29 percent of these women developed breast cancer by 25 years of follow up.
“Our observations do not support present assumptions that ADH and ALH have substantively different behaviors,” Hartmann said. “Ours is the first report with sufficient numbers of both types of atypia and long-term follow-up that was able to examine the type of subsequent breast cancer, when these occurred, and in which breast.
“We showed that even though the two types of atypia look different histologically, they behave quite similarly in terms of later breast cancers in patients.”
Importantly, she added, many have believed that women who have both atypia and a positive family history of breast cancer have a risk that is substantially higher than that of someone with atypia without a family history.
“In our large study of women with atypia, we compared the later breast cancer risk of 257 women who had a family history and 372 without a family history, and saw no difference in their later risk. How can this be? In fact, one cause for the development of atypia is having a family history–so the risk associated with family history is already accounted for by the presence of the atypia itself.
Better Risk Assessment
More than one million women undergoing a breast biopsy in the United States each year have benign findings, and about 10 percent of these biopsies reveal atypical hyperplasia, a premalignant finding with a proliferation of abnormal cells, which have some but not all the features of a breast cancer.
“Most clinicians have viewed ADH as a direct precursor to breast cancer, arguing that it requires complete surgical excision, while others have maintained that ALH serves as an indicator of heightened and equal risk of breast cancer across both breasts,” Hartmann explained.
“Whether or not ALH on a core biopsy requires surgical excision remains a topic of research investigation. Moreover, some experts have argued that women with atypia develop ‘better risk’ breast cancers—meaning low-grade cancers with a good prognosis.”
Improve Clinical Management
Findings from this study could improve clinical management of patients with breast tissue abnormalities, she said.
“Given the high-risk nature of atypia, with a risk of breast cancer of close to 30 percent at 25 years after biopsy, we recommend that such women be seen at a breast center for recommendations about surveillance and preventive therapy options.
“What we are providing is absolute risk data for a sizable cohort of women with atypia. The medical community has known for years that the relative risk of breast cancer for women with atypia is four times greater than for other women, but that does not translate into an actual number for an individual with abnormal biopsy findings. Hopefully our paper will raise awareness of the risk and encourage the most sophisticated surveillance, likely to include MRI screening, and the use of chemoprevention drugs such as tamoxifen.”
Many practitioners already encourage women with atypia to consider chemoprevention drugs, she added.
“I think that women are increasingly aware that these are options, but nevertheless, many women remain more concerned about the possible side effects associated with these agents. They also need good data about the breast cancer risks.”
She and her colleagues are now preparing a review article that may help to guide development of new guidelines reflecting their findings, she said.
Stuart Schnitt: Study Comparisons Difficult
Asked for his opinion for this article, Stuart J. Schnitt, MD, Professor of Pathology at Harvard Medical School and Director of Anatomic Pathology at Beth Israel Deaconess Medical Center, said some of the observations in this study confirm data from previous reports but that there are also new data that add to what is understood about atypical hyperplasia.
In a 2007 study published in Cancer (2007;109:180-187), he and his colleagues (first author was Laura C. Collins, MD) analyzed the magnitude and laterality of breast cancer risk based on the histologic type of atypical hyperplasia among women in the Nurses' Health Study. Like the Mayo group, they found that about 60 percent of subsequent cancers occurred in the ipsilateral breast. However, that study also suggested that the risk associated with ADH and ALH depended upon the menopausal status of the patient at the time of the benign breast biopsy, something that was not addressed in the Mayo study.
In addition, in a 2003 study in The Lancet (2003;361:125-129), researchers at Vanderbilt University, led by David L. Page, MD, looked at ALH as a unilateral predictor of breast cancer risk in 250 women in the Nashville Breast Cancer Studies cohort.
Schnitt noted that comparisons among these studies is somewhat difficult since the Nurses' Health Study benign breast disease analysis was based on a nested case-control study whereas the Mayo and Vanderbilt studies are cohort studies. “Nonetheless, despite the methodologic differences in these three studies, there are many similarities in the findings regarding atypical hyperplasias,” he said.
“We now recognize that both ADH and ALH are associated with a substantially increased risk of breast cancer, that both lesions appear to represent direct cancer precursors as well as markers of increased risk. I think the similarities rather than the differences between ADH and ALH is one of the main take-home messages from the Mayo study. The time has come to find ways to better stratify risk and identify which women with atypical hyperplasia are at highest risk.”
And, although treatment and monitoring guidelines from the American Society of Clinical Oncology or the American Cancer Society would be helpful, the extant data are not sufficiently robust to permit consensus guideline recommendations, he said.
“Guidelines need to be evidence-based, and the available evidence from individual studies is based on very small numbers in some subgroups. Perhaps attempting to combine data from the Nurses' Health Study, the Vanderbilt Study, and the Mayo study would be a worthwhile undertaking and provide more statistical power than any of the studies alone.”