A Benign Breast Biopsy That Is Not So Benign

Nick Mulcahy

December 31, 2014

UPDATED // A breast biopsy that results in a diagnosis of atypical hyperplasia is considered a benign finding, but that description obscures the riskiness of the condition, according to a special report published in the January 1, 2015, issue of the New England Journal of Medicine.

"Women with atypical hyperplasia on a 'benign' breast biopsy have a higher risk of a later breast cancer than previously thought," said lead author Lynn Hartmann, MD in an email to Medscape Medical News.

Dr Hartmann and coauthors, all of whom are from the Mayo Clinic in Rochester, Minnesota, report there is a cumulative incidence of breast cancer of 30% at 25 years of follow-up in their 698-patient cohort of women with atypical hyperplasia.

There were 143 women who developed breast cancer in the cohort, with breast cancer defined as either invasive disease (81%) or ductal carcinoma in situ (19%).

In their new special report, the authors highlight this breast cancer incidence finding, which they first published earlier this year ( Cancer Prev Res. 2014;7:211-217).

"This high cumulative incidence is not widely recognized, and thus, women with atypical hyperplasia are not included in many high-risk [breast cancer] guidelines," they write.

 
This high cumulative incidence is not widely recognized.
 

Women with atypical hyperplasia are at high risk of developing breast cancer, emphasize Dr Hartmann and colleagues.

To address this problem of underrecognized risk, the authors call for more intensive surveillance of these women and more widespread use of breast cancer chemopreventative agents such as selective estrogen-receptor modulators and aromatase inhibitors, which have been shown to benefit women with atypical hyperplasia.

For clinicians to enact such changes, they first have to fully appreciate the risk for breast cancer that is associated with atypical hyperplasia, suggest the authors.

There are more than a million breast biopsies annually in the United States that are found to be benign. Atypical hyperplasia is a lesion that is found in approximately 10% of breast biopsies with benign findings, the authors say.

There are two types of atypical hyperplasia — atypical ductal hyperplasia and atypical lobular hyperplasia — but both occur with equal frequency and confer similar risks for later breast cancer, so the authors refer to them collectively as atypical hyperplasia.

For decades, it has been recognized that atypical hyperplasia conferred a relative risk for future breast cancer of about 4, say the authors, citing multiple long-term studies.

However, "only recently" has the absolute risk for breast cancer been characterized, they point out. This refers to their own data from Mayo Clinic (and its 30% cumulative risk) and an unpublished Nashville Breast Cohort, in which 27.5% of patients with atypical hyperplasia have gone on to develop either invasive breast cancer or ductal carcinoma in situ.

Clinicians should use these new absolute risk data with patients instead of risk-prediction tools, such as the Breast Cancer Risk Assessment Tool and the International Breast Cancer Intervention Study model, say the authors. Such tools have not been validated in women with atypical hyperplasia.

The cumulative breast cancer incidence increases over time after a biopsy finding of atypical hyperplasia, according to the Mayo Clinic cohort data. At 5 years, the incidence was 6.6%. It then climbed to 12.6% at 10 years, 19.4% at 15 years, 23.1% at 20 years, and 30.3% at 25 years.

In a normal, healthy population, only about 8% of women would be expected to develop breast cancer in a similar 25-year period, Dr Hartmann said.

Increased Screening

Atypical hyperplasia "occupies a transitional zone between benign and malignant disease," say the authors.

 
Atypical hyperplasia occupies a transitional zone between benign and malignant disease.
 

That means "there is a proliferation of dysplastic, monotonous epithelial-cell populations that include clonal subpopulations." At the same time, however, atypical hyperplasia does not have all "the requisite features of a cancer and is thus considered to be premalignant."

Two histologic features stratify risk. First is the number of foci (the greater the numbers, the greater the risk). For example, in the Mayo Cohort, at 15 years, for women with only a single focus of atypical hyperplasia, there was a cumulative incidence of breast cancer of 14.2% compared with 23.3% for women with two foci and 34.4% for women with three foci or more.

Second, the extent of normal regression (involution) of background lobular units influences risk, and the greater the degree of involution, the lower the risk.

Clinicians should consider having patients with atypical hyperplasia undergo an annual breast magnetic resonance imaging screening, in addition to an annual mammogram, the authors suggest. This is already the recommendation for women with hereditary risk (who have a similar magnitude of risk as the Mayo clinic atypical hyperplasia cohort).

Guidelines need to be updated to include annual magnetic resonance imaging screening for this atypical hyperplasia population, they add.

Consider Chemoprevention

The other broad recommendation from the authors is that patients with atypical hyperplasia be offered chemopreventive agents.

There have been multiple randomized clinical trials of the use of selective estrogen-receptor modulators and aromatase inhibitors for the prevention of breast cancer.

Subgroup analyses of data on women with atypical hyperplasia were performed in four such placebo-controlled trials.

These analyses showed a total of 2009 women with atypical hyperplasia who were randomly assigned to receive either an active agent or placebo in those trials. Relative risk reductions in the atypical hyperplasia subgroups ranged from 41% to 79%. The benefit was even greater than that found in the total population treated with the active agent in those trials, the authors point out.

Of course, chemopreventive agents have undesirable adverse effects. The major risks that occur in association with all selective estrogen-receptor modulators are venous thromboembolisms. In addition, tamoxifen is associated with an increased risk for endometrial cancer. Vasomotor symptoms are induced in many women who receive treatment with either class of chemopreventive agents.

The special report authors argue that education be provided to women with atypical hyperplasia regarding the related risk for breast cancer, as well chemoprevention options and the anticipated reduction in risk and the risks for various adverse effects.

American Society of Clinical Oncology guidelines state that for women with a 5-year projected absolute risk for breast cancer of 1.7% or higher, "the use of a chemopreventive agent should be discussed," say the report authors.

"Women with atypical hyperplasia clearly meet this risk criterion," they write.

The report was supported by grants from the National Cancer Institute and the National Center for Advancing Translational Sciences. One author reports receiving grant support and personal fees outside the submitted work from Pfizer.

N Engl J Med. 2015;372:78-89. Abstract

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