Editorial: Refining Risk Assessment in Women With Benign Breast Disease: An Ongoing Dilemma
JNCI J Natl Cancer Inst (
Refining Risk Assessment in Women With Benign Breast Disease: An Ongoing Dilemma
Stuart J. Schnitt 0 1
Monica Morrow 0 1
Nadine M. Tung 0 1
0 The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions , please
1 Affiliations of authors: Department of Pathology (SJS) and Division of Hematology-Oncology (NMT), Beth Israel Deaconess Medical Center and Harvard Medical School , Boston , MA; Department of Surgery, Memorial Sloan Kettering Cancer Center , New York, NY, MM , USA
More than three decades ago, Dupont and Page published their
seminal study relating breast cancer risk to the histologic
findings in benign breast biopsies (
). The key observations of that
study were that women whose biopsy showed proliferative
lesions without atypia had about a twofold increase in the risk of
subsequent breast cancer and those with atypical hyperplasia
had about a fivefold increase in breast cancer risk when
compared with women with nonproliferative lesions. As
summarized in Table 1, subsequent studies from other groups have
yielded strikingly similar findings, despite differences in the
study design, patient populations, and pathologists involved in
the histologic classification of the benign breast biopsies (
As a result of these studies, which in aggregate have included
more than 17 000 women, atypical hyperplasia is considered a
high-risk lesion and is included in risk assessment models such
as the Gail/Breast Cancer Risk Assessment Tool (BCRAT) (
and the International Breast Cancer Intervention Study (IBIS)
model (8); proliferative lesions without atypia are also included
in the IBIS model. Further, the finding of proliferative lesions in
a benign breast biopsy, especially atypical hyperplasia, can
result in more intensive screening and pharmacologic risk
reduction with selective estrogen receptor modulators or aromatase
In this issue of the Journal, Visscher et al. report on the risk
of breast cancer among a small subset of women in the Mayo
Clinic Benign Breast Disease (BBD) cohort who had multiple
metachronous benign breast biopsies (
). Among 1414 women
who had more than one biopsy (10.5% of their study
population), there was a change in BBD category between the first and
subsequent biopsy in 43.9% of cases. Further, the authors
observed that a change from a lower-risk to a higher-risk BBD
category between the first and subsequent biopsy was associated
with an increase in breast cancer risk whereas a change from a
higher-risk to a lower-risk BBD category was associated with a
reduction in risk. What are the implications of these findings
for clinical management, and what insights do they provide
regarding the biology of breast tumor progression?
In our view, the clinical management issues are
straightforward for women whose second biopsy shows a higher-risk
category of BBD than the initial biopsy, particularly for those
women whose subsequent biopsy shows atypical hyperplasia.
According to the data of Visscher et al., these women are at
least the same level of increased risk as any other women with
atypical hyperplasia (if not higher) and they should be managed
The most interesting group is the subset of women who had
atypical hyperplasia in the first biopsy but had nonproliferative
lesions or proliferative lesions without atypia in the subsequent
biopsy. The data of Visscher et al. suggest that these women
have a 43% reduction in breast cancer risk when compared with
women who still have atypical hyperplasia in their second
). However, this scenario appears to be extremely
uncommon; 42 such women were identified in this study,
representing only 3% of women with multiple biopsies and 0.3%
of the entire Mayo Clinic BBD Cohort (
). Further, before
concluding that these patients are no longer at high risk of breast
cancer, it should be noted that this reduction in risk was not
statistically significant. In addition, these women continue to
have over a threefold increase in their risk of breast cancer
(hazard ratio ¼ 3.36, 95% confidence interval ¼ 1.34 to 8.45) when
compared with women who had nonproliferative lesions in
both their first and subsequent biopsies. Finally, given the
persistently elevated breast cancer risk in this group, it is possible
that atypical hyperplasia is in fact present in the breast tissue,
but in areas other than that subjected to the subsequent biopsy.
We view this as plausible because more than half of the
subsequent biopsies in this population were performed for clinically
detectable lumps or mammographic masses (Supplementary
*CI ¼ confidence interval; RR ¼ relative risk.
RR (95% CI)
RR (95% CI)
Table 3, available online) (
); the finding of atypical hyperplasia
in such specimens is much less common than in biopsies
performed because of mammographic microcalcifications.
Therefore, we believe that it would be premature to recommend
altering the follow-up or management strategy for women who
have atypical hyperplasia on a first biopsy but nonproliferative
lesions or proliferative lesions without atypia on any
subsequent biopsies. Among the 156 women whose first biopsy
showed proliferative disease without atypia and whose
subsequent biopsy showed nonproliferative lesions, there was a
statistically significant 51% reduction in breast cancer risk
compared with those whose subsequent biopsy continued to
show proliferative disease without atypia. However, once again,
there is a suggestion that these women have an increased risk
of breast cancer when compared with those who had
nonproliferative lesions in both biopsies, though this difference was not
statistically significant (Table 3) (
Long-term follow-up studies have indicated that only a
minority of women with atypical hyperplasia develop invasive
breast cancer, even without risk-reducing interventions (
suggests that some of these lesions do not progress or may even
regress. Conversely, some women with lower-risk lesions in a
benign breast biopsy may develop atypical hyperplasia over
time, putting them in a higher-risk group than would have been
anticipated based on the results of their initial benign breast
biopsy. However, it is unclear in how many cases changes in BBD
category from one biopsy to another represent “progression” or
“regression” of lesions in the breast tissue as a whole and in
how many this is the result of sampling error. In this regard, it
would be of interest to study women who have had more than
two biopsies to determine how the BBD category varies among
these multiple biopsies over time. A related area worthy of
further study is the relationship between level of risk and time
since the biopsy demonstrating proliferative changes or atypia.
This is an unresolved issue, with some studies suggesting a
diminution of risk over time (
), some an increase (
some no change (
). Other histologic findings such as the
degree of lobular involution have been reported to modify the risk
associated with atypical hyperplasia (
), but the interaction
between involution and multiple biopsies in modifying risk was
not considered in this study.
Breast cancer risk assessment is a challenge. Current models
are better at predicting risk for a population than an individual
and highlight the need to identify additional factors to
incorporate into these models. Before the results of the study by
Visscher et al. (
) can be used to refine risk assessment, they
will need to be confirmed and shown to predict risk
independent of other factors that might explain changes in benign
breast pathology, for example, hormone use, menopausal
status, change in weight, or mammographic breast density. If a
change in the category of BBD over time alters the risk of breast
cancer, identifying modifiable factors associated with such
changes (e.g., medications, lifestyle choices) could be important
for breast cancer prevention. Until then, considering the
“highest-risk” lesion identified in any breast biopsy will remain
the standard of care to assess the risk of developing breast
cancer and guide clinical management.
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