Editorial: Refining Risk Assessment in Women With Benign Breast Disease: An Ongoing Dilemma

JNCI: Journal of the National Cancer Institute, Oct 2017

Schnitt, Stuart J, Morrow, Monica, Tung, Nadine M

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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 ( 1 ). 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 ( 1–5 ). 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) ( 6,7 ) 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 inhibitors ( 9 ). 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 ( 10 ). 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 accordingly ( 10 ). 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 biopsy ( 10 ). 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 ( 10 ). 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. Nonproliferative disease RR (95% CI) Proliferative disease without atypia RR (95% CI) 1 (ref) 1 (ref) Table 3, available online) ( 10 ); 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) ( 10 ). 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 ( 9 ). This 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 ( 11 ), some an increase ( 9 ), and some no change ( 12 ). Other histologic findings such as the degree of lobular involution have been reported to modify the risk associated with atypical hyperplasia ( 13 ), 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. ( 10 ) 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. 1. Dupont WD , Page DL . Risk factors for breast cancer in women with proliferative breast disease . N Engl J Med . 1985 ; 312 ( 3 ): 146 - 151 . 2. Collins LC , Aroner SA , Connolly JL , Colditz GA , Schnitt SJ , Tamimi RM . Breast cancer risk by extent and type of atypical hyperplasia: An update from the Nurses' Health Studies . Cancer . 2016 ; 122 ( 4 ): 515 - 520 . 3. Kabat GC , Jones JG , Olson N , et al. A multi-center prospective cohort study of benign breast disease and risk of subsequent breast cancer . Cancer Causes Control . 2010 ; 21 ( 6 ): 821 - 828 . 4. Hartmann LC , Sellers TA , Frost MH , et al. Benign breast disease and the risk of breast cancer . N Engl J Med . 2005 ; 353 ( 3 ): 229 - 237 . 5. Dupont WD , Parl FF , Hartmann WH , et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia . Cancer . 1993 ; 71 ( 4 ): 1258 - 1265 . 6. Gail MH , Brinton LA , Byar DP , et alþ. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually . J Natl Cancer Inst . 1989 ; 81 ( 24 ): 1879 - 1886 . 7. Costantino JP , Gail MH , Pee D , et al. Validation studies for models projecting the risk of invasive and total breast cancer incidence . J Natl Cancer Inst . 1999 ; 91 ( 18 ): 1541 - 1548 . 8. Tyrer J , Duffy SW , Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors . Stat Med . 2004 ; 23 ( 7 ): 1111 - 1130 . 9. Hartmann LC , Degnim AC , Santen RJ , Dupont WD , Ghosh K. Atypical hyperplasia of the breast-risk assessment and management options . N Engl J Med . 2015 ; 372 ( 1 ): 78 - 89 . 10. Visscher D , Frank RD , Carter JM , et al. Breast cancer risk and progressive histology in serial benign biopsies . J Natl Cancer Inst . 2017 ; 109 ( 10 ): djx035 . 11. Dupont WD , Page DL . Relative risk of breast cancer varies with time since diagnosis of atypical hyperplasia . Hum Pathol . 1989 ; 20 ( 8 ): 723 - 725 . 12. Collins LC , Baer HJ , Tamimi RM , Connolly JL , Colditz GA , Schnitt SJ . Magnitude and laterality of breast cancer risk according to histologic type of atypical hyperplasia: Results from the Nurses' Health Study . Cancer . 2007 ; 109 ( 2 ): 180 - 187 . 13. Milanese TR , Hartmann LC , Sellers TA , et al. Age-related lobular involution and risk of breast cancer . J Natl Cancer Inst . 2006 ; 98 ( 22 ): 1600 - 1607 .


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Schnitt, Stuart J, Morrow, Monica, Tung, Nadine M. Editorial: Refining Risk Assessment in Women With Benign Breast Disease: An Ongoing Dilemma, JNCI: Journal of the National Cancer Institute, 2017, DOI: 10.1093/jnci/djx036