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Figure 1.  Rates of Atypical Ductal Hyperplasia (ADH) per 10 000 Screening Mammograms
Rates of Atypical Ductal Hyperplasia (ADH) per 10 000 Screening Mammograms

The rates of ADH ranged from a low of 2 in 1995 to a high of 6 per 10 000 mammograms in 2011.

Figure 2.  Mode of Detection of Atypical Ductal Hyperplasia (ADH) by Study Year
Mode of Detection of Atypical Ductal Hyperplasia (ADH) by Study Year

The proportion of ADH diagnosed by core needle biopsy increased between 1996 and 2012 from 21% to 77%.

Table 1.  Hazard Ratios Obtained Using Cox Proportional Hazards Regression Modelsa
Hazard Ratios Obtained Using Cox Proportional Hazards Regression Modelsa
Table 2.  Estimated 10-Year Probability of Invasive Breast Cancer After ADH Diagnosis
Estimated 10-Year Probability of Invasive Breast Cancer After ADH Diagnosis
1.
Page  DL, Dupont  WD, Rogers  LW, Rados  MS.  Atypical hyperplastic lesions of the female breast: a long-term follow-up study.  Cancer. 1985;55(11):2698-2708.PubMedGoogle ScholarCrossref
2.
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.PubMedGoogle ScholarCrossref
3.
Fisher  B, Costantino  JP, Wickerham  DL,  et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study.  J Natl Cancer Inst. 1998;90(18):1371-1388.PubMedGoogle ScholarCrossref
4.
Coopey  SB, Mazzola  E, Buckley  JM,  et al.  The role of chemoprevention in modifying the risk of breast cancer in women with atypical breast lesions.  Breast Cancer Res Treat. 2012;136(3):627-633.PubMedGoogle ScholarCrossref
5.
Goss  PE, Ingle JN, Alés-Martínez JE, et al; NCIC CTG MAP.3 Study Investigators.  Exemestane for breast-cancer prevention in postmenopausal women.  N Engl J Med. 2011;364:2381-2391.PubMedGoogle ScholarCrossref
6.
Zheng  Y, Heagerty  PJ.  Partly conditional survival models for longitudinal data.  Biometrics. 2005;61(2):379-391.PubMedGoogle ScholarCrossref
7.
Lee  E, Wei  L, Amato  D.  Cox-Type Regression Analysis for Large Numbers of Small Groups of Correlated Failure Time Observations. Dordrecht, the Netherlands: Kluwer Academic Publishers; 1992.
8.
Dupont  WD, Page  DL.  Risk factors for breast cancer in women with proliferative breast disease.  N Engl J Med. 1985;312(3):146-151.PubMedGoogle ScholarCrossref
9.
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.PubMedGoogle ScholarCrossref
10.
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.PubMedGoogle ScholarCrossref
11.
Elmore  JG, Gigerenzer  G.  Benign breast disease—the risks of communicating risk.  N Engl J Med. 2005;353(3):297-299.PubMedGoogle ScholarCrossref
12.
Carter  CL, Corle  DK, Micozzi  MS, Schatzkin  A, Taylor  PR.  A prospective study of the development of breast cancer in 16,692 women with benign breast disease.  Am J Epidemiol. 1988;128(3):467-477.PubMedGoogle Scholar
13.
Tice  JA, Miglioretti  DL, Li  CS, Vachon  CM, Gard  CC, Kerlikowske  K.  Breast density and benign breast disease: risk assessment to identify women at high risk of breast cancer.  J Clin Oncol. 2015;33(28):3137-3143.PubMedGoogle ScholarCrossref
14.
Worsham  MJ, Raju  U, Lu  M,  et al.  Risk factors for breast cancer from benign breast disease in a diverse population.  Breast Cancer Res Treat. 2009;118(1):1-7.PubMedGoogle ScholarCrossref
15.
Zhou  WB, Xue  DQ, Liu  XA, Ding  Q, Wang  S.  The influence of family history and histological stratification on breast cancer risk in women with benign breast disease: a meta-analysis.  J Cancer Res Clin Oncol. 2011;137(7):1053-1060.PubMedGoogle ScholarCrossref
16.
Collins  LC, Baer  HJ, Tamimi  RM, Connolly  JL, Colditz  GA, Schnitt  SJ.  The influence of family history on breast cancer risk in women with biopsy-confirmed benign breast disease: results from the Nurses’ Health Study.  Cancer. 2006;107(6):1240-1247.PubMedGoogle ScholarCrossref
17.
Waters  EA, McNeel  TS, Stevens  WM, Freedman  AN.  Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010.  Breast Cancer Res Treat. 2012;134(2):875-880.PubMedGoogle ScholarCrossref
18.
Hartmann  LC, Radisky  DC, Frost  MH,  et al.  Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study.  Cancer Prev Res (Phila). 2014;7(2):211-217.PubMedGoogle ScholarCrossref
19.
Whiffen  A, El-Tamer  M, Taback  B, Feldman  S, Joseph  KA.  Predictors of breast cancer development in women with atypical ductal hyperplasia and atypical lobular hyperplasia.  Ann Surg Oncol. 2011;18(2):463-467.PubMedGoogle ScholarCrossref
20.
Kabat  GC, Jones  JG, Olson  N,  et al.  Risk factors for breast cancer in women biopsied for benign breast disease: a nested case-control study.  Cancer Epidemiol. 2010;34(1):34-39.PubMedGoogle ScholarCrossref
21.
Tice  JA, O’Meara  ES, Weaver  DL, Vachon  C, Ballard-Barbash  R, Kerlikowske  K.  Benign breast disease, mammographic breast density, and the risk of breast cancer.  J Natl Cancer Inst. 2013;105(14):1043-1049.PubMedGoogle ScholarCrossref
22.
Pankratz  VS, Hartmann  LC, Degnim  AC,  et al.  Assessment of the accuracy of the Gail model in women with atypical hyperplasia.  J Clin Oncol. 2008;26(33):5374-5379.PubMedGoogle ScholarCrossref
23.
Breast Cancer Surveillance Consortium Risk Calculator. Risk Calculator V2. http://tools.bcsc-scc.org/BC5yearRisk/calculator.htm. Updated July 17, 2015. Accessed August 6, 2016.
24.
Lin  W. BCSC Risk Calculator. https://itunes.apple.com/us/app/bcsc-risk-calculator/id919034661?ls=1&mt=8. Published 2016. Accessed August 6, 2016.
Original Investigation
January 2017

Subsequent Breast Cancer Risk Following Diagnosis of Atypical Ductal Hyperplasia on Needle Biopsy

Author Affiliations
  • 1Department of Surgery, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
  • 2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  • 3Department of Medicine, University of California, San Francisco
  • 4Department of Epidemiology and Biostatistics, University of California, San Francisco
  • 5Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 6Department of Pathology, Mount Sinai Medical Center, New York, New York
  • 7Radiology Associates of Albuquerque, Albuquerque, New Mexico
  • 8Department of Radiology, University of New Mexico, Albuquerque
  • 9Group Health Research Institute, Group Health Cooperative, Seattle, Washington
  • 10Division of Biostatistics, Department of Public Health Sciences, University of California Davis School of Medicine, Sacramento
JAMA Oncol. 2017;3(1):36-41. doi:10.1001/jamaoncol.2016.3022
Key Points

Question  Is the risk of breast cancer associated with atypical ductal hyperplasia (ADH) diagnosed on needle biopsy lower than the reported risks based on historical cohorts?

Findings  In a cohort study comparing the risk of invasive breast cancer in 955 331 women undergoing mammography with and without a diagnosis of ADH, 10-year cumulative risk was lower in women with ADH diagnosed with a needle biopsy compared with excisional biopsy. Both risks were lower than those reported from cohorts evaluated in earlier studies.

Meaning  Current 10-year risks of invasive breast cancer after a diagnosis of ADH may be lower than those previously reported.

Abstract

Importance  Atypical ductal hyperplasia (ADH) is a known risk factor for breast cancer. Published risk estimates are based on cohorts that included women whose ADH was diagnosed before widespread use of screening mammograms and did not differentiate between the methods used to diagnose ADH, which may be related to the size of the ADH focus. These risks may overestimate the risk in women with presently diagnosed ADH.

Objective  To examine the risk of invasive cancer associated with ADH diagnosed using core needle biopsy vs excisional biopsy.

Design  A cohort study was conducted comparing the 10-year cumulative risk of invasive breast cancer in 955 331 women undergoing mammography with and without a diagnosis of ADH. Data were obtained from 5 breast imaging registries that participate in the National Cancer Institute–funded Breast Cancer Surveillance Consortium.

Exposures  Diagnosis of ADH on core needle biopsy or excisional biopsy in women undergoing mammography.

Main Outcomes and Measures  Ten-year cumulative risk of invasive breast cancer.

Results  The sample included 955 331 women with 1727 diagnoses of ADH, 1058 (61.3%) of which were diagnosed by core biopsy and 635 (36.8%) by excisional biopsy. The mean (interquartile range) age of the women at diagnosis was 52.6 (46.9-60.4) years. From 1996 to 2012, the proportion of ADH diagnosed by core needle biopsy increased from 21% to 77%. Ten years following a diagnosis of ADH, the cumulative risk of invasive breast cancer was 2.6 (95% CI, 2.0-3.4) times higher than the risk in women with no ADH. Atypical ductal hyperplasia diagnosed via excisional biopsy was associated with an adjusted hazard ratio (HR) of 3.0 (95% CI, 2-4.5) and, via core needle biopsy, with an adjusted HR of 2.2 (95% CI, 1.5-3.4). Ten years after an ADH diagnosis, an estimated 5.7% (95% CI, 4.3%-10.1%) of the women had a diagnosis of invasive cancer. Women with ADH diagnosed on excisional biopsy had a slightly higher risk (6.7%; 95% CI, 3.0%-12.8%) compared with those with ADH diagnosed via core needle biopsy (5%; 95% CI, 2.2%-8.9%).

Conclusions and Relevance  Current 10-year risks of invasive breast cancer after a diagnosis of ADH may be lower than those previously reported. The risk associated with ADH is slightly lower for women whose ADH was diagnosed by needle core biopsy compared with excisional biopsy.

Introduction

Atypical ductal hyperplasia (ADH) is a risk factor for breast cancer.1 In a recent report,2 the projected cumulative incidence of breast cancer (invasive and ductal carcinoma in situ) after ADH was 29% over 25 years. Most of the studies reporting on the increased risk of breast cancer in women with ADH were done before the widespread use of screening mammograms and core needle biopsies to evaluate nonpalpable suspicious lesions. Today ADH is more often detected by needle biopsy of an imaging finding than by excisional biopsy. With the increased use of needle biopsies for imaging abnormalities and improvement in imaging technologies, very small foci of ADH are diagnosed. The significance of small ADH foci is not clear; however, common practice is to consider these women as having an increased risk of breast cancer and offer them increased surveillance and risk-reducing strategies.3-5

The purpose of the present study was to assess cumulative invasive breast cancer risk in women with ADH by comparing detection using core needle biopsy with that using excisional biopsy. Because an association between the number of foci of ADH and subsequent risk of breast cancer was reported,2 we speculated that, as imaging technology advances, smaller lesions are observed and biopsied and the risk associated with small foci of ADH detected on core needle biopsy may be lower than risks previously reported from general populations of women with ADH.

We used data prospectively collected by the Breast Cancer Surveillance Consortium (BCSC) to compare the risk of invasive breast cancer in women with ADH diagnosed on core needle biopsy vs excisional biopsy and to compare these risks with the risk in women undergoing mammography without an ADH diagnosis.

Methods
Data Sources

Five breast imaging registries that participate in the National Cancer Institute–funded BCSC (http://breastscreening.cancer.gov) were included: Carolina Mammography Registry, Group Health Cooperative in Washington State, New Hampshire Mammography Network, New Mexico Mammography Project, and Vermont Breast Cancer Surveillance System. These registries collect information on mammographic examinations done in their defined catchment areas. Each mammography registry annually links women in its database to a state tumor registry or regional Surveillance, Epidemiology, and End Results program that collects population-based cancer data and pathology databases that collect information on both benign and malignant diagnoses. The BCSC Statistical Coordinating Center pooled and analyzed the data in the present study. Each BCSC registry and the Statistical Coordinating Center has received institutional review board approval for either active or passive consenting processes or a waiver of consent to enroll participants, link data, and perform analytic studies. All procedures comply with the Health Insurance Portability and Accountability Act, and all registries and the Statistical Coordinating Center have received federal certificates of confidentiality and other protection for the identities of women, physicians, and facilities studied by this research. The present study was approved by the BCSC steering committee.

Data Collection

Two data sets were analyzed from the BCSC. The first of these was created to estimate the rates of ADH per 10 000 screening mammograms by calendar year and included screening mammograms performed between 1994 and 2011 in women 35 years or older with at least 1 prior screening mammogram performed within 5 years and no personal history of breast cancer, lobular carcinoma in situ, or breast augmentation. Screening mammograms were defined using the standard BCSC definition (http://breastscreening.cancer.gov/data/bcsc_data_definitions.pdf). Examinations were excluded if the date through which biopsy or pathology records were considered to be at least 94% complete was less than 1 year following a screening mammogram. In the data set, the most proximal screening mammogram within 1 year before a biopsy diagnosing ADH was associated with the ADH diagnosis. The type of findings noted on mammography leading to biopsy is not available.

The second data set (1994-2012) was created to estimate the risk of invasive breast cancer in the 10 years following an ADH diagnosis compared with the risk in the general population of women undergoing screening mammography with no diagnosis of ADH. Women were excluded if, before entering the BCSC, they had a biopsy or a diagnosis of breast cancer, ductal carcinoma in situ (DCIS), or lobular carcinoma in situ. Each woman contributed 1 or 2 observations. The follow-up for the first record started 6 months after the first screening or diagnostic mammogram that occurred when she entered the BCSC to exclude breast cancers associated with the index mammogram. The follow-up period for the second record started 6 months after a biopsy detecting ADH was performed.

For each observation, follow-up continued for up to 10 years after the index date and ended at a diagnosis of invasive breast cancer (the event of interest) or a censoring event, including diagnosis of DCIS or lobular carcinoma in situ, end of complete cancer capture, death, or exit from the cohort. Characteristics of the woman and mammogram modality (digital vs film) were collected at the preceding mammogram most proximal to the time of study entry. The type of biopsy detecting ADH (core needle vs excisional) and all subsequent excisional biopsies in a 6-month follow-up were recorded. Data on the number of findings biopsied are not available.

Statistical Analysis

Crude rates of ADH diagnoses per 10 000 screening mammograms by screening mammogram calendar year were calculated using the first analysis data set. Using the second data set, the fraction of ADH diagnosed by core needle vs excisional biopsies across study years was calculated.

Partially conditional Cox proportional hazards regression models were used to estimate relative rates of invasive breast cancer after a screening mammogram without a subsequent ADH diagnosis vs an ADH diagnosis in the 10-year follow-up period.6 Because the same woman may contribute 2 observations, SEs were based on a robust sandwich estimator to account for woman-level clustering.7 Separate models were fit to examine the association between rates of invasive breast cancer and ADH diagnosis according to the mode of ADH detection (core needle vs excisional biopsy). Core needle biopsy refers to all types of percutaneous biopsies in which breast tissue is procured for pathologic examination (including core and vacuum biopsies). Fine-needle aspiration and biopsies of unknown type (n = 34) were excluded from this analysis.

All models were adjusted for age at mammogram or ADH diagnosis (linear and quadratic terms), race/ethnicity, family history of breast cancer, menopausal status and use of hormone therapy, mammogram modality (digital vs film), and Breast Imaging Reporting and Data System (BI-RADS) breast density at baseline. Using time-dependent, partially conditional Cox proportional hazards regression models, the association between time since diagnosis (modeling time categorized as 0-2, 2-5, and >5 years after diagnosis) and risk associated with ADH were examined.

Ten-year probability of an invasive breast cancer by ADH status, mode of ADH detection, and mammogram modality leading to ADH detection were calculated using the estimated hazard ratios (HRs) and the empirical estimate of baseline hazard, assuming the covariate distribution observed at baseline. We calculated SEs for these estimates via a parametric bootstrap using resampling Cox proportional hazards regression coefficient estimates from a multivariate normal distribution, with mean and covariance set at the estimated values. All analyses were conducted using R, version 3.2.2 (R Foundation; http://www.R-project.org/).

Results

The characteristics of the study population are summarized in the eTable in the Supplement. There were 956 508 observations in the sample corresponding to 955 331 women and 1727 diagnoses of ADH. There were 1058 (61.3%) ADH diagnoses made by core needle biopsy, 635 (36.8%) diagnosed by excision, and 34 (2%) of unknown type. The mean (interquartile range) age of the women at diagnosis was 52.6 (46.9-60.4) years. Atypical ductal hyperplasia was associated with white race, first-degree family history of breast cancer, and high breast density noted on mammography.

Figure 1 shows the rates of ADH diagnoses per 10 000 mammograms by study year. The rates ranged from a low of 2 in 1995 to a high of 6 per 10 000 mammograms in 2011. Figure 2 presents the proportion of ADH diagnosed via core needle and excisional biopsy. Detection by core needle biopsy increased over time, and diagnosis by excisional biopsy decreased. In the beginning of the study (1995), all ADH was diagnosed by excisional biopsy; this percentage decreased to 23% by 2012. The proportion of ADH diagnosed by core needle biopsy increased between 1996 and 2012 from 21% to 77%.

There were 1655 invasive breast cancers diagnosed in the 10 years of follow-up after a screening mammogram (n = 954 781) and 72 cancers among women with a diagnosis of ADH. Invasive cancer was diagnosed in 34 of 1024 women (3.3%) with diagnosis determined on core biopsy and 36 of 599 (6%) in those with diagnosis by excisional biopsy. After adjusting for age, race/ethnicity, family history, menopausal and hormonal therapy status, mammogram modality, and breast density, within 10 years following a diagnosis of ADH, the rates of invasive breast cancer were 2.6 (95% CI, 2.0-3.4) times higher than those in women with no ADH diagnosis at baseline (Table 1). Atypical ductal hyperplasia diagnosed using excisional biopsy was associated with an adjusted HR of 3.0 (95% CI, 2.0-4.5) and, with core needle biopsy, an adjusted HR of 2.2 (95% CI 1.5-3.4); however, a test for differences in adjusted HRs by biopsy type was nonsignificant (P = .28). Sensitivity analysis adjusting for calendar year did not change the HRs (J.L., unpublished data, June 7, 2016).

The adjusted HR of invasive breast cancer after a diagnosis of ADH varied with time since diagnosis, with slightly higher rates seen in the first 2 years compared with those noted in subsequent years. Ten years after an ADH diagnosis, 5.7% (95% CI, 4.3%-10.1%) of women were estimated to develop invasive cancer (Table 2). Women with ADH diagnosed on excisional biopsy had a slightly higher estimated risk (6.7%; 95% CI, 3%-12.8%) compared with those with ADH diagnosed via core needle biopsy (5%; 95% CI, 2.2%-8.9%). In contrast, 2.2% (95% CI, 1.7%-3.9%) of those without ADH were estimated to develop invasive cancer.

Discussion

The risk of breast cancer associated with ADH was reported by studies8-10 that followed large cohorts of women undergoing breast biopsies. Most of these studies were done before the widespread use of screening mammography and image-guided needle biopsies and did not report the indication for biopsy. Although the information was not detailed, one can assume, based on the study years, that a palpable finding led to many of these biopsies, possibly lessening the ability to generalize these results to women undergoing image-guided biopsies today.

The most cited study is that of Dupont and Page,8 which reported the outcome of women undergoing excisional biopsies between 1950 and 1968. In that study, women with ADH were at a 4-times-higher risk of subsequent invasive breast cancer compared with the general population.

When communicating the risk of disease, clinicians and patients were better able to interpret cumulative risks than relative risks.11 The Mayo cohort2 of women with benign results of breast biopsies included women whose diagnosis was determined mainly by excision (86%) between 1967 and 2001. In that cohort, the projected cumulative risk of cancer for women with atypia (ADH or atypical lobular hyperplasia) was 29% over 25 years. Lower risks obtained from the Breast Cancer Detection Demonstration Project were published12; although it was an early study (women were enrolled between 1973 and 1978), all participants underwent screening mammography. Of 1305 women with atypia, between 5% and 10% developed invasive breast cancer within 8 years. Tice et al13 recently reported a 10-year risk of invasive breast cancer of 7% in women with atypia (either ductal or lobular) using data from the BCSC.

The present report represents what we believe to be the largest study on outcomes of women with ADH diagnosed by contemporary imaging and biopsy technology. Using data from the BCSC, we found that rates of ADH in present-day practice range between 4 and 6 per 10 000 mammograms. During the study years, the proportion of ADH diagnosed via excisional biopsy decreased substantially but remained above 20% in 2012. The 10-year cumulative risk of invasive breast cancer after a diagnosis of ADH was 5.7%, with a higher rate seen in women whose diagnosis was determined with excisional biopsies vs core needle biopsies (6.7% vs 5%). These results are consistent with our hypothesis that, over time with the advancements in imaging and biopsy technology, smaller foci of ADH are being diagnosed, which may carry a lower risk for invasive breast cancer.

There may be other explanations for the lower rates of breast cancer found in our study. We did not include DCIS as an outcome, which was counted in other reports.2,14,15 In those studies, the proportion of DCIS from subsequent cancers ranged between 19% and 50%. We limited our study to women with ADH, whereas other studies2,13 examined the risk of breast cancer in women with either ADH or atypical lobular hyperplasia. The risk of breast cancer appears to be higher after a diagnosis of atypical lobular hyperplasia compared with ADH,9,16 which can explain the lower 10-year risk of invasive cancer we found even when compared with contemporary reports.13 Use of chemoprevention, such as tamoxifen citrate, after a diagnosis of ADH can reduce the risk of subsequent breast cancer; however, low acceptance of chemoprevention has been documented in the US population.17 Tamoxifen use was reported in 7.3% of women (96 of 1308) with an ADH diagnosis for whom subsequent self-report data were available in our study regardless of the type of biopsy. Therefore, the lower risk found in our study cannot be attributed to tamoxifen use.

There are several modifiers to the risk associated with ADH. The risk of breast cancer is inversely associated with age at diagnosis of ADH.18 Family history of breast cancer has been shown to increase the risk associated with ADH by some studies1 but not by others.18,19 Reproductive risk factors20 and alcohol use21 were reported to modify this risk as well. The risk associated with ADH is increased in women with dense breasts compared with women with fatty breasts.21 Although the number of foci of atypia correlated with the risk of cancer in the Mayo clinic cohort,2 a recent report from the Nurses’ Health Study9 did not demonstrate such an association in the subgroup of women with ADH. Calculators using several risk factors can better stratify women and help in consulting them on their risk and risk reduction options.13,22 The BCSC Risk Calculator23,24 incorporates age, race/ethnicity, family history of breast cancer, and BI-RADS breast density and results of biopsy to determine the probability of the subsequent 5- and 10-year risk of breast cancer.

Our study has several limitations, including no central pathologic review, which could reclassify ADH either to DCIS or to hyperplasia with no atypia. However, because most women do not obtain a second opinion after a diagnosis of ADH, the findings of this study can be generalized to women receiving such a diagnosis in community practice. No correlation to imaging findings was done, which is important to the assumption in this study that, with the advancement of imaging technology, smaller lesions are being detected and biopsied, leading to the diagnosis of smaller ADH foci. We were unable to assess underascertainment of cancer events owing to relocation and loss to follow-up. However, this lack of data should occur nondifferentially and not affect the HR estimates.

Conclusions

Women with ADH diagnosed by core needle and excisional biopsy had a slightly lower risk of invasive breast cancer than noted in previously reported studies. Because the risk associated with ADH is modified in the presence of other risk factors, clinicians should not recommend increased surveillance and risk-reducing strategies without accounting for other risk factors. An assessment of an individual’s risk based on multiple factors should be preferred13,22 before deciding on prevention strategies.

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Article Information

Corresponding Author: Tehillah S. Menes, MD, Department of Surgery, Tel Aviv-Sourasky Medical Center, 6 Weizmann St, Tel Aviv, Israel 64239 (tehillahm@tlvmc.gov.il).

Accepted for Publication: June 12, 2016.

Published Online: September 8, 2016. doi:10.1001/jamaoncol.2016.3022

Author Contributions: Dr Lange had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Menes, Kerlikowske, Lange, Miglioretti.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Lange, Miglioretti.

Obtaining funding: Kerlikowske, Miglioretti.

Administrative, technical, or material support: Kerlikowske, Miglioretti.

Study supervision: Menes, Kerlikowske, Miglioretti.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by grant HHSN261201100031C from the National Cancer Institute–funded Breast Cancer Surveillance Consortium (BCSC). Data collection for this work was additionally supported, in part, by grants P01CA154292 and U54CA163303 from the National Cancer Institute. The collection of cancer and vital status data used in this study was supported, in part, by several state public health departments and cancer registries throughout the United States (http://breastscreening.cancer.gov/work/acknowledgement.html).

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Additional Information: A list of the BCSC investigators is provided at http://breastscreening.cancer.gov.

Additional Contributions: We thank the participating women, mammography facilities, and radiologists for the data they have provided for this study.

References
1.
Page  DL, Dupont  WD, Rogers  LW, Rados  MS.  Atypical hyperplastic lesions of the female breast: a long-term follow-up study.  Cancer. 1985;55(11):2698-2708.PubMedGoogle ScholarCrossref
2.
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.PubMedGoogle ScholarCrossref
3.
Fisher  B, Costantino  JP, Wickerham  DL,  et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study.  J Natl Cancer Inst. 1998;90(18):1371-1388.PubMedGoogle ScholarCrossref
4.
Coopey  SB, Mazzola  E, Buckley  JM,  et al.  The role of chemoprevention in modifying the risk of breast cancer in women with atypical breast lesions.  Breast Cancer Res Treat. 2012;136(3):627-633.PubMedGoogle ScholarCrossref
5.
Goss  PE, Ingle JN, Alés-Martínez JE, et al; NCIC CTG MAP.3 Study Investigators.  Exemestane for breast-cancer prevention in postmenopausal women.  N Engl J Med. 2011;364:2381-2391.PubMedGoogle ScholarCrossref
6.
Zheng  Y, Heagerty  PJ.  Partly conditional survival models for longitudinal data.  Biometrics. 2005;61(2):379-391.PubMedGoogle ScholarCrossref
7.
Lee  E, Wei  L, Amato  D.  Cox-Type Regression Analysis for Large Numbers of Small Groups of Correlated Failure Time Observations. Dordrecht, the Netherlands: Kluwer Academic Publishers; 1992.
8.
Dupont  WD, Page  DL.  Risk factors for breast cancer in women with proliferative breast disease.  N Engl J Med. 1985;312(3):146-151.PubMedGoogle ScholarCrossref
9.
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.PubMedGoogle ScholarCrossref
10.
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.PubMedGoogle ScholarCrossref
11.
Elmore  JG, Gigerenzer  G.  Benign breast disease—the risks of communicating risk.  N Engl J Med. 2005;353(3):297-299.PubMedGoogle ScholarCrossref
12.
Carter  CL, Corle  DK, Micozzi  MS, Schatzkin  A, Taylor  PR.  A prospective study of the development of breast cancer in 16,692 women with benign breast disease.  Am J Epidemiol. 1988;128(3):467-477.PubMedGoogle Scholar
13.
Tice  JA, Miglioretti  DL, Li  CS, Vachon  CM, Gard  CC, Kerlikowske  K.  Breast density and benign breast disease: risk assessment to identify women at high risk of breast cancer.  J Clin Oncol. 2015;33(28):3137-3143.PubMedGoogle ScholarCrossref
14.
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