This cohort study estimates the risk of breast cancer among women diagnosed with histopathologic benign breast disease in the era of percutaneous biopsy vs historical surgical biopsy.
Key Points
Question
What is the breast cancer (BC) risk among patients diagnosed with benign breast disease (BBD) in the percutaneous biopsy era (2002-2013)?
Findings
In this cohort study including 4819 women with BBD, BC risk was increased significantly vs the general population. Increased foci of BBD lesions, classified as nonproliferative, proliferative disease without atypia, or atypical hyperplasia (AH), were associated with progressively increased BC risk, particularly for women with 3 or more AH foci.
Meaning
The findings suggest that opportunities to improve BC risk stratification exist for women with BBD.
Abstract
Importance
Benign breast disease (BBD) comprises approximately 75% of breast biopsy diagnoses. Surgical biopsy specimens diagnosed as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) are associated with increasing breast cancer (BC) risk; however, knowledge is limited on risk associated with percutaneously diagnosed BBD.
Objectives
To estimate BC risk associated with BBD in the percutaneous biopsy era irrespective of surgical biopsy.
Design, Setting, and Participants
In this retrospective cohort study, BBD biopsy specimens collected from January 1, 2002, to December 31, 2013, from patients with BBD at Mayo Clinic in Rochester, Minnesota, were reviewed by 2 pathologists masked to outcomes. Women were followed up from 6 months after biopsy until censoring, BC diagnosis, or December 31, 2021.
Exposure
Benign breast disease classification and multiplicity by pathology panel review.
Main Outcomes
The main outcome was diagnosis of BC overall and stratified as ductal carcinoma in situ (DCIS) or invasive BC. Risk for presence vs absence of BBD lesions was assessed by Cox proportional hazards regression. Risk in patients with BBD compared with female breast cancer incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) program were estimated.
Results
Among 4819 female participants, median age was 51 years (IQR, 43-62 years). Median follow-up was 10.9 years (IQR, 7.7-14.2 years) for control individuals without BC vs 6.6 years (IQR, 3.7-10.1 years) for patients with BC. Risk was higher in the cohort with BBD than in SEER data: BC overall (standard incidence ratio [SIR], 1.95; 95% CI, 1.76-2.17), invasive BC (SIR, 1.56; 95% CI, 1.37-1.78), and DCIS (SIR, 3.10; 95% CI, 2.54-3.77). The SIRs increased with increasing BBD severity (1.42 [95% CI, 1.19-1.71] for NP, 2.19 [95% CI, 1.88-2.54] for PDWA, and 3.91 [95% CI, 2.97-5.14] for AH), comparable to surgical cohorts with BBD. Risk also increased with increasing lesion multiplicity (SIR: 2.40 [95% CI, 2.06-2.79] for ≥3 foci of NP, 3.72 [95% CI, 2.31-5.99] for ≥3 foci of PDWA, and 5.29 [95% CI, 3.37-8.29] for ≥3 foci of AH). Ten-year BC cumulative incidence was 4.3% for NP, 6.6% for PDWA, and 14.6% for AH vs an expected population cumulative incidence of 2.9%.
Conclusions and Relevance
In this contemporary cohort study of women diagnosed with BBD in the percutaneous biopsy era, overall risk of BC was increased vs the general population (DCIS and invasive cancer combined), similar to that in historical BBD cohorts. Development and validation of pathologic classifications including both BBD severity and multiplicity may enable improved BC risk stratification.
Introduction
Over 75% of breast biopsies performed annually in the US are diagnosed as benign breast disease (BBD),1 a term including biologically diverse lesions that are associated with variable increases in breast cancer (BC) risk. While subclassification of BBD as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) stratifies BC risk among groups of patients, models that accurately predict individual risk are lacking. Furthermore, BC risk estimates for patients with BBD vary by study populations, inclusion and exclusion criteria, clinical methods, study designs, length of follow-up, cancer end points, and statistical methods (major studies published since 2000 are summarized in eTable 1 in Supplement 1).2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28
Prior to 2000, introduction and widespread adoption of mammographic screening contributed to substantial increases in diagnosis of nonpalpable lesions, particularly ductal carcinoma in situ (DCIS), which subsequently plateaued among non-Hispanic White women.29 Since 2000, diagnostic methods shifted from film-based mammography and surgical biopsy to digital mammography and percutaneous biopsy, and the prevalence of several BC risk factors changed, including increases in obesity30 and late age at first birth31 and a decline in use of menopausal hormone replacement.32 However, the frequency of BBD lesions and their associations with BC risk have been largely unexamined in contemporary studies based on detailed histopathologic review.
To assess BC risk associated with BBD in recent practice, we developed the Mayo Percutaneous BBD Cohort, enrolling patients diagnosed with histopathologic BBD between 2002 and 2013 and followed up through 2021. We estimated BC risk associated with the presence vs absence of specific BBD lesions among cohort participants, expressed as hazard ratios (HRs), and BC risk associated with BBD vs population-based BC rates, derived from the Iowa Surveillance, Epidemiology, and End Results (SEER) program, expressed as standard incidence ratios (SIRs). The Iowa SEER population and participants in the Mayo cohort share similar demographic features. These data are important for management of BBD and for tailoring screening and preventive interventions in the current era of percutaneous breast biopsy.
Methods
Design of the Mayo Percutaneous BBD Cohort
In this cohort study, we identified women aged 18 years or older who underwent a BBD biopsy from January 1, 2002, to December 31, 2013, at Mayo Clinic, Rochester, Minnesota. The study was approved by the Mayo Clinic institutional review board. Women who denied the use of their data through the Minnesota research authorization initiative and either refused or did not return a study consent form were excluded from the study. All others were included via informed consent (if the study’s Health Insurance Portability and Accountability Act form and/or consent form was signed and returned) or waiver of consent. The manuscript was prepared according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Women were identified by searching electronic medical records for relevant diagnosis and procedure codes and by querying the Mayo Clinic pathology database for keywords such as breast, bx, and biopsy. We excluded women who underwent fine needle aspiration, breast skin biopsy, or breast reduction, but we included women who underwent surgical biopsy. We identified BC events (ie, invasive BC or DCIS) by searching for relevant International Classification of Diseases, Ninth Revision, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, and SNOMED codes; querying the Mayo Clinic Tumor Registry; and reviewing the pathology database. We also applied electronic queries to identify reasons for exclusion due to prebiopsy instances of DCIS, lobular carcinoma in situ (LCIS), breast reductions, and prophylactic mastectomies. We supplemented electronic queries with patient questionnaire data and medical review as needed to confirm eligibility and case status. We excluded women with BC or LCIS diagnosed before, concurrently with, or within 6 months after the BBD biopsy. We imposed additional exclusions to define the final analytical cohort as presented in eFigure 1 in Supplement 1. Race and ethnicity were ascertained by self-report via Mayo Clinic’s electronic health record and were summarized to assess representativeness of the cohort compared with the general population. Race was broadly categorized as American Indian or Native Alaskan, Asian, Black or African American, Hawaiian or Other Pacific Islander, White, unknown, and other, and ethnicity was broadly categorized as Hispanic or Latino, not Hispanic or Latino, and unknown.
Pathology Review
Original diagnostic pathology slides for BBD biopsies were reviewed independently by M.E.S. or J.M.C., who were masked to original diagnoses, clinical annotation, and follow-up. We recorded the level of normal lobule involution (0%, ≤25%, 26%-74%, or ≥75%) and number and type of specific BBD lesions. Features evaluated included severity of ductal hyperplasia (DH), apocrine change and other metaplastic changes, dilated ducts, adenosis, radial scar, columnar cell change, papilloma, fibroadenoma, AH (ductal or lobular), mastitis, pseudoangiomatous stromal hyperplasia (PASH), and rare entities. Ductal hyperplasia was defined as moderate when approximately 6 or more epithelial layers were present or complex irregular secondary spaces formed and as florid when greater multilayering filled and expanded ducts (risks for these categories were similar and therefore combined). When percutaneous and surgical biopsies were performed sequentially as part of the same workup, we only considered the former if DCIS, LCIS, and invasive BC were absent in the resection. Proliferative disease without atypia included moderate or florid DH, adenosis, radial scar, columnar cell change, and papilloma; all lesions except AH and PDWA were considered NP. Atypical hyperplasia lesions were confirmed by review of study pathologists (M.E.S., J.M.C.), and biopsy specimens containing flat epithelial atypia were not coded as AH unless co-occurring with AH. Numbers of NP and PDWA BBD lesions and of atypical foci were coded as 0 to 3 or more. Hierarchy of lesion severity was AH (highest), PDWA, and NP (lowest) per standard BBD categorization.
Follow-Up and Ascertainment of Outcomes
We observed women from the BBD biopsy date until a censoring event or end point, defined as pathologic DCIS or invasive BC, further classified by estrogen receptor (ER) status. Censoring events included LCIS; prophylactic, unilateral, or bilateral mastectomy; death; and end of follow-up (December 31, 2021). To minimize the possibility of occult BC in benign biopsy findings, follow-up began at 6 months after biopsy.
Statistical Analysis
Data were summarized using frequencies and percentages for categorical variables and means with SDs or medians and IQRs for continuous variables. We compared distributions of demographic and clinical characteristics across age at benign biopsy finding (≤50 vs >50 years) using χ2 tests for categorical variables and Wilcoxon rank sum tests for continuous variables. Hazard ratios and corresponding 95% CIs assessing the association of the presence vs absence of BBD lesions with BC risk were estimated using Cox proportional hazards regression analysis including age at BBD biopsy as a covariate. Tests for proportional hazards for each of the 41 primary Cox proportional hazards regression analyses revealed only 2 deviations at the α = .05 level, a rate well within that expected by chance alone. We estimated overall and lesion-specific risks of BC using SIRs with 95% CIs, dividing the observed number of postbiopsy BCs by population-based expected counts. We calculated expected events by distributing each woman’s follow-up time into 5-year age and calendar period categories and applying those person-years to incidence rates from the Iowa SEER registry, a National Cancer Institute–supported, population-based cancer registry that has recorded all cancers occurring in the state of Iowa since 1973. We chose the Iowa registry because its population closely resembles the demographic characteristics of patients seen at Mayo Clinic in Rochester, Minnesota. The Kaplan-Meier curves display observed BC cumulative incidence by levels of histologic impression.33 Cumulative incidence was examined both before and after we accounted for death as a competing risk. Expected cumulative incidence for the entire cohort was calculated for a series of 1000 postbiopsy time points by applying the observed follow-up time for each participant to Iowa SEER incidence rates using the approach by Ederer et al.34 Postbiopsy screening rates, defined as the number of times a woman underwent screening mammography at Mayo Clinic after the BBD biopsy (excluding the mammography visit that detected the BC) divided by person-years of follow-up, were examined for outcomes of DCIS or invasive BC, age at benign biopsy findings, and presence of AH.
Primary analyses modeled time from biopsy to BC overall (defined as invasive BC or DCIS). In exploratory analyses, we stratified women by age 50 years or younger and older than 50 years at BBD biopsy, and we subset end points to DCIS only, invasive BC, and invasive ER-positive BC. For these analyses, women with a BC event not of the type of interest or with missing BC type were right censored at the date of diagnosis. We also examined the potential influence of mammographic screening on associations between AH and risk of BC by fitting Cox proportional hazards regression models before and after adjustment for screening rate. Data were analyzed using SAS Studio, version 3.81 (SAS Institute Inc). Two-sided P < .05 was considered significant.
Results
Study Population
Of 9677 women who underwent a BBD biopsy during the study period, we excluded women with BC or LCIS diagnosed before (n = 1753), concurrently with (n = 726), or within 6 months after (n = 149) the BBD biopsy. The analysis included 4819 women, of whom 4113 (85.3%) were White, non-Hispanic and 355 (7.4%) were White with unknown ethnicity; each of the other combinations of race and ethnicity encompassed less than 2% of all women. The median age was 51 years (IQR, 43-62 years) (Table 1). A history of a first-degree relative with BC was reported by 946 participants (20.4%). Original diagnostic pathology slides for 4819 BBD biopsy specimens (4308 [89.4%] percutaneous) were reviewed. A total of 338 women (7.0%) were diagnosed with incident BC, including 99 (2.1%) with DCIS and 220 (4.6%) with invasive BC (19 [0.4%] had unknown invasiveness). Of the 220 invasive BCs, 195 (88.6%) were ER positive. Median follow-up for patients with BC was 6.6 years (IQR, 3.7-10.1 years) and was approximately 1 year less for DCIS (6.2 years [IQR, 3.0-9.1 years]) than for invasive BC (7.2 years [IQR, 4.3-10.8 years]); controls without BC were followed up for a median of 10.9 years (IQR, 7.7-14.2 years). Among the 331 cases of BC for whom side of BBD and side of BC were both known, 211 (63.7%) developed BC ipsilateral to the BBD biopsy.
Table 1. Demographic and Clinical Characteristics of Participants Who Underwent a BBD Biopsy by Age at Benign Biopsy Findings.
| Characteristic | Patientsa | P value | ||
|---|---|---|---|---|
| Age ≤50 y (n = 2347) | Age >50 y (n = 2472) | Total (N = 4819) | ||
| Age at BBD diagnosis, y | ||||
| Mean (SD) | 40.8 (7.70) | 62.7 (8.69) | 52.1 (13.71) | <.001b |
| Median (IQR) | 43 (38-47) | 62 (55-69) | 51 (43-62) | |
| Age at biopsy, y | ||||
| <45 | 1419 (60.5) | 0 | 1419 (29.4) | <.001c |
| 45-55 | 928 (39.5) | 675 (27.3) | 1603 (33.3) | |
| >55 | 0 | 1797 (72.7) | 1797 (37.3) | |
| Histologic impression | ||||
| NP | 1312 (55.9) | 1136 (46.0) | 2448 (50.8) | <.001c |
| PDWA | 923 (39.3) | 1102 (44.6) | 2025 (42.0) | |
| AH | 112 (4.8) | 234 (9.5) | 346 (7.2) | |
| First-degree family history of BC | ||||
| No | 1796 (80.2) | 1886 (78.9) | 3682 (79.6) | .28c |
| Yes | 443 (19.8) | 503 (21.1) | 946 (20.4) | |
| Vital status | ||||
| Alive | 2266 (96.5) | 1907 (77.1) | 4173 (86.6) | <.001c |
| Dead | 81 (3.5) | 565 (22.9) | 646 (13.4) | |
| Case status | ||||
| No BC | 2223 (94.7) | 2258 (91.3) | 4481 (93.0) | <.001c |
| BC | 124 (5.3) | 214 (8.7) | 338 (7.0) | |
| Duration of follow-up, y | ||||
| Controls without BC | ||||
| Mean (SD) | 11.6 (5.17) | 10.8 (4.89) | 11.2 (5.05) | <.001b |
| Median (IQR) | 11.5 (8.4-15.0) | 10.5 (7.2-13.7) | 10.9 (7.7-14.2) | |
| Patients with BC | ||||
| Mean (SD) | 8.2 (4.44) | 7.0 (4.21) | 7.4 (4.33) | .015b |
| Median (IQR) | 7.2 (4.7-11.2) | 6.3 (2.9-9.5) | 6.6 (3.7-10.1) | |
| Type of BC, No./total No. (%) | ||||
| Invasive | 75/124 (60.5) | 145/214 (67.8) | 220/338 (65.1) | .34c |
| DCIS | 40/124 (32.3) | 59/214 (27.6) | 99/338 (29.3) | |
| Unknown | 9/124 (7.3) | 10/214 (4.7) | 19/338 (5.6) | |
| ER status among patients with invasive BC, No./total No. (%) | ||||
| Negative | 4/75 (5.3) | 14/145 (9.7) | 18/220 (8.2) | .27c |
| Positive | 70/75 (93.3) | 125/145 (86.2) | 195/220 (88.6) | |
| Unknown | 1/75 (1.3) | 6/145 (4.1) | 7/220 (3.2) | |
Abbreviations: AH, atypical hyperplasia; BBD, benign breast disease; BC, breast cancer; DCIS, ductal carcinoma in situ; ER, estrogen receptor; NP, nonproliferative disease; PDWA, proliferative disease without atypia.
Data are presented as number (percentage) of patients unless otherwise indicated.
Wilcoxon rank sum test.
χ2 Test.
BBD Overall and BC Risk
Of the 4819 women in the cohort, 3818 (79.2%) underwent core biopsy only, 491 (10.2%) underwent core biopsy and surgical excision, and 510 (10.6%) underwent excisional biopsy only, with the frequency of the latter declining from 21 of 118 (17.8%) in 2002 to 2 of 34 (5.9%) in 2013. Based on the most severe lesion identified, 2448 biopsy specimens (50.8%) were classified as NP, 2025 (42.0%) as PDWA, and 346 (7.2%) as AH. Of those with NP, 118 (4.8%) developed a subsequent BC compared with 169 (8.3%) of those with PDWA and 51 (14.7%) of those with AH. Data on BC risk are presented in Table 2 as both HRs (presence vs absence of lesion within the cohort) and SIRs (rates of BC among cohort members vs the general population). Compared with cohort members diagnosed with NP, those with PDWA had higher BC risk (HR, 1.61; 95% CI, 1.27-2.04), as did those with AH (HR, 2.99; 95% CI, 2.15-4.18). The SIR for BC overall (DCIS plus invasive BC) among patients with BBD compared with the general population of women in Iowa was 1.95 (95% CI, 1.76-2.17) and increased progressively by severity of histologic impression (NP, 1.42 [95% CI, 1.19-1.71]; PDWA, 2.19 [95% CI, 1.88-2.54]; AH, 3.91 [95% CI, 2.97-5.14]).
Table 2. BBD Lesion–Specific Associations With Risk of DCIS or Invasive BC Among Women Who Underwent a BBD Biopsy.
| Lesion characteristic | Patients, No. (%) | Person-years | HR (95% CI)a | P valuea | Expected events, No.b | SIR (95% CI)b | |
|---|---|---|---|---|---|---|---|
| With BC | Without BC | ||||||
| All individuals | 338 (7.0) | 4481 (93.0) | 49 796 | NA | NA | 173.1 | 1.95 (1.76-2.17) |
| Histologic impression | |||||||
| NP | 118 (34.9) | 2330 (52.0) | 25 308 | 1 [Reference] | <.001 | 82.8 | 1.42 (1.19-1.71) |
| PDWA | 169 (50.0) | 1856 (41.4) | 21 233 | 1.61 (1.27-2.04) | 77.2 | 2.19 (1.88-2.54) | |
| AH | 51 (15.1) | 295 (6.6) | 3255 | 2.99 (2.15-4.18) | 13.1 | 3.91 (2.97-5.14) | |
| Fibroadenoma | |||||||
| No | 262 (77.5) | 3252 (72.6) | 36 232 | 1 [Reference] | .26 | 132.2 | 1.98 (1.76-2.24) |
| Yes | 76 (22.5) | 1229 (27.4) | 13 563 | 0.86 (0.67-1.12) | 40.9 | 1.86 (1.48-2.33) | |
| Apocrine metaplasia | |||||||
| No | 235 (69.5) | 3245 (72.4) | 36 081 | 1 [Reference] | .32 | 123.4 | 1.90 (1.68-2.16) |
| Yes | 103 (30.5) | 1236 (27.6) | 13 715 | 1.13 (0.89-1.42) | 49.7 | 2.07 (1.71-2.51) | |
| TDLU involution, % | |||||||
| ≥75 | 91 (30.1) | 1081 (27.6) | 11 750 | 1 [Reference] | .54 | 50.6 | 1.80 (1.46-2.21) |
| 25-74 | 166 (55.0) | 2139 (54.7) | 24 103 | 1.16 (0.88-1.52) | 78.5 | 2.11 (1.82-2.46) | |
| 0-24 | 45 (14.9) | 692 (17.7) | 7697 | 1.06 (0.74-1.52) | 22.3 | 2.02 (1.50-2.70) | |
| Dilated ducts | |||||||
| No | 293 (86.7) | 4023 (89.8) | 44 806 | 1 [Reference] | .12 | 154.3 | 1.90 (1.69-2.13) |
| Yes | 45 (13.3) | 458 (10.2) | 4989 | 1.29 (0.94-1.76) | 18.8 | 2.39 (1.79-3.20) | |
| Columnar cell change | |||||||
| No | 184 (54.4) | 3315 (74.0) | 36 201 | 1 [Reference] | <.001 | 123.7 | 1.49 (1.29-1.72) |
| Yes | 154 (45.6) | 1166 (26.0) | 13 595 | 2.19 (1.77-2.72) | 49.4 | 3.12 (2.66-3.65) | |
| Sclerosing adenosis | |||||||
| No | 271 (80.2) | 3791 (84.6) | 41 689 | 1 [Reference] | .08 | 144.2 | 1.88 (1.67-2.12) |
| Yes | 67 (19.8) | 690 (15.4) | 8107 | 1.28 (0.98-1.67) | 28.9 | 2.32 (1.82-2.94) | |
| Radial scar | |||||||
| No | 325 (96.2) | 4363 (97.4) | 48 475 | 1 [Reference] | .27 | 168.0 | 1.93 (1.73-2.16) |
| Yes | 13 (3.8) | 118 (2.6) | 1320 | 1.37 (0.78-2.41) | 5.1 | 2.57 (1.49-4.42) | |
| Papilloma | |||||||
| No | 276 (81.7) | 3999 (89.2) | 44 388 | 1 [Reference] | <.001 | 152.6 | 1.81 (1.61-2.03) |
| Yes | 62 (18.3) | 482 (10.8) | 5408 | 1.70 (1.29-2.25) | 20.5 | 3.03 (2.36-3.88) | |
| PASH | |||||||
| None | 334 (98.8) | 4326 (96.5) | 48 059 | 1 [Reference] | .046 | 167.8 | 1.99 (1.79-2.22) |
| Present | 4 (1.2) | 155 (3.5) | 1736 | 0.37 (0.14-0.98) | 5.3 | 0.76 (0.28-2.01) | |
| Sum of NP lesions | |||||||
| 0-1 | 96 (28.4) | 1519 (33.9) | 17 020 | 1 [Reference] | .001 | 55.8 | 1.72 (1.41-2.10) |
| 2 | 77 (22.8) | 1236 (27.6) | 13 382 | 0.96 (0.71-1.29) | 48.5 | 1.59 (1.27-1.99) | |
| ≥3 | 165 (48.8) | 1726 (38.5) | 19 393 | 1.47 (1.14-1.88) | 68.9 | 2.40 (2.06-2.79) | |
| Ductal hyperplasia | |||||||
| None | 181 (53.6) | 2984 (66.6) | 32 951 | 1 [Reference] | <.001 | 110.9 | 1.63 (1.41-1.89) |
| Mild | 59 (17.5) | 759 (16.9) | 8657 | 1.21 (0.90-1.62) | 30.7 | 1.92 (1.49-2.48) | |
| Moderate or florid | 98 (29.0) | 738 (16.5) | 8187 | 2.01 (1.57-2.57) | 31.5 | 3.11 (2.55-3.79) | |
| Sum of PDWA lesions | |||||||
| ≤1 | 263 (77.8) | 3882 (86.6) | 42 939 | 1 [Reference] | <.001 | 147.7 | 1.78 (1.58-2.01) |
| 2 | 58 (17.2) | 488 (10.9) | 5616 | 1.62 (1.21-2.15) | 20.9 | 2.78 (2.15-3.60) | |
| ≥3 | 17 (5.0) | 111 (2.5) | 1241 | 2.14 (1.29-3.53) | 4.6 | 3.72 (2.31-5.99) | |
| Atypical hyperplasia | |||||||
| No | 287 (84.9) | 4186 (93.4) | 46 541 | 1 [Reference] | <.001 | 160.1 | 1.79 (1.60-2.01) |
| Yes | 51 (15.1) | 295 (6.6) | 3255 | 2.31 (1.71-3.13) | 13.1 | 3.91 (2.97-5.14) | |
| Atypia foci | |||||||
| 0 | 287 (84.9) | 4186 (93.4) | 46 541 | 1 [Reference] | <.001 | 160.1 | 1.79 (1.60-2.01) |
| 1 | 20 (5.9) | 142 (3.2) | 1568 | 1.84 (1.16-2.91) | 6.4 | 3.11 (2.01-4.82) | |
| 2 | 12 (3.6) | 75 (1.7) | 767 | 2.38 (1.34-4.25) | 3.0 | 3.96 (2.25-6.98) | |
| ≥3 | 19 (5.6) | 78 (1.7) | 920 | 3.10 (1.93-4.97) | 3.6 | 5.29 (3.37-8.29) | |
Abbreviations: AH, atypical hyperplasia; BBD, benign breast disease; BC, breast cancer; DCIS, ductal carcinoma in situ; HR, hazard ratio; SIR, standardized incidence ratio; NA, not applicable; NP, nonproliferative disease; PASH, pseudoangiomatous stromal hyperplasia; PDWA, proliferative disease without atypia; TDLU, terminal duct lobular unit.
Cox proportional hazards regression analysis adjusting for age at benign biopsy.
Using Iowa Surveillance, Epidemiology, and End Results program breast cancer incidence rates as the population standard.
Specific BBD Lesions and BC Risk
Within-cohort comparisons demonstrated increased BC risk associated with identification of columnar cell change, papilloma, DH, and AH and decreased risk for PASH (Table 2). By SIR assessment, the highest BC risks associated with individual lesion types were observed for AH (SIR, 3.91; 95% CI, 2.97-5.14) and moderate or florid DH (SIR, 3.11; 95% CI, 2.55-3.79). Risk generally increased with lesion multiplicity, such that women with 3 or more foci of NP had an increased risk compared with the Iowa SEER population (SIR, 2.40; 95% CI, 2.06-2.79), and women with 3 or more foci of PDWA had greater risk (SIR, 3.72; 95% CI, 2.31-5.99). Risk for AH increased with detection of multiple foci (SIR for single focus, 3.11 [95% CI, 2.01-4.82]; 2 foci, 3.96 [95% CI, 2.25-6.98]; ≥3 foci, 5.29 [95% CI, 3.37-8.29]). Absolute 10-year cumulative incidence for BC overall was 4.3% for NP, 6.6% for PDWA, and 14.6% for AH compared with an expected 10-year cumulative incidence of 2.9% for the general population in SEER (Figure). Cumulative incidence for AH was approximately 1% per year.
Figure. Observed Cumulative Incidence of Breast Cancer by Histologic Impression With Corresponding Overall Expected Cumulative Incidence for the Entire Cohort of Women Who Underwent a Benign Breast Disease Biopsy.
Data are for 4819 women aged 18 years or older who underwent biopsy at Mayo Clinic, Rochester, Minnesota, from January 1, 2002, to December 31, 2013. AH indicates atypical hyperplasia; NP, nonproliferative disease; and PDWA, proliferative disease without atypia.
Comparative Risks of DCIS and Invasive BC
Compared with women in the general population, patients with BBD experienced increased risk of invasive BC (SIR, 1.56; 95% CI, 1.37-1.78) (eTable 2 in Supplement 1) and DCIS (SIR, 3.10; 95% CI, 2.54-3.77) (eTable 3 in Supplement 1). Risks associated with specific BBD lesions were generally similar for BC overall, invasive BC, and DCIS, although some estimates were imprecise. Women with 3 or more AH foci showed a markedly elevated albeit imprecise risk of DCIS (SIR, 9.06; 95% CI, 4.07-20.20).
Exploratory Analyses of BBD and BC Risk
For women with multiple PDWA or AH lesions, BC overall risks were not significantly different among those aged 50 years or younger compared with older women (eTable 4 in Supplement 1). Risks of invasive BC overall and of invasive ER-positive BCs were similar, although analysis of risk of ER-negative BC was limited by small numbers (eTable 5 in Supplement 1). Mean (SD) annual screening rate among women who were not diagnosed with BC was 0.46 (0.34) compared with 0.57 (0.35) for women diagnosed with invasive BC and 0.63 (0.37) for those diagnosed with DCIS (P < .001) (eFigure 2 in Supplement 1). The frequency of screening of women with AH and lower risk categories of BBD were not significantly different (eFigure 3 in Supplement 1), and adjusting for screening frequency did not impact estimates of BC risk among women with AH (eTable in Supplement 2).
Discussion
Defining BC risk among patients with BBD diagnosed in the percutaneous biopsy era is important for guiding clinical management, screening, and prevention. Development of percutaneous biopsy began with smaller needles (18 gauge) and progressed to large needles (9-11 gauge) with vacuum assistance, reducing the risk of undersampling and missed cancers. In this analysis, we found that BBD diagnosed by percutaneous biopsies was associated with an increased risk of BC overall, with progressively increasing risk for NP, PDWA, and AH, as reported in older surgical biopsy cohorts.6,7,8,11,12,16,18,19,20,25,27 However, our data showed some differences compared with the literature for surgical biopsies.6,7,8,11,12,16,18,19,20,25,27
Consistent with prior reports,6,11,12,16,19,27 we report that NP and PDWA accounted for over 92.8% of the BBD lesions in this cohort. In contrast, we found that AH was diagnosed in 7.2% of BBD biopsies compared with a considerably lower percentage reported historically6,11,12,16,19,27 (eTable 1 in Supplement 1). Of the 346 women diagnosed with AH, 51 (14.7%) developed DCIS or invasive BC, reflecting an increase in BC risk compared with the general population, consistent with prior reports21,24 (eTable 1 in Supplement 1). Risk was higher for women with 3 or more AH foci compared with a single focus, especially at age 50 years or younger. These results were unaffected by adjustment for screening frequency and trends of rising detection rates of DCIS and of ER-positive BCs among younger women. Similar to findings on AH in the Mayo surgical cohort with BBD,24 (1) risk was higher with 3 or more foci of AH compared with a single focus, (2) risk was higher among younger compared with older women with AH, and (3) absolute risk was approximately 1% per year overall for all women with AH.
Current clinical BBD diagnoses primarily reflect the highest-risk lesion present but not the number and type of specific lesions. However, we also observed a pattern of increasing risk with increasing numbers of NP and PDWA lesions, a pattern that generally persisted after adjusting for the presence of AH. The higher BC risk associated with percutaneous biopsy specimens with multiple BBD lesions may reflect a field effect of multiple lesions across both breasts, corroborating similar data from surgical biopsies.14,21,26
Similarly, detection of multiple clusters of mammographic calcifications, a radiologic marker of multifocal BBD, is associated with increased risk.35 Higher polygenic risk scores for BC have been associated with detection of increased clusters of mammographic calcifications,36 suggesting that genetic factors might influence BC risk through increasing BBD multifocality. As 36.3% of BCs diagnosed after BBD occurred in the contralateral breast and ipsilateral BCs among patients with prior BBD diagnoses often develop in a different quadrant, understanding BBD multiplicity may be important for risk prediction.
In this percutaneous biopsy era cohort, a notable difference from a prior surgical BBD cohort in a study conducted by some of us37,38 is that increasing lobular involution was not significantly associated with decreased BC risk. Analysis of levels of involution in percutaneous biopsy specimens may be less accurate than in surgical biopsy specimens and may result in misclassification because fewer normal lobules are available for evaluation. Furthermore, lobules in closest proximity to BBD lesions may differ from those throughout the breast. Finally, previous studies demonstrated that lobules surrounding BC showed molecular alterations representing cancer field effects39 and that levels of lobular involution were reduced in tissues surrounding triple-negative vs luminal BCs in Asian, Black, and White populations.40,41,42 A similar phenomenon could occur around BBD lesions. Looking forward, improved technology and computational methods may provide a more quantitative and informative assessment of lobule involution43 and enable evaluation of multiple BBD lesions and the stromal microenvironment throughout an entire biopsy specimen. Comprehensive assessment of pathology may provide more accurate risk assessment compared with reporting the single most severe class of BBD present. Controversy remains about the potential harms of mammographic screening, including false-positive findings and biopsies that show (only) benign findings.44 However, we believe that information from benign breast biopsy findings helps to stratify a woman’s future breast cancer risk and allows prevention in cases of atypical hyperplasia. Recognition that mammography has imperfect sensitivity, especially in dense breasts, has spurred techniques, such as magnetic resonance imaging45 and contrast enhanced mammography,46 which may also have implications for the future landscape of BBD.
Limitations
Although this analysis included nearly 5000 women followed up for over 10 years on average, precision was limited for less common BBD lesions. Furthermore, our data are most relevant to White, non-Hispanic screened populations. Although we examined screening frequency in exploratory analyses, we acknowledge that our institution is a referral center and that we are unable to account for screening performed elsewhere. We found relatively small albeit statistically significant increases in screening frequency among women diagnosed with BC compared with those who remained cancer free, but adjustment for screening frequency had negligible influence on risk estimates. Our data raise important, unresolved questions about whether detection of DCIS among patients with BBD could reduce risk of invasive BC by truncating the natural history of precancerous lesions (“interception”), detection of a “reservoir of disease” that may be clinically inconsequential, or both.
Conclusions
Data from this study in the percutaneous biopsy era showed that BBD was associated with a similar degree of increased breast cancer risk compared with surgically diagnosed BBD and that risks of both invasive BC and, notably, DCIS remained elevated among patients with BBD compared with the general population. Although SIRs were higher for DCIS than for invasive BC, invasive disease accounted for 65.0% of BCs after BBD. Based on these findings, current clinical management of BBD in the percutaneous biopsy era should remain the same, with close surveillance and consideration of preventive therapy for women with AH. Exhaustive BBD analysis as performed in this study would be impractical in routine diagnostic practice, so our finding of higher risk associated with multiple BBD lesions is not immediately actionable at this time. However, increased use of digital images with application of computational pathology approaches may enable more comprehensive future analysis of BBD biopsy specimens and improve evaluation of BC risk prediction.
eTable 1. Literature Summary
eTable 2. BBD Lesion–Specific Associations With Risk of Invasive BC Among Women Who Underwent a BBD Biopsy
eTable 3. BBD Lesion–Specific Associations With Risk of DCIS Among Women Who Underwent a BBD Biopsy
eTable 4. BBD Lesion–Specific Associations With BC Risk (DCIS or Invasive) Among Women Who Underwent a BBD Biopsy, Stratified by Age at Benign Biopsy
eTable 5. BBD Lesion–Specific Associations With Risk of Invasive ER-Positive BC Among Women Who Underwent a BBD Biopsy
eFigure 1. CONSORT Diagram of Women Who Underwent a BBD Biopsy
eFigure 2. Postbiopsy Breast Cancer Screening Rates by Age at Benign Biopsy and BC Status Among Women Who Underwent a BBD Biopsy, Grouped as Patients Subsequently Developing Invasive BC, Subsequently Developing DCIS, and With No Subsequent BC
eFigure 3. Postbiopsy Breast Cancer Screening Rates Among Women Who Underwent a BBD Biopsy, by Presence of AH on Benign Biopsy and BC Status, Grouped as Patients Subsequently Developing Invasive BC, Subsequently Developing DCIS, and With No Subsequent BC
eTable. Age-Adjusted and Age and Screening Mammogram Rate–Adjusted Associations of ALH, ADH, and Any AH at Benign Biopsy With Risk of Overall BC
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Literature Summary
eTable 2. BBD Lesion–Specific Associations With Risk of Invasive BC Among Women Who Underwent a BBD Biopsy
eTable 3. BBD Lesion–Specific Associations With Risk of DCIS Among Women Who Underwent a BBD Biopsy
eTable 4. BBD Lesion–Specific Associations With BC Risk (DCIS or Invasive) Among Women Who Underwent a BBD Biopsy, Stratified by Age at Benign Biopsy
eTable 5. BBD Lesion–Specific Associations With Risk of Invasive ER-Positive BC Among Women Who Underwent a BBD Biopsy
eFigure 1. CONSORT Diagram of Women Who Underwent a BBD Biopsy
eFigure 2. Postbiopsy Breast Cancer Screening Rates by Age at Benign Biopsy and BC Status Among Women Who Underwent a BBD Biopsy, Grouped as Patients Subsequently Developing Invasive BC, Subsequently Developing DCIS, and With No Subsequent BC
eFigure 3. Postbiopsy Breast Cancer Screening Rates Among Women Who Underwent a BBD Biopsy, by Presence of AH on Benign Biopsy and BC Status, Grouped as Patients Subsequently Developing Invasive BC, Subsequently Developing DCIS, and With No Subsequent BC
eTable. Age-Adjusted and Age and Screening Mammogram Rate–Adjusted Associations of ALH, ADH, and Any AH at Benign Biopsy With Risk of Overall BC
Data Sharing Statement
