The Breast 54 (2020) 343e348 Contents lists available at ScienceDirect The Breast journal homepage: www.elsevier.com/brst Original article Differences in breast cancer risk after benign breast disease by type of screening diagnosis Javier Louro a, b, c, d, Marta Roma n a, b, c, Margarita Posso a, b, c, Laura Comerma e, Carmen Vidal f, Francina Saladie  g, Rodrigo Alcantara h, Mar Sanchez i, M. Jesús Quintana , Javier del Riego l, Joana Ferrer m, Lupe Pen j, k ~ alva n, Xavier Bargallo  o, p a, b, c a, b, c, * Miguel Prieto , María Sala , Xavier Castells a IMIM (Hospital Del Mar Medical Research Institute), Barcelona, Spain b Research Network on Health Services in Chronic Diseases (REDISSEC), Barcelona, Spain c Servei D’Epidemiologia I Avaluacio , Hospital Del Mar, Barcelona, Spain d European Higher Education Area (EHEA) Doctoral Programme in Methodology of Biomedical Research and Public Health in Department of Pediatrics, Obstetrics and Gynecology, Preventive Medicine and Public Health, Universitat Auto noma de Barcelona (UAB), Bellaterra, Barcelona, Spain e Servei de Patologia, Hospital Del Mar, Barcelona, Spain f Catalan Institute of Oncology (ICO), Barcelona, Spain g Cancer Epidemiology and Prevention Service, Hospital Universitari Sant Joan de Reus, Institut D’Investigacio  Sanitaria Pere Virgili, Universitat Rovira I Virgili, Reus, Spain h Servei de Diagno stic per La Imatge, Hospital Del Mar, Barcelona, Spain i Direction General of Public Health, Cantabria, Spain j Department of Clinical Epidemiology and Public Health, University Hospital de La Santa Creu I Sant Pau, IIB Sant Pau, Barcelona, Spain k CIBER of Epidemiology and Public Health (CIBERESP), Spain l Women’s Imaging, Department of Radiology, UDIAT Centre Diagno stic, Parc Taulí Hospital Universitari, Sabadell, Barcelona, Spain m Radiology Department, Hospital de Santa Caterina, Salt, Girona, Spain n Vall es Oriental Breast Cancer Early Detection Program, Spain o Radiology Department, Hospital Clinic, Barcelona, Spain p Breast Cancer Screening Program, Principality of Asturias, Spain a r t i c l e i n f o a b s t r a c t Article history: Introduction: We aimed to assess differences in breast cancer risk across benign breast disease diagnosed Received 3 July 2020 at prevalent or incident screens. Received in revised form Materials and methods: We conducted a retrospective cohort study with data from 629,087 women 24 August 2020 participating in a long-standing population-based breast cancer screening program in Spain. Each benign Accepted 4 September 2020 breast disease was classified as non-proliferative, proliferative without atypia, or proliferative with Available online 3 October 2020 atypia, and whether it was diagnosed in a prevalent or incident screen. We used partly conditional Cox hazard regression to estimate the adjusted hazard ratios of the risk of breast cancer. Keywords: Breast neoplasms Results: Compared with women without benign breast disease, the risk of breast cancer was significantly Early cancer detection higher (p-value ¼ 0.005) in women with benign breast disease diagnosed in an incident screen (aHR, Benign breast disease 2.67; 95%CI: 2.24e3.19) than in those with benign breast disease diagnosed in a prevalent screen (aHR, Risk factors 1.87; 95%CI: 1.57e2.24). The highest risk was found in women with a proliferative benign breast disease with atypia (aHR, 4.35; 95%CI: 2.09e9.08, and 3.35; 95%CI: 1.51e7.40 for those diagnosed at incident and prevalent screens, respectively), while the lowest was found in women with non-proliferative benign breast disease (aHR, 2.39; 95%CI: 1.95e2.93, and 1.63; 95%CI: 1.32e2.02 for those diagnosed at incident and prevalent screens, respectively). Conclusion: Our study showed that the risk of breast cancer conferred by a benign breast disease differed according to type of screen (prevalent or incident). To our knowledge, this is the first study to analyse the impact of the screening type on benign breast disease prognosis. © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). . Passeig Marítim 25-29, Barcelona, 08003, Spain. * Corresponding author. Hospital del Mar, Servei d’Epidemiologia I Avaluacio E-mail address: xcastells@parcdesalutmar.cat (X. Castells). https://doi.org/10.1016/j.breast.2020.09.005 0960-9776/© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). n, M. Posso et al. J. Louro, M. Roma The Breast 54 (2020) 343e348 1. Introduction women for the analysis. Benign breast disease is associated with an increased risk of 2.2. Procedures breast cancer both in the clinical setting [1,2] and in population- based screening [3]. Quantification of the increased risk according All women with screening mammograms scored BIRADS 0, 3, 4 to the characteristics of each lesion is constantly under study. or 5 were recalled for further assessments. If cancer could not be Benign breast disease lesions are most commonly classified as non- ruled out with non-invasive procedures when women were proliferative lesions, proliferative lesions without atypia, or prolif- attending recall, core-needle or open biopsy was performed. All erative lesions with atypia [4e6]. The risk of subsequent breast biopsies were examined and classified by hospital pathologists in cancer is higher in proliferative lesions than in non-proliferative each screening centre. All biopsies with a non-malignant classifi- lesions, while the risk is highest in proliferative lesions with aty- cation were classified as benign breast disease. Following the pia [3,7]. criteria of Page et al. and Dupont et al. [4e6], we classified benign Benign breast disease has been proposed as a key risk factor in breast diseases as: non-proliferative, proliferative without atypia, several breast cancer risk prediction models [8e11]. These models and proliferative with atypia. Only women with asymptomatic are essential for the development of personalised screening stra- benign breast disease diagnosed at screening were included in the tegies designed to improve the risk-benefit balance of breast cancer study. screening [12,13]. Therefore, it is important to fully understand Both cancers detected at routine screening and interval cancers differences in breast cancer risk in women diagnosed with benign (those diagnosed within 24 months after a negative screening breast disease. episode and before the next screening invitation) were included in In population-based breast cancer screening in Spain, women the study regardless of whether they were invasive or in situ. In- are invited to undergo a mammographic examination every 2 years terval cancers were identified by merging population-based cancer from the age of 50e69 years. Mammographic examinations can registries and hospital-based cancer registries with data from therefore be classified as prevalent screens, ie, women’s first screening participants. Benign breast disease identified at the same participation in screening mammography, and incident screens, ie, time as cancers were excluded from the benign breast disease all subsequent screening participations. The results of prevalent group. and incident screens differ in several screening outcomes, such as a higher detection rate and a higher recall rate at prevalent screens 2.3. Analysis [14], resulting in higher sensitivity and lower specificity [15,16]. However, breast cancer diagnosed at prevalent screens has been We used the chi-squared test to compare proportions of shown to be less aggressive and to have slower growth [17,18]. Even different variables among those women without a benign breast so, no studies have evaluated the risk of breast cancer associated to disease diagnosis, those with a diagnosis in a prevalent screen and bening breast disease according to type of examination (incident or those with a diagnosis in an incident screen. prevalent). We hypothesised that benign breast disease diagnosed We calculated incident breast cancer rates using person-years at in a prevalent screen confer a lower risk of subsequent breast risk for women with and without a diagnosis of benign breast cancer than that diagnosed in incident screens, regardless of the disease. Women without benign breast disease contributed person- benign breast disease subtype. years at risk from the date of the first screening mammogram until Using data from a long-standing population-based screening breast cancer diagnosis (screen-detected or interval cancer), benign program in Spain, we aimed to assess differences in the risk of breast disease diagnosis, or 2 years after the last mammographic breast cancer after diagnosis of benign breast disease according to examination, whichever came first. Women with benign breast the screening type and histological subtype of benign breast disease contributed person-years at risk from the date of benign disease. breast disease diagnosis until breast cancer diagnosis or 2 years after last screening examination, whichever occurred first. 2. Materials and methods We used a partly conditional Cox proportional hazards model to estimate the adjusted hazard ratios (aHR) and the 95% confidence 2.1. Study design and participants intervals (95%CI) for the risk of breast cancer by screening type and benign breast disease subtype. These models are an extension of The Spanish Breast Cancer Screening Program follows the rec- the Cox hazards model for repeated measures, which allowed us to ommendations of the European Guidelines for Quality Assurance in update the changes in benign breast disease status during the study Breast Cancer Diagnosis [19]. At age 50 years, women are invited to period. All analyses were adjusted for age and calendar year. We undergo 2-dimensional digital screening mammography. Two adjusted for age because women with benign breast disease diag- projections (mediolateral-oblique and craniocaudal views) are nosed in a prevalent screen were expected to be younger than those interpreted according to the Breast Imaging Reporting and Data diagnosed in incident screens. Adjustment by calendar year was System (BI-RADS) [20] scale by trained breast radiologists. Women included to capture possible differences in benign breast disease with abnormal mammographic findings are recalled for further diagnosis techniques and classification during the study period. An assessments to confirm or rule out malignancy. Women without a interaction between screening type and benign breast disease breast cancer diagnosis are invited back for routine screening at 2 subtype was tested; the interaction was found to be non-significant years. and was consequently not included in the final models (p for We analysed data from seven centres in the Spanish Screening interaction ¼ 0.83). Robust standard errors were used to estimate program, which routinely gathers information on benign breast 95% confidence intervals. The proportional hazards assumption was disease diagnoses. The study population included 632,299 women assessed by plotting the log-minus-log of the survival function who underwent at least one screening mammogram between 1994 against log time for each predictive variable. The proportional and 2015 and who were followed up until December 2017. Due to hazards assumption was reasonable for all predictors. the longitudinal nature of the study, women with breast cancer We plotted the adjusted cumulative incidence curves by esti- diagnosed in their first screen (n ¼ 3,212) were excluded from the mating the age- and calendar-year adjusted risk of cancer devel- analyses as there was no time for follow-up, leaving left 629,087 opment of the average woman in each category with the partly 344 n, M. Posso et al. J. Louro, M. Roma The Breast 54 (2020) 343e348 conditional Cox model. Statistical tests were two-sided and all p- non-proliferative benign breast disease (aHR, 2.39; 95%CI: values <0.05 were considered statistically significant. All analyses 1.95e2.93, and 1.63; 95%CI: 1.32e2.02 for those diagnosed at were performed using the statistical software R version 3.5.0 incident and prevalent screens, respectively, p-value for compari- (Development Core Team, 2014). son; p ¼ 0.011). We examined the adjusted cumulative incident curves of breast cancer across the different classifications of benign breast disease 3. Results and screening types. The probability of breast cancer diverged over time. The average 10-year breast cancer probability of women We analysed information from 629,087 women who underwent without a benign breast disease diagnosis was 1.9%. Among women 2,327,384 mammographic examinations between January 1994 and with benign breast disease, the probability was higher in women December 2015. During the study period, 9431 cases of breast diagnosed in an incident screen than in those diagnosed in a cancer and 9184 cases of benign breast disease were diagnosed. We prevalent screen (average 10-year probability of breast cancer 4.9% found no differences in the distribution of benign breast disease vs 3.5%). Among benign breast disease subtypes, the highest subtypes across incident and prevalent screens (p ¼ 0.48) (Table 1). probability of cancer was found in women with a proliferative The proportion of breast cancer cases was significantly lower in benign breast disease with atypia followed by those with prolifer- women without benign breast disease than in those with benign ative benign breast disease without atypia and those with a non- breast disease (1.5% vs 2.7%, p < 0.001). Among women with a proliferative benign breast disease (average 10-year breast cancer diagnosis of benign breast disease, the proportion of breast cancer probability 6.9%, 5.8% and 3.6%, respectively) (Fig. 3). The highest cases was higher in women diagnosed in an incident screen than in probability was found in women with proliferative benign breast those diagnosed in a prevalent screen (3.0% vs 2.4%, p ¼ 0.07). disease diagnosed in an incident screen, with an average 10-year Women with benign breast disease had a higher risk of breast probability of breast cancer of 7.8% (Fig. 4). cancer than those without benign breast disease, regardless of the subtype of benign breast disease. The highest risk was found in women with proliferative benign breast disease with atypia (aHR, 4. Discussion 3.82; 95%CI: 2.23e6.56), followed by those with proliferative benign breast disease without atypia (aHR, 3.19; 95%CI: 2.46e4.13) In this study of more than 600,000 women with follow-up for and those with non-proliferative benign breast disease (aHR, 1.95; more than 20 years, we found that a diagnosis of benign breast 95%CI: 1.68e2.27) (Fig. 1). In addition, among women with benign disease in an incident screen conferred a higher risk of subsequent breast disease, risk was higher in those diagnosed in an incident breast cancer than diagnosis in a prevalent screen, regardless of the screen than in those diagnosed in a prevalent screen (aHR, 2.67; histological subtype. These findings highlight the importance of 95%CI: 2.24e3.19, and aHR, 1.87; 95%CI: 1.57e2.24, respectively). considering the screening type when benign breast disease was The hazard ratios associated within each combination of diagnosed in risk of breast cancer estimation. To our knowledge, screening type and benign breast disease subtype are shown in this is the first study to include screening type in the assessment of Fig. 2. Across benign breast disease subtypes, those diagnosed in an the impact of benign breast disease on the risk of subsequent breast incident screen conferred a higher risk than those diagnosed in cancer. prevalent screens, although not statistically significant for al sub- Over the past decades, multiple studies have assessed the types. Compared with women without a benign breast disease, the relationship between benign breast disease and the risk of breast highest risk was found in those women with a proliferative benign cancer [2e6]. Particular efforts have been made to assess the as- breast disease with atypia (aHR, 4.35; 95%CI: 2.09e9.08, and 3.35; sociation of this risk with the various benign breast disease sub- 95%CI: 1.51e7.40 for those diagnosed at incident and prevalent types [4e6]. As seen in previous reports, our study showed that screens, respectively, p-value for comparison; p ¼ 0.634), followed women with benign breast disease had an increased risk of breast by women with proliferative benign breast disease without atypia cancer [2]. Consistently, we found that the risk of breast cancer was (aHR, 3.83; 95%CI: 2.63e5.58, and 2.78; 95%CI: 1.95e3.96 for those highest among women with a proliferative benign breast disease diagnosed at incident and prevalent screens, respectively; p-value with atypia, while proliferative benign breast disease without for comparison p ¼ 0.223). The lowest was found in women with atypia conferred a higher risk than non-proliferative benign breast Table 1 Characteristics of the study population. No benign breast disease N ¼ 619,864 Benign breast disease diagnosed Benign breast disease diagnosed in an in a prevalent screen N ¼ 5,049 incident screen N ¼ 4,174 Age at first screen 50-54 360,020 (58.1%) 3,420 (67.7%) 2,687 (64.4%) 55-59 123,994 (20.0%) 758 (15.0%) 936 (22.4%) 60-64 100,956 (16.3%) 637 (12.6%) 499 (12.0%) 65-69 34,894 (5.6%) 234 (4.6%) 52 (1.2%) Year of first screen <2005 299,173 (48.3%) 2,111 (41.8%) 2,856 (68.4%) 2005e2010 167,747 (27.1%) 1,220 (24.2%) 1,038 (24.9%) >2010 152,944 (24.7%) 1,718 (34%) 280 (6.7%) Type of benign breast disease No benign breast disease 619,864 (100%) 0 (0.0%) 0 (0.0%) Non-proliferative 0 (0.0%) 3,948 (78.2%) 3,282 (78.6%) Proliferative without atypia 0 (0.0%) 877 (17.4%) 728 (17.4%) Proliferative with atypia 0 (0.0%) 224 (4.4%) 164 (3.9%) Breast Cancer No 610,680 (98.5%) 4,928 (97.6%) 4,048 (97%) Si 9,184 (1.5%) 121 (2.4%) 126 (3.0%) 345 n, M. Posso et al. J. Louro, M. Roma The Breast 54 (2020) 343e348 Fig. 1. Adjusted hazard ratios (aHR) of breast cancer incidence in women with benign breast disease compared with women with negative screening tests. Fig. 2. Adjusted hazard ratios (aHR) of breast cancer incidence in women with benign breast disease compared with women with negative screening tests testing the combined effect of type of benign breast disease, and round at benign breast disease diagnosis. Fig. 3. Adjusted survival curves for breast cancer incidence based on Cox proportional hazards model for women with benign breast disease vs women with negative screening tests. Fig. 3 a. Solid line represents negative screening test group; dashed line represents benign breast disease diagnosed at prevalent round, dotted line benign breast disease diagnosed in incident round. Fig. 3 b. Solid line represents negative screening test group; dashed line represents nonproliferative benign breast disease, dashdotted line represent proliferative benign breast disease without atypia, dotted line represents proliferative benign breast disease with atypia. disease [3]. Although the reduced sample size for some BBD sub- included, the risk attributed to benign breast disease diagnosed in types led to non-significant differences in some subgroup com- prevalent screens could be overestimated, and that for incident parisons, we found that the difference in risk across benign breast screens could be underestimated. disease subtypes remained proportional within prevalent and Previous studies performed in the last decade have assessed incident screens and was systematically higher in those BBD differences in breast cancer screening outcomes, such as cancer diagnosed in incident screens. This finding is particularly relevant detection rates and false positive rates, by screening type [14e16]. since 55% of benign breast diseases are diagnosed in prevalent Moreover, previous authors found differences in breast cancer screens. Screening type therefore provides key information for risk characteristics depending on whether the cancers were diagnosed prediction in benign breast disease. Unless this information is in a prevalent or incident screen [17,18], suggesting that latent 346 n, M. Posso et al. J. Louro, M. Roma The Breast 54 (2020) 343e348 the statistical analysis on other breast cancer risk factors such as breast density or familial history of breast cancer. A strength of this study is that we analysed a large cohort of more than 600,000 women screened in a well-established popu- lation-based screening program with a 20-year follow-up. This is one of the largest cohorts analysing histopathologically confirmed benign breast disease, with nearly 10,000 diagnoses during follow- up. In summary, our study shows that, regardless of the type of benign breast disease, women with benign breast disease diag- nosed in an incident screen have a significantly higher subsequent risk of breast cancer than those with a benign breast disease diagnosed in a prevalent screen. To our knowledge, this is the first study to analyse this topic. It is important to consider this risk when developing risk-based personalised screening strategies. Funding Fig. 4. Adjusted survival curves for breast cancer incidence based on Cox proportional This study was supported by grants from Instituto de Salud hazards model for women with benign breast disease vs women with negative screening tests. Carlos III FEDER (grant numbers: PI15/00098 and PI17/00047), and by the Research Network on Health Services in Chronic Diseases (RD12/0001/0015). cancers diagnosed in prevalent screens have a slower growth pattern. The lower risk of breast cancer observed in women with benign breast disease diagnosed in prevalent screens might be Ethics approval and consent to participate partially explained by a slower growth pattern in prevalent benign breast disease. Age may play an important role in this effect, since The study was approved by the Clinic Research Ethics Com- women with benign breast disease diagnosed in incident screens mittee of Hospital del Mar Medical Research Institute (2015/6189/I). are, on average, older than those diagnosed in a prevalent screen. The review boards of the institutions providing data granted However, to control for this potential confounding effect, we approval for data analyses. This is an entirely register based study adjusted all analyses by age and calendar year. that used anonymised retrospective data and hence written con- The results of this study may have implications for clinical de- sent was not required. cisions on the follow-up of women with a diagnosis of benign breast disease, in which distinct follow-up strategies may be rec- Declaration of competing interest ommended depending on the benign breast disease subtype and screening type at diagnosis. The findings may also have implica- None declared. tions for individualised risk prediction. The Breast Cancer Surveil- lance Consortium model [21] is being used in a large international randomised clinical trial to define the individual risk of the popu- Acknowledgments lation targeted for breast cancer screening with a view to offering them personalised screening strategies [22]. Our findings reveal The authors acknowledge the dedication and support of the that screening type explained part of the risk associated with entire Benign Lesion (BELE) and Individualised Risk (IRIS) Study benign breast disease. Taking this variability into account could Groups listed here in alphabetical order and grouped by institution: help to improve the discriminatory power of breast cancer risk (a) IMIM (Hospital Del Mar Medical Research Institute), Barcelona, prediction models, which is commonly moderate [11,23]. In addi- Spain: Rodrigo Alcantara, Andrea Buro  n, Xavier Castells, Laia tion, we found that women with proliferative benign breast disease Domingo, Javier Louro, Margarita Posso, Ana Rodríguez-Arana, diagnosed in an incident screen had a 4-fold higher risk of devel- Marta Rom an, Maria Sala, Ignasi Tusquets, Ivonne Vazquez, Mar oping breast cancer than those without. This information, after Vernet-Tomas; (b) Corporacio  Sanitaria Parc Taulí, Sabadell, Spain: further analysis with adjustment for other risk factors such as Marisa Bare , Javier del Riego; (c) Catalan Institute of Oncology, breast density [24], family history [25], or a risk score using infor- Barcelona, Spain: Llucia Benito, Carmen Vidal (d) Hospital Santa mation from single nucleoid polymorphisms [26], may be key to Caterina, Girona, Spain: Joana Ferrer; (e) Catalan Institute of defining risk groups that could benefit from tailored screening Oncology, Girona, Spain: Rafael Marcos-Gragera; (f) Hospital de la strategies. Santa Creu i Sant Pau, Barcelona, Spain: Judit Sola -Roca, María Jesús This study has some limitations. First, the number of cancers Quintana; (g) General Directorate of Public Health, Government of detected after proliferative benign breast disease with atypia was Cantabria, Spain: Mar Sa nchez; (h) Principality of Asturias Health small because this subtype is uncommon, which limited our ca- Service, Spain: Miguel Prieto; (i) Fundacio  Lliga per a La Investigacio  pacity to perform some subgroup analyses. Second, there is a i Prevencio Del Cancer, Tarragona, Spain: Francina Saladie , Jaume possible bias produced by temporary changes both in the benign Galceran; (j) Hospital Clinic, Barcelona, Spain; Xavier Bargallo , breast disease classification and in biopsy techniques (because fine- Isabel Tora-Rocamora; (k) Valle s Oriental Breast Cancer Early needle aspiration cytology has become practically obsolete). This Detection Program, Spain; Lupe Pen ~ alva; (l) Catalonian Cancer bias is partially controlled as we adjusted our analysis by calendar Strategy, Barcelona, Spain: Josep Alfons Espina s. Javier Louro is a year. Third, to be able to classify benign breast disease, we restricted Ph.D. candidate at the Methodology of Biomedical Research and our study to those benign breast diseases with available informa- Public Health program, Universitat Auto noma de Barcelona (UAB), tion on their histological subtype. Last, it was not possible to adjust Barcelona, Spain. 347 n, M. Posso et al. J. Louro, M. Roma The Breast 54 (2020) 343e348 References approaches at a population level. Cancer 2014;120(19):2955e64. [14] Blanks RG, Given-Wilson R, Alison R, Jenkins J, Wallis MG. An analysis of 11.3 million screening tests examining the association between needle biopsy [1] Carter CL, Corle DK, Micozzi MS, Schatzkin A, Taylor PR. 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