Joana Ferrer

Reduction in False-Positive Results after Introduction of Digital Mammography: Analysis from Four Population-based Breast Cancer Screening Programs in Spain

PURPOSEnTo evaluate the effect of the introduction of digital mammography on the recall rate, detection rate, false-positive rate, and rates of invasive procedures in a cohort of women from four population-based breast cancer screening programs in Spain.nnnMATERIALS AND METHODSnThe study was approved by the ethics committee; informed consent was not required. A total of 242,838 mammograms (171,191 screen film [screen-film mammography group] and 71,647 digital [digital mammography group]) obtained in 103,613 women aged 45-69 years were included. False-positive results for any additional procedure and for invasive procedures, the breast cancer rate, and the positive predictive value in each group were compared by using Pearson χ(2) test. The effect of the mammographic technology used (screen-film or digital) on the false-positive results and cancer detection risk was evaluated with multivariate logistic regression models, adjusted according to womens and the screening programs characteristics and time trends.nnnRESULTSnThe false-positive rate was higher for screen-film than for digital mammography (7.6% and 5.7%, respectively; P < .001). False-positive results after an invasive procedure were significantly higher for screen-film than for digital mammography (1.9% and 0.7%, respectively; P < .001). No significant differences were observed in the overall cancer detection rate between the two groups (0.45% and 0.43% in the screen-film and digital mammography groups, respectively; P = .59). The adjusted risk of a false-positive result was higher for screen-film than for digital mammography (odds ratio = 1.32). The adjusted risk was also lower for the digital mammography group when time trends were taken into account.nnnCONCLUSIONnThe lower false-positive risk with use of digital mammography should be taken into account when balancing the risks and benefits of breast cancer screening.

Mammographic and clinical characteristics of different phenotypes of screen-detected and interval breast cancers in a nationwide screening program

In the context of a population-based screening program, we aimed to evaluate the major mammographic features and clinicopathological characteristics of breast tumors at diagnosis and the associations between them, focusing on tumors with the worst prognosis. We analyzed cancers diagnosed in a cohort of 645,764 women aged 45–69 years participating in seven population-based screening programs in Spain, between January 1, 2000 and December 31, 2006 and followed up until June 2009. We included all interval cancers and a sample of screen-detected cancers, whether invasive or in situ. We compared tumor-related information and breast density for different phenotypes (Triple-negative (TN), HER2+, Luminal B and Luminal A) in screen-detected and interval cancers. We used Chi-square or Fisher’s exact test to compare major mammographic features of invasive versus in situ tumors, of screen-detected versus interval cancers, and of different types of interval cancers. We included 2582 tumors (1570 screen-detected and 1012 interval cancers). There were significant differences in the distribution of most clinicopathological variables between screen-detected and interval cancers. Invasive TN interval tumors were more common than other phenotypes in breasts with low mammographic density; three-quarters of these tumors presented as masses without associated calcifications. HER2+ tumors were more common in denser breasts and were associated with calcifications and multifocality. Architectural distortion was more common in Luminal A and Luminal B tumors. Certain radiologic findings are associated with pre-invasive lesions; these differ among invasive tumor phenotypes. We corroborate that TN and HER2+ cancers have distinctive appearances also in the context of population-based screening programs. This information can be useful for establishing protocols for diagnostic strategies in screening units.

Breast cancer risk after diagnosis by screening mammography of nonproliferative or proliferative benign breast disease: a study from a population-based screening program

Benign breast disease increases the risk of breast cancer. This association has scarcely been evaluated in the context of breast cancer screening programs although it is a prevalent finding in mammography screening. We assessed the association of distinct categories of benign breast disease and subsequent risk of breast cancer, as well as the influence of a family history of breast cancer. A retrospective cohort study was conducted in 545,171 women aged 50–69xa0years biennially screened for breast cancer in Spain. The median of follow-up was 6.1xa0years. The age-adjusted rate ratio (RR) of breast cancer for women with benign breast disease, histologically classified into nonproliferative and proliferative disease with and without atypia, compared with women without benign breast disease was estimated by Poisson regression analysis. A stratified analysis by family history of breast cancer was performed in a subsample. All tests were two-sided. The age-adjusted RR of breast cancer after diagnosis of benign breast disease was 2.51 (95xa0% CI: 2.14–2.93) compared with women without benign breast disease. The risk was higher in women with proliferative disease with atypia (RRxa0=xa04.56, 95xa0% CI: 2.06–10.07) followed by those with proliferative disease without atypia (RRxa0=xa03.58; 95xa0% CIxa0=xa02.61–4.91). Women with nonproliferative disease and without a family history of breast cancer remained also at increased risk of cancer (ORxa0=xa02.23, 95xa0% CI: 1.86–2.68). An increased risk of breast cancer was observed among screening participants with proliferative or nonproliferative benign breast disease, regardless of a family history of breast cancer. This information may be useful to explore risk-based screening strategies.

Impact of Risk Factors on Different Interval Cancer Subtypes in a Population-Based Breast Cancer Screening Programme

Background Interval cancers are primary breast cancers diagnosed in women after a negative screening test and before the next screening invitation. Our aim was to evaluate risk factors for interval cancer and their subtypes and to compare the risk factors identified with those associated with incident screen-detected cancers. Methods We analyzed data from 645,764 women participating in the Spanish breast cancer screening program from 2000–2006 and followed-up until 2009. A total of 5,309 screen-detected and 1,653 interval cancers were diagnosed. Among the latter, 1,012 could be classified on the basis of findings in screening and diagnostic mammograms, consisting of 489 true interval cancers (48.2%), 235 false-negatives (23.2%), 172 minimal-signs (17.2%) and 114 occult tumors (11.3%). Information on the screening protocol and womens characteristics were obtained from the screening program registry. Cause-specific Cox regression models were used to estimate the hazard ratios (HR) of risks factors for interval cancer and incident screen-detected cancer. A multinomial regression model, using screen-detected tumors as a reference group, was used to assess the effect of breast density and other factors on the occurrence of interval cancer subtypes. Results A previous false-positive was the main risk factor for interval cancer (HRu200a=u200a2.71, 95%CI: 2.28–3.23); this risk was higher for false-negatives (HRu200a=u200a8.79, 95%CI: 6.24–12.40) than for true interval cancer (HRu200a=u200a2.26, 95%CI: 1.59–3.21). A family history of breast cancer was associated with true intervals (HRu200a=u200a2.11, 95%CI: 1.60–2.78), previous benign biopsy with a false-negatives (HRu200a=u200a1.83, 95%CI: 1.23–2.71). High breast density was mainly associated with occult tumors (RRRu200a=u200a4.92, 95%CI: 2.58–9.38), followed by true intervals (RRRu200a=u200a1.67, 95%CI: 1.18–2.36) and false-negatives (RRRu200a=u200a1.58, 95%CI: 1.00–2.49). Conclusion The role of womens characteristics differs among interval cancer subtypes. This information could be useful to improve effectiveness of breast cancer screening programmes and to better classify subgroups of women with different risks of developing cancer.

Risk of Breast Cancer in Women with False-Positive Results according to Mammographic Features

Purpose To assess the risk of breast cancer in women with false-positive screening results according to radiologic classification of mammographic features. Materials and Methods Review board approval was obtained, with waiver of informed consent. This retrospective cohort study included 521 200 women aged 50-69 years who underwent screening as part of the Spanish Breast Cancer Screening Program between 1994 and 2010 and who were observed until December 2012. Cox proportional hazards regression analysis was used to estimate the age-adjusted hazard ratio (HR) of breast cancer and the 95% confidence interval (CI) in women with false-positive mammograms as compared with women with negative mammograms. Separate models were adjusted for screen-detected and interval cancers and for screen-film and digital mammography. Time without a breast cancer diagnosis was plotted by using Kaplan-Meier curves. Results When compared with women with negative mammograms, the age-adjusted HR of cancer in women with false-positive results was 1.84 (95% CI: 1.73, 1.95; P < .001). The risk was higher in women who had calcifications, whether they were (HR, 2.73; 95% CI: 2.28, 3.28; P < .001) or were not (HR, 2.24; 95% CI: 2.02, 2.48; P < .001) associated with masses. Women in whom mammographic features showed changes in subsequent false-positive results were those who had the highest risk (HR, 9.13; 95% CI: 8.28, 10.07; P < .001). Conclusion Women with false-positive results had an increased risk of breast cancer, particularly women who had calcifications at mammography. Women who had more than one examination with false-positive findings and in whom the mammographic features changed over time had a highly increased risk of breast cancer. Previous mammographic features might yield useful information for further risk-prediction models and personalized follow-up screening protocols. (©) RSNA, 2016 Online supplemental material is available for this article.

Prevalence of persistent pain after breast cancer treatment by detection mode among participants in population-based screening programs.

BackgroundTo date, the study of the risks and benefits of breast cancer screening has not included the onset of persistent pain after breast cancer treatment within the context of population-based screening programs. Our purpose was to investigate the prevalence of persistent pain and associated factors in women diagnosed with breast cancer (screening or interval) in the context of a population-based breast cancer screening program in Spain.MethodsA total of 1,057 women participating in a population-based breast cancer screening program were diagnosed with breast cancer between 2000 and 2008. The women were treated surgically and followed-up to 2013. The risk of developing persistent pain was estimated through multivariate logistic regression analysis.ResultsBreast cancer was detected during routine screening in 732 women (69.3xa0%) and emerged as an interval cancer between two screening rounds in 325 (30.7xa0%). Persistent pain was present in 118 women (11.3xa0%). Women diagnosed through routine screening reported a higher prevalence of persistent pain (12.9xa0%) than those with interval cancers (7.8xa0%)(Pu2009<u20090.05). Multivariate logistic regression analysis identified two other variables associated with persistent pain: having a Charlson indexu2009>u2009=2 (Odds Ratio [OR]: 4.5 95xa0% Confidence Interval [CI]: 2.1-9.5) versus no comorbidities, and having undergone an axillary lymph node dissection (OR: 2.0 95xa0% CI: 1.0-4.0) versus sentinel lymph node biopsy.ConclusionsThe prevalence of persistent pain was relatively low. The detection mode was not related to the onset of persistent pain. The factors associated with persistent pain were a Charlson indexu2009>u2009=2 and the performance of axillary lymph node dissection. Women treated for breast cancer are at risk for developing persistent pain regardless of the detection mode, especially those with comorbidities and those who have undergone axillary lymph node dissection.

Clinical and radiological features of breast tumors according to history of false-positive results in mammography screening.

BACKGROUNDnWomen with a false-positive result after a screening mammogram have an increased risk of cancer detection in subsequent participations, especially after assessments involving cytology or biopsy. We aimed to compare womens personal characteristics, tumoral features and the radiological appearance of cancers with and without a previous false-positive result generated by additional imaging or invasive procedures.nnnMETHODSnFrom 1996 to 2007, 111,098 women aged 45-69 years participated in four population-based breast cancer screening programs in Spain, and 1281 cancers were detected. We included all cancers detected in subsequent screenings (n=703) and explored the occurrence of previous false-positive results. We identified false-positives requiring additional imaging or invasive procedures. Differences on tumoral features (invasiveness, tumor size, and lymph node status) and radiological appearance were assessed by Chi-square test, and agreement between the location of cancer and prior suspicious by Cohens kappa coefficient. A multivariate analysis was preformed to evaluate the effect of previous screening results and age on the odds of presenting an in situ carcinoma.nnnRESULTSnAmong the 703 cancers detected in subsequent screenings, 148 women (21.1%) had a previous false-positive result. Of these, 105 were by additional imaging and 43 by invasive procedures. Women with prior false-positive result requiring invasive assessment, compared to women with negative tests, and women with prior false-positive requiring additional imaging, had a higher proportion of in situ carcinomas (31.7%, 15.3%, 12.9%, respectively; p=0.014) and microcalcifications (37.2%, 20.2%, 9.5%, respectively; p=0.003). The proportion of in situ carcinomas was even higher in women over 60 years (39.2%, 12.5%, 13.0%, respectively; p=0.001). Ipsilateral cancer was observed in 65.7% of cases with prior cytology or biopsy (k=0.479; 95%CI: 0.330-0.794).nnnCONCLUSIONnA large number of in situ malignancies and calcification patterns were found among women with prior false-positive result in mammography screening requiring cytology or biopsies, suggesting progression from a previously benign lesion.

Biomarkers expression in benign breast diseases and risk of subsequent breast cancer: a case–control study

Women with benign breast diseases (BBD) have a high risk of breast cancer. However, no biomarkers have been clearly established to predict cancer in these women. Our aim was to explore whether estrogen receptor (ER), progesterone receptor (PR), and Ki67 expression stratify risk of breast cancer in screened women with BBD. We conducted a nested case–control study. Women with breast cancer and prior BBDs (86 cases) were matched to women with prior BBDs who were free from breast cancer (172 controls). The matching factors were age at BBD diagnosis, type of BBD, and follow‐up time since BBD diagnosis. ER, PR, and Ki67 expression were obtained from BBDs’ specimens. Conditional logistic regression was used to estimate odds ratios (ORs), and 95% confidence intervals (CIs) of breast cancer risk according to ER, PR, and Ki67 expression. Women with >90% of ER expression had a higher risk of breast cancer (OR = 2.63; 95% CI: 1.26–5.51) than women with ≤70% of ER expression. Similarly, women with >80% of PR expression had a higher risk of breast cancer (OR = 2.22; 95% CI: 1.15–4.27) than women with ≤40% of PR expression. Women with proliferative disease and ≥1% of Ki67 expression had a nonsignificantly increased risk of breast cancer (OR = 1.16; 95% CI: 0.46–2.90) than women with <1% of Ki67 expression. A high expression of ER and PR in BBD is associated with an increased risk of subsequent breast cancer. In proliferative disease, high Ki67 expression may also have an increased risk. This information is helpful to better characterize BBD and is one more step toward personalizing the clinical management of these women.

Cumulative risk of breast cancer screening outcomes according to the presence of previous benign breast disease and family history of breast cancer: supporting personalised screening

Background:Our aim was to assess the cumulative risk of false-positive screening results, screen-detected cancer, and interval breast cancer in mammography screening among women with and without a previous benign breast disease and a family history of breast cancer.Methods:The cohort included 42u2009928 women first screened at the age of 50–51 years at three areas of the Spanish Screening Programme (Girona, and two areas in Barcelona) between 1996 and 2011, and followed up until December 2012. We used discrete-time survival models to estimate the cumulative risk of each screening outcome over 10 biennial screening exams.Results:The cumulative risk of false-positive results, screen-detected breast cancer, and interval cancer was 36.6, 5.3, and 1.4 for women with a previous benign breast disease, 24.1, 6.8, and 1.6% for women with a family history of breast cancer, 37.9, 9.0, and 3.2%; for women with both a previous benign breast disease and a family history, and 23.1, 3.2, and 0.9% for women without either of these antecedents, respectively.Conclusions:Women with a benign breast disease or a family history of breast cancer had an increased cumulative risk of favourable and unfavourable screening outcomes than women without these characteristics. A family history of breast cancer did not increase the cumulative risk of false-positive results. Identifying different risk profiles among screening participants provides useful information to stratify women according to their individualised risk when personalised screening strategies are discussed.

Survival and disease-free survival by breast density and phenotype in interval breast cancers

Background: We aimed to evaluate survival and disease-free survival in different subtypes of interval cancers by breast density, taking into account clinical and biological characteristics. Methods: We included 374 invasive breast tumors (195 screen-detected cancers; 179 interval cancers, classified into true interval, false-negatives, occult tumors and minimal-sign cancers) diagnosed in women ages 50–69 years undergoing biennial screening from 2000–2009, followed up to 2014. Breast density was categorized into non-dense (<25% dense tissue) and mixed dense breasts (≥25%). Survival curves were generated by the Kaplan–Meier method and compared by the log-rank test. Cox proportional hazard regression models were computed to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) for death and recurrences by comparing women with interval and true interval cancers versus women with screen-detected cancers, controlling for tumor and patient characteristics. All analyses were stratified by breast density. Results: Interval cancers were detected in younger women, at more advanced stages, in denser breasts and showed a higher proportion of triple-negative cancers, especially among true interval cancers. Women with interval cancer and non-dense breasts had an aHR for death of 3.40 (95% CI, 0.92–12.62). Women with true interval cancers detected in non-dense breasts had the highest adjusted risk of death (aHR, 6.55; 95% CI, 1.37–31.39). Conclusions: Women with true interval cancer in non-dense breasts had a higher risk of death than women with screen-detected cancers. Impact: These results support the advisability of routinely collecting information on breast density, both for further tailoring of screening strategies and as a prognostic factor for diagnosed breast cancers. Cancer Epidemiol Biomarkers Prev; 27(8); 908–16. ©2018 AACR.