Impact of mammographic screening and advanced cancer definition on the percentage of advanced-stage cancers in a steady-state breast screening programme in the Netherlands.

BACKGROUND: To estimate the percentages of advanced-stage breast cancers (BCs) detected during the course of a steady-state screening programme when using different definitions of advanced BC. METHODS: Data of women aged 49-74 years, diagnosed with BC in 2006-2015, were selected from the Netherlands Cancer Registry and linked to the screening registry. BCs were classified as screen-detected, interval or non-screened. Three definitions of advanced BC were used for comparison: TNM stage (III-IV), NM stage (N+ and/or M+) and T size (invasive tumour ≥15 mm). Analyses were performed assuming a 10% overdiagnosis rate. In sensitivity analyses, this assumption varied from 0 to 30%. RESULTS: We included 46,734 screen-detected, 17,362 interval and 24,189 non-screened BCs. By TNM stage, 4.9% of screen-detected BCs were advanced, compared with 19.4% and 22.8% of interval and non-screened BCs, respectively (p < 0.001). Applying the other definitions led to higher percentages of advanced BC being detected. Depending on the definition interval, non-screened BCs had a 2-5-times risk of being advanced. CONCLUSION: Irrespective of the definition, screen-detected BCs were less frequently in the advanced stage. These findings provide evidence of a stage shift to early detection and support the potential of mammographic screening to reduce treatment-related burdens and the mortality associated with BC.

Is the incidence of advanced-stage breast cancer affected by whether women attend a steady-state screening program?

In this cross-sectional population-based study, we assessed the incidence of advanced breast cancer based on screening attendance. Women from the Netherlands Cancer Registry were included if aged ≥49 years and diagnosed with breast cancer between 2006 and 2011, and data were linked with the screening program. Cancers were defined as screen-related (diagnosed <24 months after screening) or nonscreened (all other breast cancers). Two cut-offs were used to define advanced breast cancer: TNM-stage (III-IV vs 0-I-II) and T-stage alone (≥15 mm vs <15 mm or DCIS). The incidence rates were adjusted for age and logistic regression was used to compare groups. Of the 72,612 included women diagnosed with breast cancer, 44,246 (61%) had screen-related breast cancer. By TNM stage, advanced cancer was almost three times as likely to be at an advanced TNM stage in the nonscreened group compared with the screen-related group (38 and 94 per 100,000, respectively; OR: 2.86, 95%CI: 2.72-3.00). By T-stage, the incidence of advanced cancer was higher overall, and in nonscreened women was significantly higher than in screened women (210 and 169 per 100,000; OR: 1.85, 95%CI: 1.78-1.93). Data on actual screening attendance showed that the incidence of advanced breast cancer was significantly higher in nonscreened women than in screened women, supporting the expectation that screening would cause a stage shift to early detection. Despite critical evaluations of breast cancer screening programs, our data show that breast cancer screening is a valuable tool that can reduce the disease burden in women.

Influence of breast compression pressure on the performance of population-based mammography screening.

BACKGROUND: In mammography, breast compression is applied to reduce the thickness of the breast. While it is widely accepted that firm breast compression is needed to ensure acceptable image quality, guidelines remain vague about how much compression should be applied during mammogram acquisition. A quantitative parameter indicating the desirable amount of compression is not available. Consequently, little is known about the relationship between the amount of breast compression and breast cancer detectability. The purpose of this study is to determine the effect of breast compression pressure in mammography on breast cancer screening outcomes. METHODS: We used digital image analysis methods to determine breast volume, percent dense volume, and pressure from 132,776 examinations of 57,179 women participating in the Dutch population-based biennial breast cancer screening program. Pressure was estimated by dividing the compression force by the area of the contact surface between breast and compression paddle. The data was subdivided into quintiles of pressure and the number of screen-detected cancers, interval cancers, false positives, and true negatives were determined for each group. Generalized estimating equations were used to account for correlation between examinations of the same woman and for the effect of breast density and volume when estimating sensitivity, specificity, and other performance measures. Sensitivity was computed using interval cancers occurring between two screening rounds and using interval cancers within 12 months after screening. Pair-wise testing for significant differences was performed. RESULTS: Percent dense volume increased with increasing pressure, while breast volume decreased. Sensitivity in quintiles with increasing pressure was 82.0%, 77.1%, 79.8%, 71.1%, and 70.8%. Sensitivity based on interval cancers within 12 months was significantly lower in the highest pressure quintile compared to the third (84.3% vs 93.9%, p = 0.034). Specificity was lower in the lowest pressure quintile (98.0%) compared to the second, third, and fourth group (98.5%, p < 0.005). Specificity of the fifth quintile was 98.4%. CONCLUSION: Results suggest that if too much pressure is applied during mammography this may reduce sensitivity. In contrast, if pressure is low this may decrease specificity.

The effect of population-based mammography screening in Dutch municipalities on breast cancer mortality: 20 years of follow-up.

Long-term follow-up data on the effects of screening are scarce, and debate exists on the relative contribution of screening versus treatment to breast cancer mortality reduction. Our aim was therefore to assess the long-term effect of screening by age and time of implementation. We obtained data on 69,630 breast cancer deaths between 1980 and 2010 by municipality (N = 431) and age of death (40-79) in the Netherlands. Breast cancer mortality trends were analyzed by defining the municipality-specific calendar year of introduction of screening as Year 0. Additionally, log-linear Poisson regression was used to estimate the turning point in the trend after Year 0, per municipality, and the annual percentage change (APC) before and after this point. Twenty years after introduction of screening breast cancer mortality was reduced by 30% in women aged 55-74 and by 34% in women aged 75-79, compared to Year 0. A similar and significant decrease was present in municipalities that started early (1987-1992) and late (1995-1997) with screening, despite the difference in availability of effective adjuvant treatment. In the age groups 55-74 and 75-79, the turning point in the trend in breast cancer mortality was estimated in Years 2 and 6 after the introduction of screening, respectively, after which mortality decreased significantly by 1.9% and 2.6% annually. These findings show that the implementation of mammography screening in Dutch municipalities is associated with a significant decline in breast cancer mortality in women aged 55-79, irrespective of time of implementation.

Towards personalized screening: Cumulative risk of breast cancer screening outcomes in women with and without a first-degree relative with a history of breast cancer.

Several reviews have estimated the balance of benefits and harms of mammographic screening in the general population. The balance may, however, differ between individuals with and without family history. Therefore, our aim is to assess the cumulative risk of screening outcomes; screen-detected breast cancer, interval cancer, and false-positive results, in women screenees aged 50-75 and 40-75, with and without a first-degree relative with a history of breast cancer at the start of screening. Data on screening attendance, recall and breast cancer detection were collected for each woman living in Nijmegen (The Netherlands) since 1975. We used a discrete time survival model to calculate the cumulative probability of each major screening outcome over 19 screening rounds. Women with a family history of breast cancer had a higher risk of all screening outcomes. For women screened from age 50-75, the cumulative risk of screen-detected breast cancer, interval cancer and false-positive results were 9.0, 4.4 and 11.1% for women with a family history and 6.3, 2.7 and 7.3% for women without a family history, respectively. The results for women 40-75 followed the same pattern for women screened 50-75 for cancer outcomes, but were almost doubled for false-positive results. To conclude, women with a first-degree relative with a history of breast cancer are more likely to experience benefits and harms of screening than women without a family history. To complete the balance and provide risk-based screening recommendations, the breast cancer mortality reduction and overdiagnosis should be estimated for family history subgroups.

Mammographic positioning quality of newly trained versus experienced radiographers in the Dutch breast cancer screening programme.

PURPOSE: Our purpose was to compare mammographic positioning quality of new (NR) versus experienced screening radiographers (ER) in the Netherlands. METHODS AND MATERIALS: Before starting to work in breast screening, NR must complete an education programme including a theoretical course (four days), practical training (six weeks), and a portfolio-review of 50 mammographic screening examinations performed by the radiographer. Furthermore, Dutch screening has an extensive system of quality assurance, including an audit-review of positioning quality of mammograms by ER. We analysed 13,520 portfolio views (NR) and 14,896 audit views (ER) based on pre-specified criteria, e.g., depiction of inframammary angle. RESULTS: Overall positioning was more adequate for NR than ER (CC views: 97% versus 86%, p = 0.00; MLO views: 92% versus 84%, p = 0.00). NR scored better for most of the CC-criteria and showed, for instance, less folds (inadequate: 10% versus 16%, p = 0.00). In contrast, NR encountered more difficulties for MLO views in, for example, depiction of infra-mammary angle (inadequate: 38% versus 34%, p = 0.00). Overall, mammograms from NR were more often considered adequate, because of less severe errors. CONCLUSION: NR perform better than ER in overall positioning technique. These results stress the need for continuous monitoring and training in breast screening programmes to keep positioning skills up to date. KEY POINTS: • We evaluated positioning quality of new and experienced Dutch screening radiographers. • New radiographers outperform their experienced colleagues in mammographic positioning quality. • New radiographers make less severe errors compared to experienced colleagues. • There is a need for a continuous individual monitoring and feedback system.

Discrepant screening mammography assessments at blinded and non-blinded double reading: impact of arbitration by a third reader on screening outcome.

OBJECTIVES: To determine the value of adding a third reader for arbitration of discrepant screening mammography assessments. METHODS: We included a consecutive series of 84,927 digital screening mammograms, double read in a blinded or non-blinded fashion. Arbitration was retrospectively performed by a third screening radiologist. Two years' follow-up was performed. RESULTS: Discrepant readings comprised 57.2% (830/1452) and 29.1% (346/1188) of recalls at blinded and non-blinded double readings, respectively. At blinded double reading, arbitration would have decreased recall rate (3.4 to 2.2%, p < 0.001) and programme sensitivity (83.2 to 76.0%, p = 0.013), would not have influenced the cancer detection rate (CDR; 7.5 to 6.8 per 1,000 screens, p = 0.258) and would have increased the positive predictive value of recall (PPV; 22.3 to 31.2%, p < 0.001). At non-blinded double reading, arbitration would have decreased recall rate (2.8 to 2.3%, p < 0.001) and increased PPV (23.2 to 27.5%, p = 0.021), but would not have affected CDR (6.6 to 6.3 per 1,000 screens, p = 0.604) and programme sensitivity (76.0 to 72.7%, p = 0.308). CONCLUSION: Arbitration of discrepant screening mammography assessments is a good tool to improve recall rate and PPV, but is not desirable as it reduces the programme sensitivity at blinded double reading. KEY POINTS: • Blinded double reading results in higher programme sensitivity than non-blinded reading. • Discrepant readings occur more often at blinded compared to non-blinded reading. • Arbitration of discrepant readings reduces the recall rate and PPV. • Arbitration would reduce the programme sensitivity at blinded double reading.

Value of audits in breast cancer screening quality assurance programmes.

OBJECTIVES: Our aim was to retrospectively evaluate the results of all audits performed in the past and to assess their value in the quality assurance of the Dutch breast cancer screening programme. METHODS: The audit team of the Dutch Reference Centre for Screening (LRCB) conducts triennial audits of all 17 reading units. During audits, screening outcomes like recall rates and detection rates are assessed and a radiological review is performed. This study investigates and compares the results of four audit series: 1996-2000, 2001-2005, 2003-2007 and 2010-2013. RESULTS: The analysis shows increased recall rates (from 0.66%, 1.07%, 1.22% to 1.58%), increased detection rates (from 3.3, 4.5, 4.8 to 5.4 per 1000) and increased sensitivity (from 64.5%, 68.7%, 70.5% to 71.6%), over the four audit series. The percentage of 'missed cancers' among interval cancers and advanced screen-detected cancers did not change (p = 0.4). CONCLUSIONS: Our audits not only provide an opportunity for assessing screening outcomes, but also provide moments of self-reflection with peers. For radiologists, an accurate understanding of their performance is essential to identify points of improvement. We therefore recommend a radiological review of screening examinations and immediate feedback as part of an audit. KEY POINTS: • Radiological review and immediate feedback are recommended as part of an audit. • For breast screening radiologists, audits provide moments of self-reflection with peers. • Radiological review of screening examinations provides insights in recall behaviour. • Accurate understanding of radiologists' performance is essential to identify points of improvement.

Comparison of a flexible versus a rigid breast compression paddle: pain experience, projected breast area, radiation dose and technical image quality.

PURPOSE: To compare pain, projected breast area, radiation dose and image quality between flexible (FP) and rigid (RP) breast compression paddles. METHODS: The study was conducted in a Dutch mammographic screening unit (288 women). To compare both paddles one additional image with RP was made, consisting of either a mediolateral-oblique (MLO) or craniocaudal-view (CC). Pain experience was scored using the Numeric Rating Scale (NRS). Projected breast area was estimated using computer software. Radiation dose was estimated using the model by Dance. Image quality was reviewed by three radiologists and three radiographers. RESULTS: There was no difference in pain experience between both paddles (mean difference NRS: 0.08 ± 0.08, p = 0.32). Mean radiation dose was 4.5 % lower with FP (0.09 ± 0.01 p = 0.00). On MLO-images, the projected breast area was 0.79 % larger with FP. Paired evaluation of image quality indicated that FP removed fibroglandular tissue from the image area and reduced contrast in the clinically relevant retroglandular area at chest wall side. CONCLUSIONS: Although FP performed slightly better in the projected breast area, it moved breast tissue from the image area at chest wall side. RP showed better contrast, especially in the retroglandular area. We therefore recommend the use of RP for standard MLO and CC views.

Geographic variation in volumetric breast density between screening regions in the Netherlands.

OBJECTIVES: Differences in breast density between populations may explain part of the variation in regional breast cancer screening performance. This study aimed to determine whether regional differences in breast density distribution are present in the Dutch screening population. METHODS: As part of the DENSE trial, mammographic density was measured using a fully-automated volumetric method. The regions in our study were based on the geographic coverage of 14 reading units representing a large part of the Netherlands. General linear models were used. RESULTS: Four hundred eighty-five thousand and twenty-one screening participants with a median age of 60 years were included (2013-2014). The proportion of women with heterogeneously or extremely dense breasts ranged from 32.5% to 45.7% between regions. Mean percent dense volume varied between 6.51% (95% confidence interval [CI]: 6.46-6.55) and 7.68% (95% CI: 7.66-7.71). Age differences could not explain the variation. Socio-economic status (SES) was positively associated with volumetric density in all analyses (low SES: 6.95% vs. high SES: 7.63%; p trend < 0.0001), whereas a potential association between urbanisation and breast density only became apparent after SES adjustment. CONCLUSION: There appears to be geographic variation in mammographic density in the Netherlands, emphasizing the importance of including breast density as parameter in the evaluation of screening performance. KEY POINTS: • Mammographic density may affect regional breast cancer screening performance. • Volumetric breast density varies across screening areas. • SES is positively associated with breast density. • Implications of volumetric breast density differences need to be studied further.

Pain-preventing strategies in mammography: an observational study of simultaneously recorded pain and breast mechanics throughout the entire breast compression cycle.

BACKGROUND: Many women consider mammography painful. Existing studies on pain-preventing strategies only mention pain scores reported before and after breast compression. Studying the pain dynamics during the entire compression cycle may provide new insights for effective pain-preventing strategies. METHODS: This observational study included 117 women who consented to use a custom turning knob to indicate their pain experience during standard mammographic breast compressions in the Academic Medical Center in Amsterdam, The Netherlands. The breast thickness, compression force, contact area, contact pressure and pain experience were recorded continuously. Breast volume was calculated retrospectively from the mammograms. We visualized the progression of pain in relation to breast mechanics for five groups of breast volumes and we performed multivariable regressions to identify factors that significantly predict pain experience. RESULTS: Breast compressions consisted of a deformation phase for flattening, and a clamping phase for immobilization. The clamping phase lasted 12.8 ± 3.6 seconds (average ± standard deviation), 1.7 times longer than the 7.5 ± 2.6 seconds deformation phase. During the clamping phase, the average pain score increased from 4.75 to 5.88 (+24 %) on a 0 - 10 Numerical Rating Scale (NRS), and the proportion of women who reached severe pain (NRS ≥ 7) increased from 23 % to 50 % (more than doubled). Moderate pain (NRS ≥ 4) was reported up to four days after the mammogram. Multivariable analysis showed that pain recollection of the previous mammogram and breast pain before the compression, are significant predictors for pain. Women with smallest breasts experienced most pain: They received highest contact pressures (force divided by contact area) and the pressure increased at the highest rate. CONCLUSION: We suggest further research on two pain-preventing strategies: 1) using a personalized compression protocol by applying to all breasts the same target pressure at the same, slow rate, and 2) shortening the phase during which the breast is clamped.

Breast cancer diagnosis and death in the Netherlands: a changing burden.

BACKGROUND: Lifetime risks are often used in communications on cancer to the general public. The most-cited estimate for breast cancer risk (1 in 8 women), however, appears to be outdated. Here we describe the breast cancer burden in the Netherlands over time by means of lifetime and age-conditional risks. The aim is to identify changes in absolute risk of primary breast cancer diagnosis and death. METHODS: Data on breast cancer incidence, mortality and size of the female population were retrieved from the Netherlands Cancer Registry and Statistics Netherlands. Lifetime and age-conditional risks were calculated for 1990, 2000 and 2010 using the life-table method (DevCan software). RESULTS: The lifetime risk of developing breast cancer (ductal carcinoma in situ and invasive) in 1990, 2000 and 2010 was estimated at 10.8 (1 in 9.3 women), 13.5 (1 in 7.4) and 15.2% (1 in 6.6), respectively. Most women were still diagnosed after the age of 50, with the highest risk between 60 and 70 years in 2010. The lifetime risk of breast cancer death was 3.8% (1 in 27) in 2010, which is lower than in 1990 (4.5%; 1 in 22) and 2000 (4.2%; 1 in 24). CONCLUSION: Breast cancer risk has increased to 1 in 6.6 women being diagnosed during their lifetime (invasive cancer only: 1 in 7.4), whereas risk of breast cancer death has decreased from 1 in 22 to 1 in 27 women. To keep cancer management and prevention up-to-date, it remains important to closely monitor the ever-changing breast cancer burden.

Re-attendance at biennial screening mammography following a repeated false positive recall.

We determined the re-attendance rate at screening mammography after a single or a repeated false positive recall and we assessed the effects of transition from screen-film mammography (SFM) to full-field digital mammography (FFDM) on screening outcome in women recalled twice for the same mammographic abnormality. The study population consisted of a consecutive series of 302,912 SFM and 90,288 FFDM screens. During a 2 years follow-up period (until the next biennial screen), we collected the breast imaging reports and biopsy results of all recalled women. Re-attendance at biennial screening mammography was 93.2 % (95 % CI 93.1-93.3 %) for women with a negative screen (i.e., no recall at screening mammography), 65.4 % (95 % CI 64.0-66.8 %) for women recalled once, 56.7 % (95 % CI 47.1-66.4 %) for women recalled twice but for different lesions and 44.3 % (95 % CI 31.4-57.1 %) for women recalled twice for the same lesion. FFDM recalls comprised a significantly larger proportion of women who had been recalled twice for the same lesion (1.9 % of recalls (52 women) at FFDM vs. 0.9 % of recalls (37 women) at SFM, P < 0.001) and the positive predictive value of these recalls (PPV) was significantly lower at FFDM (15.4 vs. 35.1 %, P = 0.03). At review, 20 of 52 women (39.5 %, all with benign outcome) would not have been recalled for a second time at FFDM if the previous hard copy SFM screen had been available for comparison. We conclude that a repeated false positive recall for the same lesion significantly lowered the probability of screening re-attendance. The first round of FFDM significantly increased the proportion of women recalled twice for the same lesion, with a significantly lower PPV of these lesions. Almost 40 % of repeatedly recalled women would not have been recalled the second time if the previous hard copy SFM screen had been available for comparison at the time of FFDM.

Computer-aided detection of masses at mammography: interactive decision support versus prompts.

PURPOSE: To compare effectiveness of an interactive computer-aided detection (CAD) system, in which CAD marks and their associated suspiciousness scores remain hidden unless their location is queried by the reader, with the effect of traditional CAD prompts used in current clinical practice for the detection of malignant masses on full-field digital mammograms. MATERIALS AND METHODS: The requirement for institutional review board approval was waived for this retrospective observer study. Nine certified screening radiologists and three residents who were trained in breast imaging read 200 studies (63 studies containing at least one screen-detected mass, 17 false-negative studies, 20 false-positive studies, and 100 normal studies) twice, once with CAD prompts and once with interactive CAD. Localized findings were reported and scored by the readers. In the prompted mode, findings were recorded before and after activation of CAD. The partial area under the location receiver operating characteristic (ROC) curve for an interval of low false-positive fractions typical for screening, from 0 to 0.2, was computed for each reader and each mode. Differences in reader performance were analyzed by using software. RESULTS: The average partial area under the location ROC curve with unaided reading was 0.57, and it increased to 0.62 with interactive CAD, while it remained unaffected by prompts. The difference in reader performance for unaided reading versus interactive CAD was statistically significant (P = .009). CONCLUSION: When used as decision support, interactive use of CAD for malignant masses on mammograms may be more effective than the current use of CAD, which is aimed at the prevention of perceptual oversights.

Comparison of digital screening mammography and screen-film mammography in the early detection of clinically relevant cancers: a multicenter study.

PURPOSE: To compare screen-film mammography with digital mammography in a breast cancer screening program, with a focus on the clinical relevance of detected cancers. MATERIALS AND METHODS: The study was approved by the regional medical ethics review board. Informed consent was not required. Before the nationwide transition to digital mammography in the Dutch biennial screening program, the performance of digital mammography was studied in three screening regions. For initial screening examinations, mediolateral oblique and craniocaudal views were obtained of each breast. In subsequent examinations, the mediolateral oblique view was standard. A craniocaudal view was added if indicated. Screening outcomes obtained with screen-film mammography and digital mammography, including radiologic and pathologic characteristics, were compared for initial and subsequent examinations. RESULTS: A total of 1,198,493 screening examinations were performed between 2003 and 2007. Recall was indicated in 18 896 cases (screen-film mammography: 2.6% at initial examinations, 1.3% at subsequent examinations; digital mammography: 4.4% at initial examinations, 2.1% at subsequent examinations; P < .001 for both). Breast cancer was diagnosed in 6410 women (detection rate per 1000 women with screen-film mammography: 5.6 at initial examinations, 5.2 at subsequent examinations; detection rate per 1000 women with digital mammography: 6.8 at initial examinations, 6.1 at subsequent examinations; P = .02 and P < .001, respectively). Digital mammography depicted significantly more ductal carcinoma in situ (DCIS) lesions, irrespective of screening round. Invasive carcinoma was detected significantly more often in subsequent examinations, particularly when associated with microcalcifications (P = .047). The distribution of the histopathologic differentiation grades for DCIS and invasive carcinoma were similar with both modalities. However, with digital mammography more high-grade DCIS lesions were detected at subsequent examinations (P = .013). CONCLUSION: In a population-based breast screening program, the performance of digital mammography in the detection of DCIS and invasive carcinoma was substantially better than that of screen-film mammography. There is no sign of an increase in detection of low-grade DCIS lesions-indicative of possible overdiagnosis-with digital breast cancer screening. Rather, digital mammography appears to add to the detection of high-grade DCIS.

Increase in perceived case suspiciousness due to local contrast optimisation in digital screening mammography.

OBJECTIVES: To determine the influence of local contrast optimisation on diagnostic accuracy and perceived suspiciousness of digital screening mammograms. METHODS: Data were collected from a screening region in the Netherlands and consisted of 263 digital screening cases (153 recalled,110 normal). Each case was available twice, once processed with a tissue equalisation (TE) algorithm and once with local contrast optimisation (PV). All cases had digitised previous mammograms. For both algorithms, the probability of malignancy of each finding was scored independently by six screening radiologists. Perceived case suspiciousness was defined as the highest probability of malignancy of all findings of a radiologist within a case. Differences in diagnostic accuracy of the processing algorithms were analysed by comparing the areas under the receiver operating characteristic curves (A(z)). Differences in perceived case suspiciousness were analysed using sign tests. RESULTS: There was no significant difference in A(z) (TE: 0.909, PV 0.917, P = 0.46). For all radiologists, perceived case suspiciousness using PV was higher than using TE more often than vice versa (ratio: 1.14-2.12). This was significant (P <0.0083) for four radiologists. CONCLUSIONS: Optimisation of local contrast by image processing may increase perceived case suspiciousness, while diagnostic accuracy may remain similar. KEY POINTS: Variations among different image processing algorithms for digital screening mammography are large. Current algorithms still aim for optimal local contrast with a low dynamic range. Although optimisation of contrast may increase sensitivity, diagnostic accuracy is probably unchanged. Increased local contrast may render both normal and abnormal structures more conspicuous.

Dutch digital breast cancer screening: implications for breast cancer care.

BACKGROUND: In comparison to other European population-based breast cancer screening programmes, the Dutch programme has a low referral rate, similar breast cancer detection and a high breast cancer mortality reduction. The referral rate in the Netherlands has increased over time and is expected to rise further, mainly following nationwide introduction of digital mammography, completed in 2010. This study explores the consequences of the introduction of digital mammography on the balance between referral rate, detection of breast cancer, diagnostic work-up and associated costs. METHODS: Detailed information on diagnostic work-up (chart review) was obtained from referred women (n = 988) in 2000-06 (100% analogue mammography) and 2007 (75% digital mammography) in Nijmegen, the Netherlands. RESULTS: The average referral rate increased from 15 (2000-06) to 34 (2007) per 1000 women screened. The number of breast cancers detected increased from 5.5 to 7.8 per 1000 screens, whereas the positive predictive value fell from 37% to 23%. A sharp rise in diagnostic work-up procedures and total diagnostic costs was seen. On the other hand, costs of a single work-up slightly decreased, as less surgical biopsies were performed. CONCLUSION: Our study shows that a low referral rate in combination with the introduction of digital mammography affects the balance between referral rate and detection rate and can substantially influence breast cancer care and associated costs. Referral rates in the Netherlands are now more comparable to other countries. This effect is therefore of value in countries where implementation of digital breast cancer screening has just started or is still under discussion.

Breast cancer among women over 75 years: an important public health problem?

Women aged >75 years are not invited for mammographic screening; if diagnosed with breast cancer, due to their anticipated short-life expectancy, they are expected to die of other causes. To describe the breast cancer health problem in women aged >75 years, we estimated breast cancer incidence in this age group and the risk of breast cancer death in patients diagnosed after 75 years of age in Nijmegen, the Netherlands. Our findings demonstrate that in this age group, 3.3% of the women will be diagnosed with breast cancer, and that one in three of these incident cases die of this disease. These patients could have benefited from continued screening.

Aggressiveness of 'true' interval invasive ductal carcinomas of the breast in postmenopausal women.

There is debate whether interval carcinomas differ from screen-detected tumours biologically. In this study, clinico-pathological parameters and the expression of well-validated biological markers were compared between 'true' interval carcinomas and screen-detected/missed carcinomas hypothesising that 'true' interval carcinomas show a more aggressive biological behaviour. The study group consisted of 92 consecutive postmenopausal women attending the breast screening programme and presenting with an invasive ductal carcinoma. All screening mammograms were re-reviewed. Sixteen patients had a 'true' interval carcinoma. Seven carcinomas were missed at screening, but detected on re-reviewing of the screening mammogram. Radiological characteristics were assessed from diagnostic mammograms. Data on patient- and tumour characteristics and follow-up data were recorded from hospital records. Median follow-up was 61 months. Immunohistochemistry for ER, PR, Her2/neu and p53 was performed on TMA sections. Univariate and multivariate logistic regression analyses were performed. In univariate analysis, 'true' interval carcinomas were significantly larger (odd ratios (OR) 7.2, 95% CI 1.8-28.1) and less frequently ER (OR 0.3, 95% CI 0.1-0.9) and PR (OR 0.3, 95% CI 0.1-1.0) positive. In multivariate analysis, 'true' interval carcinoma was independently associated with larger tumours (OR 7.0, 95% CI 1.4-36.2). A trend toward ER negativity was found (OR 0.3, 95% CI 0.1-1.1). 'True' interval carcinomas showed a trend toward a decreased relapse-free survival (HR 1.7 95% CI 0.9-3.1). Although 'true' interval carcinomas were significantly larger than screen-detected/missed interval carcinomas, it remains challenging to observe parameters that determine this difference between 'true' interval carcinomas and screen-detected lesions.

A remarkable reduction of breast cancer deaths in screened versus unscreened women: a case-referent study.

OBJECTIVE: We designed a case-referent study to investigate the effect of mammographic screening at the individual level, looking at the association of breast cancer death with screening history. METHODS: The study population included all women aged 50-75 in the province of Limburg, the Netherlands who had been invited to the screening program from 1989 to 2006. From this population, 118 cases originated who died of breast cancer in 2004 or 2005. The screening history of these cases was collected and compared with a sample of the invited population. The breast cancer death rate in the screened relative to the unscreened women was estimated as the odds ratio (OR). This OR was adjusted for self-selection bias, the difference in baseline risk for breast cancer death between screened and unscreened women. RESULTS: Analysis of the data showed a breast cancer mortality reduction of 70% in the screened versus the unscreened women (OR = 0.30, 95% CI 0.14-0.63). The magnitude of self-selection was estimated specifically for Limburg. After correction for self-selection bias, the effect of screening increased to 76% (OR = 0.24, 95% CI 0.10-0.58). CONCLUSION: Screening resulted in a remarkable reduction in breast cancer mortality. Contrary to findings in other countries, adjustment for self-selection in Limburg had no influence on the impact of screening. Thanks to a well-organized centralized screening program, similar results are expected in other regions of the Netherlands.