The prognostic potential of mammographic growth rate of invasive breast cancer in the Nijmegen breast cancer screening cohort.

OBJECTIVES: Insight into the aggressiveness of potential breast cancers found in screening may optimize recall decisions. Specific growth rate (SGR), measured on mammograms, may provide valuable prognostic information. This study addresses the association of SGR with prognostic factors and overall survival in patients with invasive carcinoma of no special type (NST) from a screened population. METHODS: In this historic cohort study, 293 women with NST were identified from all participants in the Nijmegen screening program (2003-2007). Information on clinicopathological factors was retrieved from patient files and follow-up on vital status through municipalities. On consecutive mammograms, tumor volumes were estimated. After comparing five growth functions, SGR was calculated using the best-fitting function. Regression and multivariable survival analyses described associations between SGR and prognostic factors as well as overall survival. RESULTS: Each one standard deviation increase in SGR was associated with an increase in the Nottingham prognostic index by 0.34 [95% confidence interval (CI): 0.21-0.46]. Each one standard deviation increase in SGR increased the odds of a tumor with an unfavorable subtype (based on histologic grade and hormone receptors; odds ratio 2.14 [95% CI: 1.45-3.15]) and increased the odds of diagnosis as an interval cancer (versus screen-detected; odds ratio 1.57 [95% CI: 1.20-2.06]). After a median of 12.4 years of follow-up, 78 deaths occurred. SGR was not associated with overall survival (hazard ratio 1.12 [95% CI: 0.87-1.43]). CONCLUSIONS: SGR may indicate prognostically relevant differences in tumor aggressiveness if serial mammograms are available. A potential association with cause-specific survival could not be determined and is of interest for future research.

Method of primary breast cancer detection and the disease-free interval, adjusting for lead time.

BACKGROUND: Little is known about the impact of screen-detected breast cancer compared with clinically detected breast cancer on the disease-free interval (ie, free from locoregional recurrences, distant metastasis, contralateral breast cancer). Moreover, it is thought that most studies overestimate the beneficial effect of screening, as they do not adjust for lead time. We investigated the association between method of breast cancer detection and disease-free interval, taking lead time into account. METHODS: Women aged 50-76 years, diagnosed with breast cancer between 2005 and 2008 were selected from the Netherlands Cancer Registry. Women diagnosed in 2005 were divided into screen-detected and clinically detected cancer and had a follow-up of 10 years (2005 cohort). Women diagnosed in 2006-2008 were divided into screen-detected, interval, and nonscreen-related cancer and had a follow-up of 5 years (2006-2008 cohort). A previously published method was used to adjust for lead time. Analyses were repeated correcting for confounding variables instead of lead time. RESULTS: The 2005 cohort included 6215 women. Women with screen-detected cancer had an improved disease-free interval compared with women with clinically detected cancer (hazard ratio [HR] = 0.77, 95% confidence interval [CI] = 0.68 to 0.87). The 2006-2008 cohort included 15 176 women. Women with screen-detected or interval cancer had an improved disease-free interval compared with women with nonscreen-related cancer (HR = 0.76, 95% CI = 0.66 to 0.88; HR = 0.88, 95% CI = 0.78 to 0.99, respectively). Correcting for confounders instead of lead time did not change associations. CONCLUSION: Women with screen-detected cancer had an improved disease-free interval compared with women with a nonscreen-related or clinically detected cancer, after correction for lead time.

Long-term cause of death patterns and mode of breast cancer detection in The Netherlands, 2004-2019.

OBJECTIVE: Early detection through mammographic screening and various treatment modalities of cancer may have changed life expectancy and cause-specific mortality of breast cancer patients. We aimed to determine the long-term cause of death patterns in screening-detected patients and clinically diagnosed patients in the Netherlands compared with the general population. METHODS: Using data from the Netherlands Cancer Registry and Statistics Netherlands of around 26,000 women, aged 50-75 at diagnosis and surgically treated for invasive breast cancer in 2004-2008, we compared patients with screening-detected and clinically diagnosed cancer for major causes of death until 2020. The expected number of all-cause and cause-specific deaths was calculated using rates of the general population. RESULTS: During the follow-up period, 4310 women died. The age-standardised all-cause mortality ratio for the screening-detected cancer group was 1.41 (95% confidence interval (95% CI), 1.37-1.46). A higher mortality ratio was observed for patients with clinically detected cancer: 2.27 (95% CI, 2.19-2.34). The observed versus expected breast cancer mortality ratio in the screening-detected patient group was 8.92 (95% CI, 8.45-9.40) and 20.23 (19.38-21.09) in the clinical group. Excess mortality was found for lung cancer in both patient groups, and small elevations for circulatory and respiratory disease in the clinically detected group. CONCLUSION: Our results indicate that for the screening group no other causes of death but breast and lung cancer were prominent compared with the general population. The clinical group showed excess mortality for some other causes of death as well, suggesting a less healthy group compared with the general population.

Cumulative risks of false positive recall and screen-detected breast cancer after multiple screening examinations.

Women tend to make a decision about participation in breast cancer screening and adhere to this for future invitations. Therefore, our study aimed to provide high-quality information on cumulative risks of false-positive (FP) recall and screen-detected breast cancer over multiple screening examinations. Individual Dutch screening registry data (2005-2018) were gathered on subsequent screening examinations of 92 902 women age 49 to 51 years in 2005. Survival analyses were used to calculate cumulative risks of a FP and a true-positive (TP) result after seven examinations. Data from 66 472 women age 58 to 59 years were used to extrapolate to 11 examinations. Participation, detection and additional FP rates were calculated for women who previously received FP results compared to women with true negative (TN) results. After 7 examinations, the cumulative risk of a TP result was 3.7% and the cumulative risk of a FP result was 9.1%. After 11 examinations, this increased to 7.1% and 13.5%, respectively. Following a FP result, participation was lower (71%-81%) than following a TN result (>90%). In women with a FP result, more TP results (factor 1.59 [95% CI: 1.44-1.72]), more interval cancers (factor 1.66 [95% CI: 1.41-1.91]) and more FP results (factor 1.96 [95% CI: 1.87-2.05]) were found than in women with TN results. In conclusion, due to a low recall rate in the Netherlands, the cumulative risk of a FP recall is relatively low, while the cumulative risk of a TP result is comparable. Breast cancer diagnoses and FP results were more common in women with FP results than in women with TN results, while participation was lower.

Research in Action-Students' Perspectives on the Integration of Research Activities in Undergraduate Biomedical Curricula.

We describe and evaluate our practice-based learning approach for research in undergraduate students studying Biomedical Sciences at Radboud University Nijmegen, the Netherlands. First-year students who started their study between 2015 and 2018 actively participated in data collection and measurements, including anthropometry, electrocardiogram findings, genetic variants, and lifestyle habits. All data were entered into one anonymous database, which was used by students to analyze their research questions. In 2019, 44 of the 87 students (50%) valued active measurements better than questionnaires. Most students (strongly) agreed that they have learned about data collection and were inspired to learn more about biomedical research.

Detection and interval cancer rates during the transition from screen-film to digital mammography in population-based screening.

BACKGROUND: Between 2003 and 2010 digital mammography (DM) gradually replaced screen-film mammography (SFM) in the Dutch breast cancer screening programme (BCSP). Previous studies showed increases in detection rate (DR) after the transition to DM. However, national interval cancer rates (ICR) have not yet been reported. METHODS: We assessed programme sensitivity and specificity during the transition period to DM, analysing nationwide data on screen-detected and interval cancers. Data of 7.3 million screens in women aged 49-74, between 2004 and 2011, were linked to the Netherlands Cancer Registry to obtain data on interval cancers. Age-adjusted DRs, ICRs and recall rates (RR) per 1000 screens and programme sensitivity and specificity were calculated by year, age and screening modality. RESULTS: 41,662 screen-detected and 16,160 interval cancers were analysed. The DR significantly increased from 5.13 (95% confidence interval (CI):5.00-5.30) in 2004 to 6.34 (95% CI:6.15-6.47) in 2011, for both in situ (2004:0.73;2011:1.24) and invasive cancers (2004:4.42;2011:5.07), whereas the ICR remained stable (2004: 2.16 (95% CI2.06-2.25);2011: 2.13 (95% CI:2.04-2.22)). The RR changed significantly from 14.0 to 21.4. Programme sensitivity significantly increased, mainly between ages 49-59, from 70.0% (95% CI:68.9-71.2) to 74.4% (95% CI:73.5-75.4) whereas specificity slightly declined (2004:99.1% (95% CI:99.09-99.13);2011:98.5% (95% CI:98.45-98.50)). The overall DR was significantly higher for DM than for SFM (6.24;5.36) as was programme sensitivity (73.6%;70.1%), the ICR was similar (2.19;2.20) and specificity was significantly lower for DM (98.5%;98.9%). CONCLUSIONS: During the transition from SFM to DM, there was a significant rise in DR and a stable ICR, leading to increased programme sensitivity. Although the recall rate increased, programme specificity remained high compared to other countries. These findings indicate that the performance of DM in a nationwide screening programme is not inferior to, and may be even better, than that of SFM.

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.

Predicting the stage shift as a result of breast cancer screening in low- and middle-income countries: a proof of concept.

OBJECTIVE: To provide proof of concept for a simple model to estimate the stage shift as a result of breast cancer screening in low- and middle-income countries (LMICs). Stage shift is an essential early detection indicator and an important proxy for the performance and possible further impact of screening programmes. Our model could help LIMCs to choose appropriate control strategies. METHODS: We assessed our model concept in three steps. First, we calculated the proportional performance rates (i.e. index number Z) based on 16 screening rounds of the Nijmegen Screening Program (384,884 screened women). Second, we used linear regression to assess the association between Z and the amount of stage shift observed in the programme. Third, we hypothesized how Z could be used to estimate the stage shift as a result of breast cancer screening in LMICs. RESULTS: Stage shifts can be estimated by the proportional performance rates (Zs) using linear regression. Zs calculated for each screening round are highly associated with the observed stage shifts in the Nijmegen Screening Program (Pearson's R: 0.798, R square: 0.637). CONCLUSIONS: Our model can predict the stage shifts in the Nijmegen Screening Program, and could be applied to settings with different characteristics, although it should not be straightforwardly used to estimate the impact on mortality. Further research should investigate the extrapolation of our model to other settings. As stage shift is an essential screening performance indicator, our model could provide important information on the performance of breast cancer screening programmes that LMICs consider implementing.

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.

Mammography screening and risk of breast cancer death: a population-based case-control study.

BACKGROUND: Because the efficacy of mammography screening had been shown in randomized controlled trials, the focus has turned on its effectiveness within the daily practice. Using individual data of women invited to screening, we conducted a case-control study to assess the effectiveness of the Dutch population-based program of mammography screening. METHODS: Cases were women who died from breast cancer between 1995 and 2003 and were closely matched to five controls on year of birth, year of first invitation, and number of invitations before case's diagnosis. ORs and 95% confidence intervals (CI) for the association between attending either of three screening examinations prior to diagnosis and the risk of breast cancer death were calculated using conditional logistic regression and corrected for self-selection bias. RESULTS: We included 755 cases and 3,739 matched controls. Among the cases, 29.8% was screen-detected, 34.3% interval-detected, and 35.9% never-screened. About 29.5% of the never-screened cases had stage IV tumor compared with 5.3% of the screen-detected and 15.1% of the interval-detected cases. The OR (95% CIs), all ages (49-75 years), was 0.51 (0.40-0.66) and for the age groups 50-69, 50-75, and 70-75 years were 0.61 (0.47-0.79), 0.52 (CI 0.41-0.67), and 0.16 (0.09-0.29), respectively. CONCLUSION: The study provides evidence for a beneficial effect of early detection by mammography screening in reducing the risk of breast cancer death among women invited to and who attended the screening. IMPACT: This is the first case-control study that accurately accounts for equal screening opportunity for both cases and matched controls by number of invitations before case's diagnosis.

Effective biennial mammographic screening in women aged 40-49.

BACKGROUND: The United Kingdom is currently moving the age limit for invitation in its national breast screening programme downwards from 50 to 47. In contrast, the US Preventive Services Task Force concluded that, because of borderline statistical significance on effectiveness of mammographic screening, the current evidence is insufficient to advise screening in women aged 40-49. MATERIAL AND METHODS: We designed a case-referent study to investigate the effect of biennial mammographic screening on breast cancer mortality for women in their forties. In Nijmegen, the Netherlands, screening started in 1975. A total of 272 breast cancer deaths were identified, and 1360 referents aged 40-69 were sampled from the population invited for screening. Effectiveness was estimated by calculating the odds ratio (OR) indicating the breast cancer death rate in screened versus unscreened women. RESULTS: In women aged 40-49, the effect of screening was OR = 0.50 (95% confidence interval (CI) = 0.30-0.82). This result is similar to those aged 50-59 (OR = 0.54; 95% CI = 0.35-0.85) and 60-69 (OR = 0.65; 95% CI = 0.38-1.13). CONCLUSION: Our results add convincing evidence about the effectiveness of biennial mammographic screening in women aged 40-49.

Life expectancy of screen-detected invasive breast cancer patients compared with women invited to the Nijmegen screening program.

BACKGROUND: Screening can lead to earlier detection of breast cancer and thus to an improvement in survival. The authors studied the life expectancy of women with screen-detected invasive breast cancer (patients) compared with women invited to the breast cancer screening program in Nijmegen, the Netherlands (comparison group). METHODS: Each patient diagnosed between 1975 and 2006 was randomly age-matched with a woman invited in the same calendar year and free from breast cancer at the time of diagnosis of the patient. Survival analyses were performed to study differences in life expectancy. RESULTS: The life expectancy for 858 patients was 6 years shorter than for the comparison group. However, for 360 patients with small (<15 mm) invasive breast cancer, life expectancy was similar to that of the comparison group. In contrast, for patients detected with larger tumors (> or = 15 mm) the life expectancy was 6 to 12 years shorter, depending on tumor size. Furthermore, life expectancy was modified by screening history. For patients who had a negative screening examination 2 years before the detection of their breast cancer, the difference in life expectancy from the comparison group became smaller for the larger tumor sizes (> or = 15 mm). CONCLUSIONS: In conclusion, about 40% (360 of 858) of all women with invasive screen-detected breast cancer have the same life expectancy as women from the comparison group (reflecting the general population). For women diagnosed with larger tumors at diagnosis, life expectancy diminishes with increasing tumor size and is modified by screening history.

Impressive time-related influence of the Dutch screening programme on breast cancer incidence and mortality, 1975-2006.

The aim of this study was to assess changes in the trends in breast cancer mortality and incidence from 1975 to 2006 among Dutch women, in relation to the implementation of the national breast cancer screening programme. Screening started in 1989 for women aged 50-69 and was extended to women aged 70-75 years in 1998 (attendance rate approximately >80%). A joinpoint Poisson regression analysis was used to identify significant changes in rates over time. Breast cancer mortality rates increased until 1994 (age group 35-84), but thereafter showed a marked decline of 2.3-2.8% per annum for the age groups 55-64 and 65-74 years, respectively. For the age group of 75-84 years, a decrease started in the year 2001. In women aged 45-54, an early decline in breast cancer mortality rates was noted (1971-1980), which is ongoing from 1992. For all ages, breast cancer incidence rates showed an increase between 1989 and 1993, mainly caused by the age group 50-69, and thereafter, a moderate increase caused by age group 70-74 years. This increase can partly be explained by the introduction of screening. The results indicate an impressive decrease in breast cancer mortality in the age group invited for breast cancer screening, starting to show quite soon after implementation.

Personality factors and breast cancer risk: a 13-year follow-up.

Consistent scientific evidence on the possible relationship between psychologic variables and breast cancer development is lacking. In 1996, our group first reported on the present prospective, longitudinal study. We found a weak association between a high score on the antiemotionality scale (indicating an absence of emotional behavior or a lack of trust in one's own feelings) and the development of breast cancer. No associations were found between any of the other 10 studied personality traits and breast cancer development. However, the study had a relatively short follow-up and did not investigate interaction effects between various personality traits. Therefore, the current follow-up study was conducted with the same cohort, which included the 9705 women who attended a biennial population surveillance program for breast cancer and completed a self-report personality questionnaire between January 1, 1989, and December 31, 1990. Women who developed breast cancer during the period from May 17, 1995, through January 1, 2003, formed the case group (n = 217) and were compared with age-matched women without breast cancer who formed the control group (n = 868) with regard to personality traits and medical risk factors for breast cancer. None of the personality factors were statistically significantly associated with an increased risk of breast cancer, with or without adjusting for the medical risk factors. Also, the occurrence of a combination of various personality traits (eg, a so-called cancer-prone personality) was not related to breast cancer development.

Effect of soft-copy display supported by CAD on mammography screening performance.

Diagnostic performance and reading speed for conventional mammography film reading is compared to reading digitized mammograms on a dedicated workstation. A series of mammograms judged negative at screening and corresponding priors were collected. Half were diagnosed as cancer at the next screening, or earlier for interval cancers. The others were normal. Original films were read by fifteen experienced screening radiologists. The readers annotated potential abnormalities and estimated their likelihood of malignancy. More than 1 year later, five radiologists reread a subset of 271 cases (88 cancer cases having visible signs in retrospect and 183 normals) on a mammography workstation after film digitization. Markers from a computer-aided detection (CAD) system for microcalcifications were available to the readers. Performance was evaluated by comparison of A(z)-scores based on ROC and multiple-Reader multiple-case (MRMC) analysis, and localized receiver operating characteristic (LROC) analysis for the 271 cases. Reading speed was also determined. No significant difference in diagnostic performance was observed between conventional and soft-copy reading. Average A(z)-scores were 0.83 and 0.84 respectively. Soft-copy reading was only slightly slower than conventional reading. Using a mammography workstation including CAD for detection of microcalcifications, soft-copy reading is possible without loss of quality or efficiency.

Effect of recall rate on earlier screen detection of breast cancers based on the Dutch performance indicators.

BACKGROUND: The recall rate (i.e., the rate at which mammographically screened women are recalled for additional assessment) in the Dutch breast screening program (0.89% in 2000 for subsequent examinations) is the lowest worldwide, with possible consequences including higher rates of late-detected (i.e., "missed") interval and screen-detected cancers. To estimate the effect of changes in recall rate on earlier detection of cancers, we carried out a blinded review of interval and screen-detected cancers in the Dutch screening program. METHODS: A total of 495 sets of screen-negative mammograms (prediagnostic mammogram and the immediate previous mammogram) were collected from women participating in the biennial Dutch screening program. Of these, 250 were from control subjects, and 245 were from women who were subsequently diagnosed with breast cancer (123 interval and 122 screen-detected cancers). These mammograms were read by 15 radiologists who specialize in screening mammography and were blinded to outcome. Mean detection sensitivities for different false-positive rates were calculated using a linear mixed model. These results were used to calculate the effect of recall rate adjustment on earlier detection of cancers and numbers of false-positives. RESULTS: Increasing the recall rate to 2.0% would increase the detection rate from 4.20 per thousand to 4.52 per thousand due to the earlier detection of interval cancers. Moreover, 0.54 per thousand of the screen-detected cancers would be detected 2 years earlier (late screen-detected cancers). At recall rates of 3.0% and 4.0% the detection rate would increase to 4.58 per thousand and 4.63 per thousand, respectively, and 0.64 per thousand and 0.72 per thousand, respectively, of the screen-detected cancers would be detected 2 years earlier. For each 1.0% incremental increase in recall rate above 5.0%, the detection rate would increase by approximately 0.03 per thousand, with positive predictive values decreasing to below 10%. CONCLUSION: Breast cancer can be detected earlier by lowering the threshold for recall, especially for recall rates of 1%-4%. With further recall rate increases, cancer detection levels off with a disproportionate increase of false-positive rates.

Computer-aided detection versus independent double reading of masses on mammograms.

PURPOSE: To evaluate the use of a computer-aided detection (CAD) system (designed for mammographic mass detection) to help improve mass interpretation and to compare CAD results with independent double-reading results. MATERIALS AND METHODS: Screening mammograms from 500 cases were collected; 125 of these cases were screening-detected cancers, and 125 were interval cancers. Previously obtained screening mammograms (ie, prior mammograms) were available in all cases. All mammograms were analyzed by a CAD system, which detected mass regions and assigned a level of (cancer) suspicion to each mass. Ten experienced screening radiologists read the prior mammograms. For independent interpretation with CAD, the suspicion rating assigned to each finding by the radiologist was weighted with the CAD output at the area of the finding. CAD markers on areas that were not reported by the radiologist were not used. Independent double reading was implemented by using a rule to combine the levels of suspicion assigned to findings by two radiologists. Results were evaluated by using localized-response receiver operating characteristic analysis. RESULTS: In a total of 141 cases, there was a visible abnormality at the location of the cancer on the prior mammogram, and 115 of these were classified as mass cases. For prior mammograms that depicted masses, the mean sensitivity of the radiologists, as averaged among the false-positive rates lower than 10%, was 39.4%; this increased by 7.0% with CAD and by 10.5% with double reading. Differences among single, double, and CAD readings were statistically significant (P <.001). CONCLUSION: Although independent double reading yields the best detection performance, the presence and probability of CAD mass markers can improve mammogram interpretation.