J.D.M. Otten

Effect of mammographic breast density on breast cancer screening performance: a study in Nijmegen, the Netherlands.

STUDY OBJECTIVE: To study the implications of breast density on mammographic screening performance. DESIGN: Screening outcomes of women with dense breast patterns were compared with those of women with lucent breast patterns (dense > 25% densities, lucent < or = 25% densities); the women were screened in different periods (before/after improvement of the mammographic technique in 1982). SETTING: Nijmegen, the Netherlands, 1977-1994. PARTICIPANTS: Between 1977 and 1994, 73,525 repeat screenings were performed in 19,152 participants (aged 50-69 years) in the Nijmegen breast cancer screening programme (repeat screenings were defined as mammographic examinations that were preceded by an examination in the previous screening round). Participants were screened biennially with mammography. There were 258 screen detected and 145 interval cancers. MAIN RESULTS: Before 1982 (rounds 2-4) the predictive value of a positive screening test (PV+) was lower in women with dense breasts than in those with lucent breasts (dense 29% v lucent 52%, p = 0.003). Also, the ratio of screen detected cancers to the total number of screen detected plus interval cancers (as a proxy for sensitivity) was lower in this group (based on a one year interval: dense 63% v lucent 92%, p = 0.001 and based on a two year interval: dense 41% v lucent 68%, p = 0.002). Moreover, the survival rate was less favourable for those with dense breasts (p = 0.07). In rounds 5-10, there were no important differences with respect to PV+ (dense 66% v lucent 62%, p = 0.57) or survival (p = 0.48). Moreover, sensitivity based on a one year interval was nearly as high in women with dense breasts as in those with lucent breasts (85% v 86%, p = 0.75). However, based on a two year interval sensitivity was lower (dense 59% v lucent 72%, p = 0.04). CONCLUSIONS: In the early screening years (rounds 2-4) high breast density had an unfavourable effect on screening performance. Nowadays, the situation has improved with respect to PV+, survival and detecting tumours in dense breasts with a lead time of up to one year, but little improvement has occurred in the detection of tumours with a lead time greater than one year.

Changes in mammographic breast density and concomitant changes in breast cancer risk

Among participants of the biennial Nijmegen breast cancer screening programme, we examined whether diminution of mammographic breast density lowered breast cancer risk. Post-menopausal breast cancer cases (n = 108), who had to have participated in all the five screening rounds prior to their diagnosis, were matched to 400 controls on year of birth and screening history. Controls had to be free of breast cancer at the time of the cases diagnosis. Changes in breast density were measured over a 10-year period, by a fully computerized method. Women in whom 5-25% or >25% of the breast was composed of fibro-glandular density showed a threefold increased 10-year risk compared to women with <5% density. In women with 5-25% density initially, we observed a trend of decreasing risk with diminishing density: when women with <5% density throughout the whole period formed the reference category, the odds ratio (OR) for those who decreased from 5-25% to <5% density was 1.9 [95% confidence interval (CI) = 0.6-6.1] in contrast to the OR of 5.7 (95% CI = 2.2-15.2) for those with persisting 5-25% density. In women who increased from 5-25% density to >25% density the OR was 6.9 (95% CI = 2.1-22.9). In women with >25% density initially, diminishing density was not clearly associated with lowering risk, which may be partly explained by the low number of women who decreased to <5% (n = 12). Due to the limited size of the study these results have to be interpreted with caution. Although the results are not conclusive, they could indicate a trend of decreasing risk with diminishing breast density. Should this effect be real, it may have great implications for the primary prevention of breast cancer or for the identification of high-risk groups who would benefit by more frequent screening. Therefore, large-scale, long-term follow-up studies on the effects of changes in breast density are needed.

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 cases 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 cases diagnosis. Cancer Epidemiol Biomarkers Prev; 21(1); 66–73. ©2011 AACR.

Short communication: Breast parenchymal patterns and their changes with age

In studies on mass screening, it has often been reported that tumours in breasts with dense parenchyma are difficult to detect and may have a more advanced stage at diagnosis. Shorter rescreening intervals have been suggested for these women but, before recommending such a strategy, it is important to investigate how often dense breast parenchyma (P2 and DY patterns according to Wolfe) is actually present in a screening population and to what extent these patterns change with age. The prevalence of dense breast parenchyma (P2 and DY) in our study population was 33% at first examination (n = 2581), which is fairly low compared with other screening populations. Its presence was strongly, inversely age-dependent. Breast patterns of 1177 women, aged 35-85 years, were followed for 12 years. In 39% (182/461) of the women with a P2 or DY pattern at their first examination, regression to a lucent pattern (N1 and P1) occurred over the years. The majority of these women were assumed to have reached menopause in the follow-up period. These findings support the hypothesis that the presence of dense breast parenchyma is related to the reproductive period and indicate that shortening the rescreening intervals would be most effective in pre-menopausal age groups.

Parity and mammographic breast density in relation to breast cancer risk: indication of interaction

We examined whether the harmful influence of nulliparity on breast cancer risk could be mediated by high mammographic density. Another possibility is that mammographic density and nulliparity act independently or perhaps synergistically on breast cancer risk. Our study population consisted of 129 cases and 517 controls who had been participants in the Nijmegen breast cancer screening programme for 10 years. Breast density was classified with a fully automated technique on digitized mammograms from the screening examination 10 years before diagnosis. Classification was based on the proportion of the breast that was composed of high density: < 5%, 5-25% or > 25%. Data on parity and potential confounders were obtained using a questionnaire, administered at the same examination. We found that nulliparae with low breast density (< 5%) were not at increased risk compared to parous women with low density: OR 1.1 (95% CI 0.2-5.8). Parous women with < 5% density formed the reference category throughout all analyses. The risks for parous women with 5-25% or > 25% density were 2.7 (95% CI 1.3-5.6) and 3.6 (95% CI 1.7-7.7) fold increased, respectively. However, when both factors were present (nulliparity and > or = 5% density), breast cancer risk was 7.1 times higher (95% CI 3.2-15.9). This could indicate that nulliparity and high breast density might work synergistically and that breast density is not just an explanatory factor in the influence of nulliparity on breast cancer risk. It is hypothesized that high breast density (reflecting fibro-glandular tissue with increased epithelial cell proliferation) is more susceptible to carcinogenic effects in the undifferentiated epithelial breast tissue of nulliparae than in the differentiated tissue of parous women. Since there were few data, no firm conclusions can be drawn. If these findings can be confirmed in a larger study population, however, they may have important implications for the prevention and early detection of breast cancer.

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 ones 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.

High mammographic breast density and its implications for the early detection of breast cancer.

Objectives Women with high mammographic breast density are at increased risk of breast cancer. This study explores whether these women should receive intensified screening (more frequent screening or screening with alternative techniques that increase the length of the preclinical detectable phase) to reduce further breast cancer mortality. Methods Mathematical models were used to estimate the effects of intensified screening in women with high breast density. The effects were expressed as a reduction in the number of interval cancers. Results If women with >25% breast density (comprising about one fifth of all women) are screened annually instead of biennially, an 18% reduction in the total number of interval cancers can be expected. Screening these women with alternative screening techniques biennially may produce the same reduction, provided that these techniques double the mean lead time. Conclusions By screening women with dense breasts more intensively, many more breast cancers can theoretically be detected at an early stage. The results provide an early indication of what may be expected from screening strategies. Next, cost-benefit analyses are needed.

Likelihood of early detection of breast cancer in relation to false-positive risk in life-time mammographic screening: population-based cohort study

BACKGROUND Women require balanced, high-quality information when making an informed decision on screening benefits and harms before attending biennial mammographic screening. PATIENTS AND METHODS The cumulative risk of a false-positive recall and/or (small) screen-detected or interval cancer over 13 consecutive screening examinations for women aged 50 from the start of screening were estimated using data from the Nijmegen programme, the Netherlands. RESULTS Women who underwent 13 successive screens in the period 1975-1976 had a 5.3% cumulative chance of a screen-detected cancer, with a 4.2% risk of at least one false-positive recall. The risk of being diagnosed with interval cancer was 3.7%. Two decades later, these estimates were 6.9%, 7.3% and 2.9%, respectively. The chance of detection of a small, favourable invasive breast cancer, anticipating a normal life-expectancy, rose from 2.3% to 3.7%. Extrapolation to digital screening mammography indicates that the proportion of false-positive results will rise to 16%. CONCLUSION Dutch women about to participate in the screening programme can be reassured that the chance of false-positive recall in the Netherlands is relatively low. A new screening policy and improved mammography have increased the detection of an early screening carcinoma and lowering the risk of interval carcinoma.

Effect of independent multiple reading of mammograms on detection performance

The goal of this study was to assess the effect of independent combination of multiple readers in mammography on detection performance, using different rules to combine localized observer responses. A group of 12 radiologists each read a series of 192 screening mammograms, including 96 prior mammograms of breast cancer cases in which a visible sign of abnormality could be identifed in retrospect. The other 96 cases were normal. In total the 12 readers annotated 1890 findings. LROC analysis was used to measure performance. The mean sensitivity in a false positive interval from 2 to 8% was 31.4% for single reading (range: 14.4% - 46.9%). The best rule for combination of observer scores was taking the average of all radiologists, using a zero score for radiologists who did not annotate the finding. With this strategy the average performance of 2 readers combined, in the interval selected, went up to 42.2%. When the interpretations of more readers were independently combined the mean sensitivity further increased, up to a level of 64.8% for the combination of all 12 readers. Using the mean score of only those readers who reported a finding turned out to be a poor strategy, yielding results that were similar or worse than single reading.

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.