Reply to Yaffe, M.J. Correction for Self-Selection in Breast Cancer Screening. Comment on "Dibden et al. Worldwide Review and Meta-Analysis of Cohort Studies Measuring the Effect of Mammography Screening Programmes on Incidence-Based Breast Cancer Mortality. Cancers 2020, 12, 976".

In his Comment [...].

A case-control study to evaluate the impact of the breast screening programme on breast cancer incidence in England.

BACKGROUND: There is uncertainty about overdiagnosis in mammography screening. METHODS: We aimed to estimate the effect of screening on breast cancer incidence and overdiagnosis in the NHS Breast Screening Programme in England. The study included 57,493 cases and 105,653 controls, with cases defined as women diagnosed at ages 47-89 with primary breast cancer, invasive or ductal carcinoma in situ, in 2010 or 2011. Where possible, two controls were selected per case, matched on date of birth and screening area. Conditional logistic regression was used to estimate the effect of screening on breast cancer risk, with adjustment for potential self-selection bias. Results were combined with national incidence data to estimate absolute rates of overdiagnosis. Overdiagnosis was calculated as the cumulative excess of cancers diagnosed in the age group 50-77 in a woman attending three-yearly screening between ages 50 and 70 compared with a woman attending no screens. RESULTS: The estimated number of cases overdiagnosed in women attending all screens in the programme was 679.3 per 100,000 without adjustment for self-selection bias and 261.2 per 100,000 with adjustment. These corresponded to an estimated 9.5% of screen-detected cancers overdiagnosed without adjustment and 3.7% with adjustment for self-selection. CONCLUSIONS: The NHS Breast Screening Programme in England confers at worst modest levels of overdiagnosis.

A case-control study to evaluate the impact of the breast screening programme on mortality in England.

BACKGROUND: Over the past 30 years since the implementation of the National Health Service Breast Screening Programme, improvements in diagnostic techniques and treatments have led to the need for an up-to-date evaluation of its benefit on risk of death from breast cancer. An initial pilot case-control study in London indicated that attending mammography screening led to a mortality reduction of 39%. METHODS: Based on the same study protocol, an England-wide study was set up. Women aged 47-89 years who died of primary breast cancer in 2010 or 2011 were selected as cases (8288 cases). When possible, two controls were selected per case (15,202 controls) and were matched by date of birth and screening area. RESULTS: Conditional logistic regressions showed a 38% reduction in breast cancer mortality after correcting for self-selection bias (OR 0.62, 95% CI 0.56-0.69) for women being screened at least once. Secondary analyses by age group, and time between last screen and breast cancer diagnosis were also performed. CONCLUSIONS: According to this England-wide case-control study, mammography screening still plays an important role in lowering the risk of dying from breast cancer. Women aged 65 or over see a stronger and longer lasting benefit of screening compared to younger women.

Worldwide Review and Meta-Analysis of Cohort Studies Measuring the Effect of Mammography Screening Programmes on Incidence-Based Breast Cancer Mortality.

In 2012, the Euroscreen project published a review of incidence-based mortality evaluations of breast cancer screening programmes. In this paper, we update this review to October 2019 and expand its scope from Europe to worldwide. We carried out a systematic review of incidence-based mortality studies of breast cancer screening programmes, and a meta-analysis of the estimated effects of both invitation to screening and attendance at screening, with adjustment for self-selection bias, on incidence-based mortality from breast cancer. We found 27 valid studies. The results of the meta-analysis showed a significant 22% reduction in breast cancer mortality with invitation to screening, with a relative risk of 0.78 (95% CI 0.75-0.82), and a significant 33% reduction with actual attendance at screening (RR 0.67, 95% CI 0.61-0.75). Breast cancer screening in the routine healthcare setting continues to confer a substantial reduction in mortality from breast cancer.

Does Reader Performance with Digital Breast Tomosynthesis Vary according to Experience with Two-dimensional Mammography?

Purpose To assess whether individual reader performance with digital breast tomosynthesis (DBT) and two-dimensional (2D) mammography varies with number of years of experience or volume of 2D mammograms read. Materials and Methods After written informed consent was obtained, 8869 women (age range, 29-85 years; mean age, 56 years) were recruited into the TOMMY trial (A Comparison of Tomosynthesis with Digital Mammography in the UK National Health Service Breast Screening Program), an ethically approved, multicenter, multireader, retrospective reading study, between July 2011 and March 2013. Each case was read prospectively for clinical assessment and to establish ground truth. A retrospective reading data set of 7060 cases was created and randomly allocated for independent blinded review of (a) 2D mammograms, (b) DBT images and 2D mammograms, and (c) synthetic 2D mammograms and DBT images, without access to previous examinations. Readers (19 radiologists, three advanced practitioner radiographers, and two breast clinicians) who had 3-25 (median, 10) years of experience in the U.K. National Health Service Breast Screening Program and read 5000-13 000 (median, 8000) cases per annum were included in this study. Specificity was analyzed according to reader type and years and volume of experience, and then both specificity and sensitivity were analyzed by matched inference. The median duration of experience (10 years) was used as the cutoff point for comparison of reader performance. Results Specificity improved with the addition of DBT for all readers. This was significant for all staff groups (56% vs 68% and 49% vs 67% [P < .0001] for radiologists and advanced practitioner radiographers, respectively; 46% vs 55% [P = .02] for breast clinicians). Sensitivity was improved for 19 of 24 (79%) readers and was significantly higher for those with less than 10 years of experience (91% vs 86%; P = .03) and those with total mammographic experience of fewer than 80 000 cases (88% vs 86%; P = .03). Conclusion The addition of DBT to conventional 2D screening mammography improved specificity for all readers, but the gain in sensitivity was greater for readers with less than 10 years of experience.

Impact of Screening on Breast Cancer Mortality: The UK Program 20 Years On.

BACKGROUND: With changes in diagnosis, treatment, and management of breast cancer since the mammography screening trials, there is a need to evaluate contemporary breast screening programs. A case-control study was set up to assess the current impact of attendance in the English Breast Screening Program on breast cancer mortality. METHODS: Cancer registry cases who died from primary breast cancer ages 47 to 89 years in London in 2008 to 2009 (869 women) were matched to 1 or 2 general population controls (1,642 women) with no diagnosis of breast cancer at the time of the case's diagnosis, who were alive at the case's death. Cases and controls were matched for date of birth and screening area, and had been invited to breast screening at least once prior to the case's diagnosis. ORs were estimated using conditional logistic regression. Self-selection bias was addressed using contemporaneous attendance at the cervical screening program. Sensitivity analyses were undertaken to assess the likely effect of lead time bias. RESULTS: Attendance at breast screening resulted in a breast cancer mortality reduction of 39% [OR, 0.61; 95% confidence interval (CI), 0.44-0.85] after self-selection correction. Attendance in the last 3 years prior to diagnosis resulted in a 60% mortality reduction (OR, 0.40; 95% CI, 0.31-0.51). Lead time bias effects were negligible. CONCLUSION: Our results suggest that community breast screening programs provide their expected benefit in terms of reducing the risk of breast cancer death among women participating. IMPACT: Mammography is an important tool for reducing breast cancer mortality and its impact could be increased by encouraging regular attendance.

Screen detection of ductal carcinoma in situ and subsequent incidence of invasive interval breast cancers: a retrospective population-based study.

BACKGROUND: The value of screen detection and treatment of ductal carcinoma in situ (DCIS) is a matter of controversy. At present, the extent to which the diagnosis and treatment of DCIS could prevent the occurrence of invasive breast cancer in the future is not clear. We sought to estimate the association between detection of DCIS at screening and invasive interval cancers subsequent to the relevant screen. METHODS: We obtained aggregate data for screen-detected cancers from 84 local screening units within 11 regional Quality Assurance Reference Centres in England, Wales, and Northern Ireland from the National Health Service Breast Screening Programme. Data for DCIS diagnoses were obtained for women aged 50-64 years who were invited to and attended mammographic breast screening from April 1, 2003, to March 31, 2007 (4 screening years). Patient-level data for interval cancer arising in the 36 months after each of these were analysed by Poisson regression with invasive interval cancer screen detection rate as the outcome variable; DCIS detection frequencies were fitted first as a continuous and then as a categorical variable. We repeated this analysis after adjustment with both small size and high-grade invasive screen-detected cancers. FINDINGS: We analysed data for 5,243,658 women and on interval cancers occurring in the 36 months after the relevant screen. The average frequency of DCIS detected at screening was 1·60 per 1000 women screened (median 1·50 [unit range 0·54-3·56] [corrected to] per 1000 women). There was a significant negative association of screen-detected DCIS cases with the rate of invasive interval cancers (Poisson regression coefficient -0·084 [95% CI -0·13 to -0·03]; p=0·002). 90% of units had a DCIS detection frequency within the range of 1·00 to 2·22 per 1000 women; in these units, for every three screen-detected cases of DCIS, there was one fewer invasive interval cancer in the next 3 years. This association remained after adjustment for numbers of small screen-detected invasive cancers and for numbers of grade 3 invasive screen-detected cancers. INTERPRETATION: The association between screen-detected DCIS and subsequent invasive interval cancers suggests that detection and treatment of DCIS is worthwhile in prevention of future invasive disease. FUNDING: UK Department of Health Policy Research Programme and NHS Cancer Screening Programmes.

Social determinants of infant mortality in a historical Swedish cohort.

BACKGROUND: Infant mortality rates have fallen considerably in the past decades. However, because of sparseness of historical data, it is unclear how social differences in infant mortality have changed over time. METHODS: The aim of this study was to assess the association between prenatal social determinants and infant mortality in a Swedish cohort of 13,741 singletons born between 1915 and 1929. Associations and potential mediation of these determinants through other maternal and birth factors were studied using Cox regression. Analyses were repeated for deaths within the neonatal and post-neonatal periods. RESULTS: Mother's single marital status, high parity, low birthweight (LBW), low gestational age and male sex were associated with infant mortality in fully adjusted models, whereas the associations of maternal social class, region of residence and maternal age appeared to be largely mediated through other variables. Contrary to studies reporting a 'LBW paradox', no interactions between gestational age or birthweight and maternal social characteristics on infant mortality were observed in this study. High maternal age, LBW and low/high gestational age were associated with neonatal mortality, whereas single marital status, high parity, LBW, low gestational age and male sex were associated with post-neonatal mortality. An association of family social class with post-neonatal mortality was largely mediated by other maternal variables. CONCLUSIONS: Our findings of determinants of neonatal and post-neonatal mortality in 1915-1929 are strikingly consistent with results from contemporary cohorts. On the other hand, contrary to most recent findings, there is no evidence of a LBW paradox in this historical cohort.