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Supplementary Figure and Table Legends from Premenopausal Mammographic Density in Relation to Cyclic Variations in Endogenous Sex Hormone Levels, Prolactin, and Insulin-like Growth Factors

Supplementary Tables 1-4 from Premenopausal Mammographic Density in Relation to Cyclic Variations in Endogenous Sex Hormone Levels, Prolactin, and Insulin-like Growth Factors

Supplementary Information from Premenopausal Mammographic Density in Relation to Cyclic Variations in Endogenous Sex Hormone Levels, Prolactin, and Insulin-like Growth Factors

Background Differential treatment between trial arms has been suggested to bias prostate cancer (PC) mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). Objective To quantify the contribution of treatment differences to the observed PC mortality reduction between the screening arm (SA) and the control arm (CA). Design, setting, and participants A total of 14 136 men with PC (SA: 7310; CA: 6826) in the core age group (55–69 yr) at 16 yr of follow-up. Outcome measurements and statistical analysis The outcomes measurements were observed and estimated numbers of PC deaths by treatment allocation in the SA and CA, respectively. Primary treatment allocation was modeled using multinomial logistic regression adjusting for center, age, year, prostate-specific antigen, grade group, and tumor-node-metastasis stage. For each treatment, logistic regression models were fitted for risk of PC death, separately for the SA and CA, and using the same covariates as for the treatment allocation model. Treatment probabilities were multiplied by estimated PC death risks for each treatment based on one arm, and then summed and compared with the observed number of deaths. Results and limitations The difference between the observed and estimated treatment distributions (hormonal therapy, radical prostatectomy, radiotherapy, and active surveillance/watchful waiting) in the two arms ranged from −3.3% to 3.3%. These figures, which represent the part of the treatment differences between arms that cannot be explained by clinicopathological differences, are small compared with the observed differences between arms that ranged between 7.2% and 10.1%. The difference between the observed and estimated numbers of PC deaths among men with PC was 0.05% (95% confidence interval [CI] −0.1%, 0.2%) when applying the CA model to the SA, had the two groups received identical primary treatment, given their clinical characteristics. When instead applying the SA model to the CA, the difference was, as expected, very similar—0.01% (95% CI −0.3%, 0.2%). Consistency of the results of the models demonstrates the robustness of the modeling approach. As the observed difference between trial arms was 4.2%, our findings suggest that differential treatment explains only a trivial proportion of the main findings of ERSPC. A limitation of the study is that only data on primary treatment were available. Conclusions Use of prostate-specific antigen remains the predominant explanation for the reduction in PC mortality seen in the ERSPC trial and is not attributable to differential treatment between trial arms. Patient summary This study shows that prostate cancer deaths in the European screening trial (European Randomized Study of Screening for Prostate Cancer) were prevented because men were diagnosed and treated earlier through prostate-specific antigen screening, and not because of different, or better, treatment in the screening arm compared with the control arm.

Bystander intervention is showing promise as a strategy for violence reduction. Following successful preliminary evaluation of The Intervention Initiative (TII), a bystander programme for universities, a Public Health department in a local authority commissioned a DVA-specific version of TII for communities which became Active Bystander Communities (ABC). This paper documents, in narrative and reflexive form, the challenges and complexities faced by the research team and practitioners in translating TII into a new context for a new audience. We review findings from research, document the theoretical rationale underpinning the new programme, and its content and adherence to effective prevention criteria. We discuss the community readiness model and results of our engagement with a wider practitioner base and how feedback informed further programme development. We document the importance of the intersect and interplay of academic work with practitioner ‘real world’ realities. We discuss two fundamental theoretical issues: the meaning of ‘communities’ in this context, and the safety of interventions expressing social disapproval of problematic male behaviour to perpetrators designed to shift social norms. Government cuts have affected the structures and the staffing required to pilot the intervention in communities. Further research into effectiveness of the intervention and barriers to implementation is needed.

Background: The European Randomized study of Screening for Prostate Cancer (ERSPC) has previously demonstrated that prostate-specific antigen (PSA) screening decreases prostate cancer (PCa) mortality. Objective: To determine whether PSA screening decreases PCa mortality for up to 16 yr and to assess results following adjustment for nonparticipation and the number of screening rounds attended. Design, setting, and participants: This multicentre population-based randomised screening trial was conducted in eight European countries. Report includes 182 160 men, followed up until 2014 (maximum of 16 yr), with a predefined core age group of 162 389 men (55-69 yr), selected from population registry. Outcome measurements and statistical analysis: The outcome was PCa mortality, also assessed with adjustment for nonparticipation and the number of screening rounds attended. Results and limitations: The rate ratio of PCa mortality was 0.80 (95% confidence interval [CI] 0.72-0.89, p 20 ng/ml (9.9% compared with 4.1% in the second round, p

Summary Background The appropriate age range for breast cancer screening remains a matter of debate. We aimed to estimate the effect of mammographic screening at ages 40–48 years on breast cancer mortality. Methods We did a randomised, controlled trial involving 23 breast screening units across Great Britain. We randomly assigned women aged 39–41 years, using individual randomisation, stratified by general practice, in a 1:2 ratio, to yearly mammographic screening from the year of inclusion in the trial up to and including the calendar year that they reached age 48 years (intervention group), or to standard care of no screening until the invitation to their first National Health Service Breast Screening Programme (NHSBSP) screen at approximately age 50 years (control group). Women in the intervention group were recruited by postal invitation. Women in the control group were unaware of the study. The primary endpoint was mortality from breast cancers (with breast cancer coded as the underlying cause of death) diagnosed during the intervention period, before the participant's first NHSBSP screen. To study the timing of the mortality effect, we analysed the results in different follow-up periods. Women were included in the primary comparison regardless of compliance with randomisation status (intention-to-treat analysis). This Article reports on long-term follow-up analysis. The trial is registered with the ISRCTN registry, ISRCTN24647151. Findings 160 921 women were recruited between Oct 14, 1990, and Sept 24, 1997. 53 883 women (33·5%) were randomly assigned to the intervention group and 106 953 (66·5%) to the control group. Between randomisation and Feb 28, 2017, women were followed up for a median of 22·8 years (IQR 21·8–24·0). We observed a significant reduction in breast cancer mortality at 10 years of follow-up, with 83 breast cancer deaths in the intervention group versus 219 in the control group (relative rate [RR] 0·75 [95% CI 0·58–0·97]; p=0·029). No significant reduction was observed thereafter, with 126 deaths versus 255 deaths occurring after more than 10 years of follow-up (RR 0·98 [0·79–1·22]; p=0·86). Interpretation Yearly mammography before age 50 years, commencing at age 40 or 41 years, was associated with a relative reduction in breast cancer mortality, which was attenuated after 10 years, although the absolute reduction remained constant. Reducing the lower age limit for screening from 50 to 40 years could potentially reduce breast cancer mortality. Funding National Institute for Health Research Health Technology Assessment programme.

Mammographic breast density (MBD) is an important imaging biomarker of breast cancer risk, but it has been suggested that increased MBD is not a genuine finding once corrected for age and body mass index (BMI). This study examined the association of various factors, including both residing in and working in the urban setting, with MBD. Questionnaires were completed by 1144 women attending for mammography at the London Breast Institute in 2012–2013. Breast density was assessed with an automated volumetric breast density measurement system (Volpara) and compared with subjective radiologist assessment. Multivariable linear regression was used to model the relationship between MBD and residence in the urban setting as well as working in the urban setting, adjusting for both age and BMI and other menstrual, reproductive, and lifestyle factors. Urban residence was significantly associated with an increasing percent of MBD, but this association became non-significant when adjusted for age and BMI. This was not the case for women who were both residents in the urban setting and still working. Our results suggest that the association between urban women and increased MBD can be partially explained by their lower BMI, but for women still working, there appear to be other contributing factors.

Background. The UK Age trial compared annual mammography screening of women ages 40 to 49 years with no screening and found a statistically significant breast cancer mortality reduction at the 10-year follow-up but not at the 17-year follow-up. The objective of this study was to compare the observed Age trial results with the Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer model predicted results. Methods. Five established CISNET breast cancer models used data on population demographics, screening attendance, and mammography performance from the Age trial together with extant natural history parameters to project breast cancer incidence and mortality in the control and intervention arm of the trial. Results. The models closely reproduced the effect of annual screening from ages 40 to 49 years on breast cancer incidence. Restricted to breast cancer deaths originating from cancers diagnosed during the intervention phase, the models estimated an average 15% (range across models, 13% to 17%) breast cancer mortality reduction at the 10-year follow-up compared with 25% (95% CI, 3% to 42%) observed in the trial. At the 17-year follow-up, the models predicted 13% (range, 10% to 17%) reduction in breast cancer mortality compared with the non-significant 12% (95% CI, -4% to 26%) in the trial. Conclusions. The models underestimated the effect of screening on breast cancer mortality at the 10-year follow-up. Overall, the models captured the observed long-term effect of screening from age 40 to 49 years on breast cancer incidence and mortality in the UK Age trial, suggesting that the model structures, input parameters, and assumptions about breast cancer natural history are reasonable for estimating the impact of screening on mortality in this age group.

Background The European Randomized Study of Screening for Prostate Cancer (ERSPC) demonstrated that prostate-specific antigen (PSA) screening significantly reduced prostate cancer mortality (rate ratio, 0.79; 95% confidence interval, 0.69-0.91). The US Prostate, Lung, Colorectal, and Ovarian (PLCO) trial indicated no such reduction but had a wide 95% CI (rate ratio for prostate cancer mortality, 1.09; 95% CI, 0.87-1.36). Standard meta-analyses are unable to account for key differences between the trials that can impact the estimated effects of screening and the trials' point estimates. Methods The authors calibrated 2 microsimulation models to individual-level incidence and mortality data from 238,936 men participating in the ERSPC and PLCO trials. A cure parameter for the underlying efficacy of screening was estimated by the models separately for each trial. The authors changed step-by-step major known differences in trial settings, including enrollment and attendance patterns, screening intervals, PSA thresholds, biopsy receipt, control arm contamination, and primary treatment, to reflect a more ideal protocol situation and differences between the trials. Results Using the cure parameter estimated for the ERSPC, the models projected 19% to 21% and 6% to 8%, respectively, prostate cancer mortality reductions in the ERSPC and PLCO settings. Using this cure parameter, the models projected a reduction of 37% to 43% under annual screening with 100% attendance and biopsy compliance and no contamination. The cure parameter estimated for the PLCO trial was 0. Conclusions The observed cancer mortality reduction in screening trials appears to be highly sensitive to trial protocol and practice settings. Accounting for these differences, the efficacy of PSA screening in the PLCO setting is not necessarily inconsistent with ERSPC results. Cancer 2018;124:1197-206. © 2017 American Cancer Society.

Background:\ud The faecal immunochemical test (FIT) is replacing the guaiac faecal occult blood test in colorectal cancer screening. Increased uptake and FIT positivity will challenge colonoscopy services. We developed a risk prediction model combining routine screening data with FIT concentration to improve the accuracy of screening referrals.\ud \ud Methods:\ud Multivariate analysis used complete cases of those with a positive FIT (⩾20 μg g−1) and diagnostic outcome (n=1810; 549 cancers and advanced adenomas). Logistic regression was used to develop a risk prediction model using the FIT result and screening data: age, sex and previous screening history. The model was developed further using a feedforward neural network. Model performance was assessed by discrimination and calibration, and test accuracy was investigated using clinical sensitivity, specificity and receiver operating characteristic curves.\ud \ud Results:\ud Discrimination improved from 0.628 with just FIT to 0.659 with the risk-adjusted model (P=0.01). Calibration using the Hosmer–Lemeshow test was 0.90 for the risk-adjusted model. The sensitivity improved from 30.78% to 33.15% at similar specificity (FIT threshold of 160 μg g−1). The neural network further improved model performance and test accuracy.\ud \ud Conclusions:\ud Combining routinely available risk predictors with the FIT improves the clinical sensitivity of the FIT with an increase in the diagnostic yield of high-risk adenomas.

Objectives To evaluate the effectiveness of the NHS breast screening programme (NHSBSP) on breast cancer mortality in England and Wales and to compare findings with a cohort analysis of the same underlying population. Methods A nested case-control study within a cohort of 959,738 women in England and Wales aged 49–64 who were eligible for routine NHSBSP screening during 1991–2005. Cases who died from breast cancer in 1991–2005 were matched to controls without breast cancer at the case diagnosis date and alive when the case died. Risk of breast cancer mortality associated with intention to screen (ITS) (7047 cases/28,188 controls) and screening attendance (4707 cases/9413 controls) was examined. Bias was minimised in accordance with currently advocated best practice. Odds ratios (ORs) were calculated using conditional logistic regression. Results were compared with findings from an incidence-based breast cancer mortality cohort analysis. Results ITS was associated with a 21% breast cancer mortality reduction (OR = 0.79, 95% confidence interval [CI]: 0.71–0.88, P Conclusions Case-control studies designed and analysed according to current best practice guidelines offer an effective means of evaluating population breast screening.

BackgroundBowel cancer screening reduces cancer-specific mortality. There is a socioeconomic gradient in the uptake of the English NHS Bowel Cancer Screening Programme (BCSP), which may lead to inequalities in cancer outcomes.ObjectiveTo reduce socioeconomic inequalities in uptake of the NHS BCSP’s guaiac faecal occult blood test (gFOBt) without compromising uptake in any socioeconomic group.DesignWorkstream 1 explored psychosocial determinants of non-uptake of gFOBt in focus groups and interviews. Workstream 2 developed and tested four theoretically based interventions: (1) ‘gist’ information, (2) a ‘narrative’ leaflet, (3) ‘general practice endorsement’ (GPE) and (4) an ‘enhanced reminder’ (ER). Workstream 3 comprised four national cluster randomised controlled trials (RCTs) of the cost-effectiveness of each intervention.MethodsInterventions were co-designed with user panels, user tested using interviews and focus groups, and piloted with postal questionnaires. RCTs compared ‘usual care’ (existing NHS BCSP invitations) with usual care plus each intervention. The four trials tested: (1) ‘gist’ leaflet (n = 163,525), (2) ‘narrative’ leaflet (n = 150,417), (3) GPE on the invitation letter (n = 265,434) and (4) ER (n = 168,480). Randomisation was based on day of mailing of the screening invitation. The Index of Multiple Deprivation (IMD) score associated with each individual’s home address was used as the marker of socioeconomic circumstances (SECs). Change in the socioeconomic gradient in uptake (interaction between treatment group and IMD quintile) was the primary outcome. Screening uptake was defined as the return of a gFOBt kit within 18 weeks of the invitation that led to a ‘definitive’ test result of either ‘normal’ (i.e. no further investigation required) or ‘abnormal’ (i.e. requiring referral for further testing). Difference in overall uptake was the secondary outcome.ResultsThe gist and narrative trials showed no effect on the SECs gradient or overall uptake (57.6% and 56.7%, respectively, compared with 57.3% and 58.5%, respectively, for usual care; allp-values > 0.05). GPE showed no effect on the gradient (p = 0.5) but increased overall uptake [58.2% vs. 57.5% in usual care, odds ratio (OR) = 1.07, 95% confidence interval (CI) 1.04 to 1.10;p p = 0.005), with a stronger effect in the most deprived IMD quintile (14.1% vs. 13.3% in usual care, OR = 1.11, 95% CI 1.04 to 1.20;p = 0.003) than the least deprived (34.7% vs. 34.9% in usual care OR = 1.00, 95% CI 0.94 to 1.06;p = 0.98), and higher overall uptake (25.8% vs. 25.1% in usual care, OR = 1.07, 95% CI 1.03 to 1.11;p = 0.001). All interventions were inexpensive to provide.LimitationsIn line with NHS policy, the gist and narrative leaflets supplemented rather than replaced existing NHS BCSP information. This may have undermined their effect.ConclusionsEnhanced reminder reduced the gradient and modestly increased overall uptake, whereas GPE increased overall uptake but did not reduce the gradient. Therefore, given their effectiveness and very low cost, the findings suggest that implementation of both by the NHS BCSP would be beneficial. The gist and narrative results highlight the challenge of achieving equitable delivery of the screening offer when all communication is written; the format is universal and informed decision-making mandates extensive medical information.Future workSocioculturally tailored research to promote communication about screening with family and friends should be developed and evaluated.Trial registrationCurrent Controlled Trials ISRCTN74121020.FundingThis project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full inProgramme Grants for Applied Research; Vol. 5, No. 8. See the NIHR Journals Library website for further project information.

ObjectiveTo provide the first report on the main outcomes from the prevalence and incidence rounds of a large pilot of routine primary high risk human papillomavirus (hrHPV) testing in England, compared with contemporaneous primary liquid based cytology screening.DesignObservational study.SettingThe English Cervical Screening Programme.Participants578 547 women undergoing cervical screening in primary care between May 2013 and December 2014, with follow-up until May 2017; 183 970 (32%) were screened with hrHPV testing.InterventionsRoutine cervical screening with hrHPV testing with liquid based cytology triage and two early recalls for women who were hrHPV positive and cytology negative, following the national screening age and interval recommendations.Main outcome measuresFrequency of referral for a colposcopy; adherence to early recall; and relative detection of cervical intraepithelial neoplasia grade 2 or worse from hrHPV testing compared with liquid based cytology in two consecutive screening rounds.ResultsBaseline hrHPV testing and early recall required approximately 80% more colposcopies, (adjusted odds ratio 1.77, 95% confidence interval 1.73 to 1.82), but detected substantially more cervical intraepithelial neoplasia than liquid based cytology (1.49 for cervical intraepithelial neoplasia grade 2 or worse, 1.43 to 1.55; 1.44 for cervical intraepithelial neoplasia grade 3 or worse, 1.36 to 1.51) and for cervical cancer (1.27, 0.99 to 1.63). Attendance at early recall and colposcopy referral were 80% and 95%, respectively. At the incidence screen, the 33 506 women screened with hrHPV testing had substantially less cervical intraepithelial neoplasia grade 3 or worse than the 77 017 women screened with liquid based cytology (0.14, 0.09 to 0.23).ConclusionsIn England, routine primary hrHPV screening increased the detection of cervical intraepithelial neoplasia grade 3 or worse and cervical cancer by approximately 40% and 30%, respectively, compared with liquid based cytology. The very low incidence of cervical intraepithelial neoplasia grade 3 or worse after three years supports extending the screening interval.

Summary Background There is currently no national screening programme for prostate cancer in England, but eligible men can request a prostate-specific antigen (PSA) test from their general practitioner (GP). There are no routinely available data to monitor the extent of PSA testing and referral. Aim The aim of this study was to investigate the rate of PSA testing in general practice and subsequent patterns of referral. Design and setting Data obtained from the Clinical Practice Research Datalink (CPRD) for men aged 45–84 years who had a PSA test during 2010–2011, registered in practices in England with linked Hospital Episode Statistics (HES) data. Method Patient data were linked to previous tests and consultations. Rates of PSA testing and proportions of men retested and referred to secondary care were calculated. Results Overall, 8.74 (95% CI 8.67–8.82) of men per 100 person-years were tested at least once in 2010, and 9.45 (95% CI 9.37–9.53) in 2011. Rates increased with age and decreased with increasing level of deprivation. Of the 53,069 men tested in 2010, 11,289 (21.3%) had a previous PSA test within the past 12 months. Of men with raised PSA according to age specific guidelines, 22.4% (2113/9425) were referred to secondary care within 14 days, with 36% of the remainder retested within 6 months. Conclusions Rates of PSA testing have increased compared with earlier studies; the data suggest that many GPs are retesting men with raised PSA rather than referring immediately. More routine data on PSA testing, including reasons for testing, and subsequent management and outcomes, are required.

A 21% prostate cancer (PCa) mortality reduction was observed in the European Randomized Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. A direct correlation between stage shift and changes in PCa-mortality would support earlier detection through screening as the main reason for this reduction. In this study we empirically estimate how changes in the risk of being diagnosed with (advanced) PCa are related to the changes in PCa death in the ERSPC using a meta-regression approach. In total 81% and 89% of the changes in PCa mortality could be explained by changes in PCa incidence. Although this analysis cannot show direct causal relations, results support the hypothesis that PSA screening reduced PCa mortality by detecting cancer at an earlier stage while still curable. These findings do however not open the way to unrestricted PSA based screening for PCa. A balance between harm and benefit needs to be found.

Purpose: The balance of benefits and harms in prostate cancer screening has not been sufficiently characterized. We related indicators of mortality reduction and overdetection by center within the European Randomized Study of Prostate Cancer Screening (ERSPC). Experimental Design: We analyzed the absolute mortality reduction expressed as number needed to invite (NNI = 1/absolute risk reduction; indicating how many men had to be randomized to screening arm to avert a prostate cancer death) for screening and the absolute excess of prostate cancer detection as number needed for overdetection (NNO = 1/absolute excess incidence; indicating the number of men invited per additional prostate cancer case), and compared their relationship across the seven ERSPC centers. Results: Both absolute mortality reduction (NNI) and absolute overdetection (NNO) varied widely between the centers: NNI, 200–7,000 and NNO, 16–69. Extent of overdiagnosis and mortality reduction was closely associated [correlation coefficient, r = 0.76; weighted linear regression coefficient, β = 33; 95% confidence interval (CI), 5–62; R2 = 0.72]. For an averted prostate cancer death at 13 years of follow-up, 12 to 36 excess cases had to be detected in various centers. Conclusions: The differences between the ERSPC centers likely reflect variations in prostate cancer incidence and mortality, as well as in screening protocol and performance. The strong interrelation between the benefits and harms suggests that efforts to maximize the mortality effect are bound to increase overdiagnosis and might be improved by focusing on high-risk populations. The optimal balance between screening intensity and risk of overdiagnosis remains unclear. Clin Cancer Res; 22(1); 243–9. ©2015 AACR.

Background Observational studies have reported conflicting results on the impact of mammography service screening programmes on the advanced breast cancer rate (ABCR), a correlation that was firmly established in randomized controlled trials. We reviewed and summarized studies of the effect of service screening programmes in the European Union on ABCR and discussed their limitations. Methods The PubMed database was searched for English language studies published between 01-01-2000 and 01–06-2018. After inspection of titles and abstracts, 220 of the 8644 potentially eligible papers were considered relevant. Their abstracts were reviewed by groups of two authors using predefined criteria. Fifty studies were selected for full paper review, and 22 of these were eligible. A theoretical framework for their review was developed. Review was performed using a ten-point checklist of the methodological caveats in the analysis of studies of ABCR and a standardised assessment form designed to extract quantitative and qualitative information. Results Most of the evaluable studies support a reduction in ABCR following the introduction of screening. However, all studies were challenged by issues of design and analysis which could at least potentially cause bias, and showed considerable variation in the estimated effect. Problems were observed in duration of follow-up time, availability of reliable reference ABCR, definition of advanced stage, temporal variation in the proportion of unknown-stage cancers, and statistical approach. Conclusions We conclude that much of the current controversy on the impact of service screening programmes on ABCR is due to observational data that were gathered and/or analysed with methodological approaches which could not capture stage effects in full. Future research on this important early indicator of screening effectiveness should focus on establishing consensus in the correct methodology. Electronic supplementary material The online version of this article (10.1186/s12885-018-4666-1) contains supplementary material, which is available to authorized users.

BACKGROUND: A colposcopy examination is the main management option for women with an abnormal cervical screening test result. Although some women experience adverse psychological effects after colposcopy, those at greatest risk are unknown. We investigated predictors of worries about cervical cancer, sex, future fertility and general health during 12 to 30 months after colposcopy.METHODS: We invited 1,515 women, aged 20 to 59 years with low-grade cervical cytology who attended colposcopy to complete questionnaires at recruitment (∼8 weeks after cytology result) and after 12, 18, 24, and 30 months of follow up. Outcomes were worries about having cervical cancer, having sex, future fertility, and general health at any time during follow-up. Factors significantly associated with each outcome were identified using multiple logistic regression.RESULTS: At one or more time points during follow-up, 40% of women reported worries about having cervical cancer, 26% about having sex, 24% about future fertility, and 60% about general health. For all outcomes except sex, worries reported at recruitment were associated with significantly increased risk of worries during follow-up. Significant anxiety at recruitment was associated with all worries during follow-up. Women diagnosed with CIN2+ had significantly higher risks of worries about cervical cancer and future fertility. Management received was associated significantly with worries about cervical cancer and having sex. Younger women significantly more often reported worries about future fertility, whereas women who had children had reduced risk of future fertility worries but increased risk of cervical cancer worries.CONCLUSION: Clinical, sociodemographic, lifestyle, and psychological factors predicted risk of reporting worries after colposcopy.

This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/hex.12484, BACKGROUND: Colorectal cancer (CRC) screening using a faecal occult blood test (FOBt) has the potential to reduce cancer-related mortality. Symptom vigilance remains crucial as a proportion of cancers will be diagnosed between screening rounds. A negative FOBt has the potential to influence how participants respond to future symptoms of CRC. OBJECTIVE: To explore (i) understanding of a negative FOBt and (ii) the potential impact of a negative FOBt upon future symptom appraisal and help-seeking behaviour. DESIGN: Qualitative methodology utilizing focus groups with participants who received a negative FOBt within the National Bowel Cancer Screening Programme in Coventry and Lothian. Topics explored included: experience of screening participation, interpretation and understanding of a negative result, symptom awareness and attitudes towards help-seeking. RESULTS: Four broad themes were identified: (i) emotional response to a negative FOBt, (ii) understanding the limitations of FOBt screening, (iii) symptom knowledge and interpretation and (iv) over-reassurance from a negative FOBt. Participants were reassured by a negative FOBt, but there was variability in the extent to which the result was interpreted as an "all clear". Some participants acknowledged the residual risk of cancer and the temporal characteristic of the result, while others were surprised that the result was not a guarantee that they did not have cancer. DISCUSSION AND CONCLUSIONS: Participants recognized that reassurance from a negative FOBt could lead to a short-term delay in help-seeking if symptoms developed. Screening programmes should seek to emphasize the importance of the temporal nature of FOBt results with key messages about symptom recognition and prompt help-seeking behaviour.

Background Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. Methods and findings We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. Conclusions Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction., Valerie McCormack and colleagues reveal reduced breast density with increased age in women from different ethnic groups; however increased breast density in young women is a cancer risk., Author summary Why was this study done? Breast density, a measure of the amount of dense to fatty tissue in the breast, is a strong marker of breast cancer risk. Breast density determinants have been studied in high-income countries, but not in women worldwide. What did the researchers do and find? We studied how breast density differed by age and menopausal status in diverse groups of women from 22 countries worldwide. For over 11,000 women, mammograms were read centrally and risk factor data harmonised. We found that, regardless of the country and ethnic group of women, breast density was much lower in postmenopausal than in premenopausal women of the same age. Additionally, as a relative proportion of breast area, breast density was lower in older women both among premenopausal and postmenopausal women. Among premenopausal women, breast density changed with age without an increase in breast area, but among postmenopausal women, the latter also increased. What do these findings mean? That this change in breast density with age is seen internationally suggests that the change is due to a universal biological mechanism inherent to all women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

Objectives To calculate design-corrected estimates of the effect of screening on prostate cancer mortality by centre in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Setting The ERSPC has shown a 21% reduction in prostate cancer mortality in men invited to screening with follow-up truncated at 13 years. Centres either used pre-consent randomisation (effectiveness design) or post-consent randomisation (efficacy design). Methods In six centres (three effectiveness design, three efficacy design) with follow-up until the end of 2010, or maximum 13 years, the effect of screening was estimated as both effectiveness (mortality reduction in the target population) and efficacy (reduction in those actually screened). Results The overall crude prostate cancer mortality risk ratio in the intervention arm vs control arm for the six centres was 0.79 ranging from a 14% increase to a 38% reduction. The risk ratio was 0.85 in centres with effectiveness design and 0.73 in those with efficacy design. After correcting for design, overall efficacy was 27%, 24% in pre-consent and 29% in post-consent centres, ranging between a 12% increase and a 52% reduction. Conclusion The estimated overall effect of screening in attenders (efficacy) was a 27% reduction in prostate cancer mortality at 13 years’ follow-up. The variation in efficacy between centres was greater than the range in risk ratio without correction for design. The centre-specific variation in the mortality reduction could not be accounted for by the randomisation method.

The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction.To evaluate whether effects of screening on prostate cancer mortality relative to no screening differed between the ERSPC and PLCO.Cox regression of prostate cancer death in each trial group, adjusted for age and trial. Extended analyses accounted for increased incidence due to screening and diagnostic work-up in each group via mean lead times (MLTs), which were estimated empirically and using analytic or microsimulation models.Randomized controlled trials in Europe and the United States.Men aged 55 to 69 (ERSPC) or 55 to 74 (PLCO) years at randomization.Prostate cancer screening.Prostate cancer incidence and survival from randomization; prostate cancer incidence in the United States before screening began.Estimated MLTs were similar in the ERSPC and PLCO intervention groups but were longer in the PLCO control group than the ERSPC control group. Extended analyses found no evidence that effects of screening differed between trials (P = 0.37 to 0.47 [range across MLT estimation approaches]) but strong evidence that benefit increased with MLT (P = 0.0027 to 0.0032). Screening was estimated to confer a 7% to 9% reduction in the risk for prostate cancer death per year of MLT. This translated into estimates of 25% to 31% and 27% to 32% lower risk for prostate cancer death with screening as performed in the ERSPC and PLCO intervention groups, respectively, compared with no screening.The MLT is a simple metric of screening and diagnostic work-up.After differences in implementation and settings are accounted for, the ERSPC and PLCO provide compatible evidence that screening reduces prostate cancer mortality.National Cancer Institute.

Objective In addition to disease-specific mortality, a randomized controlled cancer screening trial may be evaluated in terms of excess mortality, in which case no patient-specific information on causes of death is needed. We studied the effect of not accounting for attendance on the calculated excess mortality in a prostate cancer screening trial. Methods The numerator of the excess mortality rate related to prostate cancer diagnoses in each study arm equals the excess number of deaths observed in the cancer patients. The estimation of the expected number of deaths in the absence of the prostate cancer diagnoses has to account for the self-selection of those participating in the trial, particularly if the proportion of non-participants is substantial. Setting The European prostate cancer screening trial (ERSPC). Results In the screening arm, non-attendees had roughly twice the mortality rate of attendees. Approximately twice as many cancers were detected in the screening arm compared with the control arm, primarily in attendees. Unless attendance is properly accounted for, the expected mortality of prostate cancer patients in the screening arm is overestimated by 0.9–3.6 deaths per 1000 person-years. Conclusions Attendees have a lower all-cause mortality rate (are healthier) and a higher probability of a prostate cancer diagnosis than non-attendees and the men randomized to the control arm. If attendance is not accounted for, the excess mortality and the between-arm excess mortality rate ratio are underestimated and screening is considered more effective than it actually is. These effects may be sizeable, notably if non-attendance is common. Correcting for attendance status is important in the calculation of the excess mortality rate in prostate cancer patients that can be used in conjunction with a disease-specific mortality analysis in a randomized controlled cancer screening trial.

Background: The NHS Bowel Cancer Screening Programme in England offers biennial guaiac faecal occult blood testing (gFOBt). There is a socioeconomic gradient in participation and socioeconomically disadvantaged groups have worse colorectal cancer survival than more advantaged groups. We compared the effectiveness and cost of an enhanced reminder letter with the usual reminder letter on overall uptake of gFOBt and the socioeconomic gradient in uptake. Methods: We enhanced the usual reminder by including a heading ‘A reminder to you’ and a short paragraph restating the offer of screening in simple language. We undertook a cluster-randomised trial of all 168 480 individuals who were due to receive a reminder over 20 days in 2013. Randomisation was based on the day of invitation. Blinding of individuals was not possible, but the possibility of bias was minimal owing to the lack of direct contact with participants. The enhanced reminder was sent to 78 067 individuals and 90 413 received the usual reminder. The primary outcome was the proportion of people adequately screened and its variation by quintile of Index of Multiple Deprivation. Data were analysed by logistic regression with conservative variance estimates to take account of cluster randomisation. Results: There was a small but statistically significant ( P ¼ 0.001) increase in participation with the enhanced reminder (25.8% vs 25.1%). There was significant ( P ¼ 0.005) heterogeneity of the effect by socioeconomic status with an 11% increase in the odds of participation in the most deprived quintile (from 13.3 to 14.1%) and no increase in the least deprived. We estimated that implementing the enhanced reminder nationally could result in up to 80 more people with high or intermediate risk colorectal adenomas and up to 30 more cancers detected each year if it were implemented nationally. The intervention incurred a small one- off cost of d 78 000 to modify the reminder letter. Conclusions: The enhanced reminder increases overall uptake and reduces the socioeconomic gradient in bowel cancer screening participation at little additional cost.

Background: The standard for reading cervical cytology is for a cytoscreener to manually search across an entire slide for abnormal cells using a conventional microscope. Automated technology can select fields of view to assess abnormal cells, which allows targeted reading by cytoscreeners. In the Manual Assessment Versus Automated Reading in Cytology (MAVARIC) trial, we compared the accuracy of these techniques for the detection of underlying disease.Methods: For this randomised controlled trial, women aged 25-64 years undergoing primary cervical screening in Manchester, UK, were randomly assigned (1:2) to receive either manual reading only or paired reading (automation-assisted reading and manual reading), between March 1, 2006, and Feb 28, 2009. In the paired arm, two automated systems were used - the ThinPrep Imaging System and the FocalPoint GS Imaging System. General practices and community clinics were randomised to either ThinPrep or to SurePath (for the FocalPoint system) liquid-based cytology with block randomisation stratified by deprivation index. Samples were then individually randomised to manual reading only or paired reading only. Laboratory staff were unaware of the allocation of each slide and concealment was maintained until the end of the reporting process. The primary outcome was sensitivity of automation-assisted reading relative to manual reading for the detection of underlying cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in the paired arm. This trial is registered, number ISRCTN66377374.Findings: 73266 liquid-based cytology samples were obtained from women undergoing primary cervical screening; 24688 allocated to the manual-only arm and 48578 to the paired-reading arm. Automation-assisted reading was 8% less sensitive than manual reading (relative sensitivity 0.92, 95% CI 0.89-0.95), which was equivalent to an absolute reduction in sensitivity of 6.3%, assuming the sensitivity of manual reading to be 79%. Specificity of automation-assisted reading relative to manual reading increased by 0.6% (1.006, 95% CI 1.005-1.007).Interpretation: The inferior sensitivity of automation-assisted reading for the detection of CIN2+, combined with an inconsequential increase in specificity, suggests that automation-assisted reading cannot be recommended for primary cervical screening.Funding: National Institute for Health Research Health Technology Assessment programme.

The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer depends strongly on several factors, including the age at which regular screening starts, the period over which it continues, and the duration of follow-up after screening. Furthermore, more women would need to be INVITED for screening than would need to be SCREENED to prevent one death, since not all women invited attend for screening or are screened regularly. Failure to consider these important factors accounts for many of the major discrepancies between different published estimates. The randomised evidence indicates that, in high income countries, around one breast cancer death would be prevented in the long term for every 400 women aged 50–70 years regularly screened over a ten-year period.

Summary Background There is currently no national prostate cancer screening programme in the UK. However, patients 50 years and older are entitled to a prostate specific antigen (PSA) test, if informed on the advantages and disadvantages of testing and their risk of cancer. The Prostate Cancer Risk Management Programme (PCRMP) provides this guidance. Aim The aim of this study was to access GPs’ views and understanding of PSA testing, prostate cancer screening and early detection. Method A total of 708 questionnaires were returned by GPs across two English regions in 2013 and the GP questionnaire responses were quantitatively analysed. Results In the 699 completed questionnaires, the majority of GPs were well informed about PSA testing, screening and early detection. Only 32% used guidelines for referral, 14% knew all age-specific PSA referral levels, 71% that Black men have a higher prostate cancer risk than White men (22% correctly answered threefold increase) and 82% that family history is a risk factor. A further 78% thought electronic prompts during consultation would encourage PCRMP guideline usage and 75% had never been offered a PSA test and prostate cancer educational course, of which 73% would like to attend a course. Only 23% were aware of the latest PSA screening evidence [1] and 94% would like an update. Conclusions Participating GPs seem to be well informed but need more information and tools to help follow recommended guidance. In particular, increased awareness of PCRMP guidelines especially by automated methods, further educational courses and evidence updates would be beneficial.

BACKGROUND: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types. METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences. RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p, published_or_final_version

Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer (PCa) mortality and a 1.6-fold increase in PCa incidence with prostate-specific antigen (PSA)-based screening (at 13 yr of follow-up). We evaluated PCa incidence by risk category at diagnosis across the study arms to assess the potential impact on PCa mortality. Design, setting, and participants: Information on arm, centre, T and M stage, Gleason score, serum PSA at diagnosis, age at randomisation, follow-up time, and vital status were extracted from the ERSPC database. Four risk categories at diagnosis were defined: 1, low; 2, intermediate; 3, high; 4, metastatic disease. PSA ( 100 ng/ml) was used as the indicator of metastasis. Outcome measurements and statistical analysis: Incidence rate ratios (IRRs) for screening versus control arm by risk category at diagnosis and follow-up time were calculated using Poisson regression analysis for seven centres. Follow-up was truncated at 13 yr. Missing data were imputed using chained equations. The analyses were carried out on an intention-to-treat basis. Results and limitations: In the screening arm, 7408 PCa cases were diagnosed and 6107 in the control arm. The proportion of missing stage, Gleason score, or PSA value was comparable in the two arms (8% vs 10%), but differed among centres. The IRRs were elevated in the screening arm for the low-risk (IRR: 2.14; 95% CI, 2.03-2.25) and intermediate-risk (IRR: 1.24; 95% CI, 1.16-1.34) categories at diagnosis, equal to unity for the high-risk category at diagnosis (IRR: 1.00; 95% CI, 0.89-1.13), and reduced for metastatic disease at diagnosis (IRR: 0.60; 95% CI, 0.52-0.70). The IRR of metastatic disease had temporal pattern similar to mortality, shifted forwards an average of almost 3 yr, although the mortality reduction was smaller. Conclusions: The results confirm a reduction in metastatic disease at diagnosis in the screening arm, preceding mortality reduction by almost 3 yr. Patient summary: The findings of this study indicate that the decrease in metastatic disease at diagnosis is the major determinant of the prostate cancer mortality reduction in the European Randomized study of Screening for Prostate Cancer. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Multidisciplinary, evidence-based guidelines for quality assurance in colorectal cancer screening and diagnosis have been developed by experts in a project coordinated by the International Agency for Research on Cancer. The full guideline document covers the entire process of population-based screening. It consists of 10 chapters and over 250 recommendations, graded according to the strength of the recommendation and the supporting evidence. The 450-page guidelines and the extensive evidence base have been published by the European Commission. The chapter on evaluation and interpretation of screening outcomes includes 20 graded recommendations. The content of the chapter is presented here to promote international discussion and collaboration by making the principles and standards recommended in the new EU Guidelines known to a wider professional and scientific community. Following these recommendations has the potential to enhance the control of colorectal cancer through improvement in the quality and effectiveness of the screening process, including multi-disciplinary diagnosis and management of the disease.

Background After 11 years of follow-up, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% reduction in prostate-cancer mortality among men who underwent screening for prostate-specific antigen (PSA) levels. However, the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalance this benefit is uncertain. Methods On the basis of ERSPC follow-up data, we used Microsimulation Screening Analysis (MISCAN) to predict the number of prostate cancers, treatments, deaths, and quality-adjusted life-years (QALYs) gained after the introduction of PSA screening. Various screening strategies, efficacies, and quality-of-life assumptions were modeled. Results Per 1000 men of all ages who were followed for their entire life span, we predicted that annual screening of men between the ages of 55 and 69 years would result in nine fewer deaths from prostate cancer (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and a total of 73 life-years gained (average, 8.4 years per prostate-cancer death avoided). The number of QALYs that were gained was 56 (range, -21 to 97), a reduction of 23% from unadjusted life-years gained. To prevent one prostate-cancer death, 98 men would need to be screened and 5 cancers would need to be detected. Screening of all men between the ages of 55 and 74 would result in more life-years gained (82) but the same number of QALYs (56). Conclusions The benefit of PSA screening was diminished by loss of QALYs owing to postdiagnosis long-term effects. Longer follow-up data from both the ERSPC and quality-of-life analyses are essential before universal recommendations regarding screening can be made. (Funded by the Netherlands Organization for Health Research and Development and others.)

Aim To assess pathological and radiological prognostic factors for cancers detected by screening within a multi-centre RCT trial of mammographic screening of younger women. Method The survival of 232 women with screen detected invasive cancer was ascertained. Data on invasive cancer size, histological grade, nodal status, vascular invasion, mammographic spiculation, comedo calcification and mammographic background were assessed. Kaplan–Meier and Cox proportional hazards methods were used to examine survival. Results Univariate analysis indicated that women with cancers with the following features had poorer survival; ≥30 mm, histologically grade 3, heavily node positive (4 or more positive nodes), vascular invasion positive and displaying mammographic comedo calcification. In a multivariate model survival remained poorer in women with four or more nodes positive (HR 8.36, 95% CI 2.31, 30.17) and in those with comedo calcification (HR 3.00,95% CI 1.13, 7.99). Conclusion Nodal status and the presence of mammographic comedo calcification have independent prognostic significance in young women with screen detected cancer.

Background Three large randomised trials have shown that screening for colorectal cancer (CRC) using the faecal occult blood test (FOBt) can reduce the mortality from this disease. The largest of these trials, conducted in Nottingham since 1981, randomised 152 850 individuals between the ages of 45 and 74 years to an intervention arm receiving biennial Haemoccult (FOB) test kit or to a control arm. In 2006, the National Bowel Cancer Screening Programme was launched in England using the FOBt, with the expectation that it will reduce CRC mortality. Aims To compare the CRC mortality and incidence in the intervention arm with the control arm after long-term follow-up. Methods The 152 850 randomised individuals were followed up through local health records and central flagging (Office for National Statistics). Results At a median follow-up of 19.5 years there was a 13% reduction in CRC mortality (95% CI 3% to 22%) in the intervention arm despite an uptake at first invitation of approximately 57%. The CRC mortality reduction in those accepting the first screening test, adjusted for the rate of non-compliers, was 18%. There was no significant difference in mortality from causes other than CRC between the intervention and control arms. Despite removing 615 adenomas >10 mm in size from the intervention arm, there was no significant difference in CRC incidence between the two arms. Conclusions Although the reduction in CRC mortality was sustained, further follow-up of the screened population has not shown a significant reduction in the CRC incidence. Moreover, despite the removal of many large adenomas there was no reduction in the incidence of invasive cancer which was independent of sex and site of the tumour.

background: Earlier pilot studies of human papillomavirus (HPV) triage concluded that HPV triage was feasible and cost-effective. The aim of the present study was to study the impact of wider rollout of HPV triage for women with low-grade cytology on colposcopy referral and outcomes.methods: Human papillomavirus testing of liquid-based cytology (LBC) samples showing low-grade abnormalities was used to select women for colposcopy referral at six sites in England. Samples from 10 051 women aged 25–64 years with routine call or recall cytology reported as borderline or mild dyskaryosis were included.results: Human papillomavirus-positive rates were 53.7% in women with borderline cytology and 83.9% in those with mild dyskaryosis. The range between sites was 34.8–73.3% for borderline cytology, and 73.4–91.6% for mild dyskaryosis. In the single site using both LBC technologies there was no difference in rates between the two technologies. The positive predictive value of an HPV test was 16.3% for CIN2 or worse and 6.1% for CIN3 or worse, although there was considerable variation between sites.conclusion: Triaging women with borderline cytological abnormalities and mild dyskaryosis with HPV testing would allow approximately a third of these women to be returned immediately to routine recall, and for a substantial proportion to be referred for colposcopy without repeat cytology. Variation in HPV-positive rates results in differing colposcopy workload.

Background: Mammographic density (MD) is a strong marker of breast cancer risk, but it is unclear whether tumors arise specifically within dense tissue. Methods: In 231 British women diagnosed with breast cancer after at least one negative annual screening during a mammographic screening trial, we assessed whether tumor location was related to localized MD 5 years prior to diagnosis. Radiologists identified tumor locations on digitised films. We used a validated algorithm to align serial images from the same woman to locate the corresponding point on the prediagnostic film. A virtual 1 cm square grid was overlaid on prediagnostic films and MD calculated for each square within a woman's breast (mean = 271 squares/film). Conditional logistic regression, matching on a woman's breast, was used to estimate the odds of a tumor arising in a square in relation to its prediagnostic square-specific MD. Results: Median (interquartile range) prediagnostic MD was 98.2% (46.8%–100%) in 1 cm-squares that subsequently contained the tumor and 41.0% (31.5%–53.9%) for the whole breast. The odds of a tumor arising in a 1 cm-square were, respectively, 6.1 (95% CI: 1.9–20.1), 16.6 (5.2–53.2), and 25.5-fold (8.1–80.3) higher for squares in the second, third, and fourth quartiles of prediagnostic MD relative to those in the lowest quartile within that breast (Ptrend < 0.001). The corresponding odds ratios were 2.3 (1.3–4.0), 3.9 (2.3–6.4), and 4.6 (2.8–7.6) if a 3 cm-square grid was used. Conclusion: Tumors arise predominantly within the radiodense breast tissue. Impact: Localized MD may be used as a predictor of subsequent tumor location within the breast. Cancer Epidemiol Biomarkers Prev; 20(8); 1718–25. ©2011 AACR.

Background:\ud The United Kingdom NHS Breast Screening Programme was established in 1988, and women aged between 50 and 70 are routinely invited at three yearly intervals. Expected United Kingdom interval cancer rates have been calculated previously, but this is the first publication from an exercise to collate individual-based interval cancer data at a national level.\ud \ud Methods:\ud Interval cancer case ascertainment is achieved by the regular exchange of data between Regional Breast Screening Quality Assurance Reference Centres and Cancer Registries. The present analysis includes interval cancers identified in women screened between 1st April 1997 and 31st March 2003, who were aged between 50 and 64 at the time of their last routine screen.\ud \ud Results:\ud In the periods >0–

Background: Mammographic percent density (PD) is one of the strongest known risk factors for breast cancer, with women with 75% or more density having approximately 4 times greater risk of developing breast cancer than those with little density ( Methods: A nested case-control study of 350 cases and 450 controls was conducted within the intervention arm of the Age Trial of mammographic screening in young women, in which about 54,000 women wererandomised to receive yearly mammographic screening from ages 40 to 48. Women diagnosed with breast cancer were invited to participate in the study, and for each case, healthy controls were randomly selected matched to the cases on screening centre, age and date of mammogram. We are investigating how changes in PD over time in pre-menopausal women, measured on digitised films using a computer-assisted threshold method, relate to subsequent risk of breast cancer. Additionally, we are looking at associations of risk factor variables with baseline PD and changes in PD, investigated in longitudinal analyses in a sample of over 500 breast cancer-free women. Logistic regression models were used to estimate the effect of baseline mammographic density on subsequent breast cancer risk and multilevel linear models to assess the association between longitudinal changes in percent density and risk of breast cancer. Results: Over a 10 year period between ages 40 and 50, the mean reduction in percent density was 10.9% in our sample of breast cancer-free women. Change in percent density was greatest in the women's early forties, with a decrease of 1.9% per year, which reduced to about 0.2% in their late forties/early fifties. Baseline levels and rate of change of percent density were both associated with current and past anthropometric, reproductive and lifestyle factors. Change in percent density was associated with parity, with women who had three or more children experiencing a slower rate of change (P28 kg/m2) having a slower decline in PD than women of normal BMI (22-24 kg/m2). The analysis of the case-control data is currently in progress. Conclusion: We demonstrated that change in PD was associated with known breast cancer risk factors in pre-menopausal women. The results from the nested case-control study will further our understanding of the life-course trajectory of mammographic density and its role as a mediator of breast cancer risk. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-11-01.

Background: Endogenous sex hormone levels are widely believed to be implicated in the etiology of breast cancer through indirect evidence such as early menarche and late menopause, and from direct evidence of an association between circulating levels and breast cancer risk in postmenopausal women. Epidemiological studies suggest that levels may be partly genetically determined, particularly in premenopausal women. Few studies have attempted to identify polymorphisms associated with endogenous hormone levels in premenopausal women, and their findings have been limited. Quantification of hormone levels in premenopausal women is difficult because of their cyclical nature. In particular, estrogen has a marked peak in the follicular phase and a further wider peak in the luteal phase. Methods: 789 healthy premenopausal women from the Mammography Oestrogens and Growth Factors (MOG) study and the British Breast Cancer (BBC-NCRN) study each provided a single blood sample and up to 7 urine samples. We developed a protocol designed to capture peak follicular phase urinary estrone glucuronide (E1G), and luteal phase E1G. Repeated measurements of creatinine-adjusted E1G levels were used to describe features of the E1G curve such as mean and peak follicular E1G, and luteal E1G. Endogenous sex hormone binding globulin (SHBG) and the androgens testosterone, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate were measured on single plasma samples. 691 tagging SNPs capturing common variation in genes within the estrogen synthesis and metabolism pathways were successfully genotyped. Linear regression was used to evaluate the effect of each polymorphism on (log-transformed) measures of urinary E1G levels, SHBG levels and plasma androgen levels. Results: We identified a SNP with minor allele frequency of 7%, in which the minor allele was associated with a 20% reduction in circulating levels of E1G (P Conclusions: Circulating hormone levels in premenopausal women may provide a useful intermediate phenotype in the search for low-penetrance breast cancer risk alleles. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-02.

The UK Age Trial of mammographic screening from age 40 has reported a nonsignificant 17% reduction in breast cancer mortality calculated on an “intention to treat” basis. High levels of ad hoc screening in the control arm could potentially have diluted the estimated effect. Objectives: To estimate the level of unscheduled mammography in the control arm of the UK Age Trial. Methods: Data were obtained from questionnaires sent to a random sample of 3,706 women at five centers in the control arm of this trial. Questions included in the Office for National Statistics Omnibus Surveys about the timing of and reasons for any breast screening provided comparable data. The overall response rate was 58.8%. Results: Overall, 24.9% (95% confidence interval, 23.0-26.8) of Age Trial controls responding reported ever having had a mammogram, 18.2% reported a mammogram for symptomatic reasons, and 8.4% reported unscheduled mammography. Overall, 4.0% and 1.8% of women reported symptomatic and unscheduled mammography, respectively, within the previous 12 months. Results from the Omnibus surveys were similar, 14.2% of women reported previous mammography for symptomatic reasons or follow-up after breast cancer and 6.8% reported unscheduled mammography. Conclusions: The level of contamination due to mammographic screening in the control arm of the Age Trial was low and will have had a minimal effect on the estimated reduction in mortality from breast cancer. Impact: Estimating the extent of screening in the control arm in randomized trials of screening is important to inform interpretation of the results. Cancer Epidemiol Biomarkers Prev; 19(4); 1132–6. ©2010 AACR.