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Background: Observational studies are necessary to assess the impact of population screening on breast cancer mortality. While some ecological studies have notably found little or no association, case–control studies consistently show strong inverse associations, but they are sometimes ignored, perhaps due to theoretical biases arising from the study design. We conducted a case–control study of breast cancer deaths in Western Australia to evaluate the effect of participation in the BreastScreen Australia program, paying particular attention to potential sources of bias, and undertook an updated meta-analysis of case–control studies.Methods: Our study included 427 cases (women who died from breast cancer), each matched to up to 10 controls. We estimated the association between screening participation and breast cancer mortality, quantifying the effect of potential sources of bias on our findings, including selection bias, information bias, and confounding. We also conducted a meta-analysis of published case–control studies.Results: The OR for participation in the Western Australian BreastScreen program in relation to death from breast cancer was 0.48 [95% confidence interval (CI), 0.38–0.59; P < 0.001]. We were unable to identify biases that could negate this finding: sensitivity analyses generated ORs from 0.45 to 0.52. Our meta-analysis yielded an OR of 0.51 (95% CI, 0.46–0.55).Conclusions: Our findings suggest an average 49% reduction in breast cancer mortality for women who are screened. In practice, theoretical biases have little effect on estimates from case–control studies.Impact: Case–control studies, such as ours, provide robust and consistent evidence that screening benefits women who choose to be screened. Cancer Epidemiol Biomarkers Prev; 21(9); 1479–88. ©2012 AACR.

BackgroundAustralia introduced COVID-19 infection prevention and control measures in early 2020. To help prepare health services the Australian Government Department of Health commissioned a modelled evaluation of the impact of disruptions to population breast, bowel and cervical cancer screening programs on cancer outcomes and cancer services.MethodsWe used the Policy1 modelling platforms to estimate outcomes for potential disruptions to cancer screening participation, covering periods of 3, 6, 9 and 12 months. We estimated missed screens, clinical outcomes (cancer incidence, tumour staging), and various diagnostic service impacts.ResultsWe estimated that a 12-month screening disruption would reduce breast cancer diagnoses (9.3% population-level reduction over 2020-2021) and colorectal cancer (up to 12·1% reduction over 2020-21), and increase cervical cancer diagnoses (up to 3·6% over 2020-2022), with upstaging expected for these cancer types.ConclusionsFindings illustrate that maintaining screening participation is critical to sustaining a reduced cancer burden. We provide program-specific insights into which outcomes are expected to change, when changes are likely to become apparent, and likely downstream impacts. This evaluation provided evidence to guide decision-making for screening programs, and emphasises the ongoing benefits of maintaining screening in the face of potential future disruptions.FundingAustralian Government Department of Health

Objective: To determine the government and out‐of‐pocket community costs (out‐of‐hospital medical services and prescription medicines) associated with screen‐detected and community‐detected cancers (i.e. cancers detected outside of Australia's organised screening program [BreastScreen]). Methods: We analyse administrative data on government‐subsidised medical services and prescription medicines for 568 Victorian women diagnosed with breast cancer or ductal carcinoma in situ (DCIS). Using multivariable regression analysis, we estimate the government and out‐of‐pocket community costs incurred in the three years after diagnosis for screen‐detected cancers and community‐detected cancers. Additionally, we estimate the government costs associated with diagnosis within and outside of BreastScreen. Results: Average government costs for breast cancer diagnosis were similar within and outside of BreastScreen [$808 (lower limit 676; upper limit 940) vs $837 (95%CI 671; 1,003) respectively]; however, women with community‐detected cancers incurred an additional $254 (95%CI 175; 332) out‐of‐pocket. Controlling for differences in known cancer characteristics, compared to screen‐detected cancers, community‐detected breast cancers were associated with an additional $2,622 (95%CI 644; 4,776) in government expenditure in the three years following diagnosis. Adverse cancer characteristics that were more prevalent in community‐detected cancers (high grade, lymph node involvement, HER2 positive receptor status) were associated with increased government and out‐of‐pocket costs. Conclusions: Community‐detected breast cancers were associated with increased government and out‐of‐pocket costs. Implications for public health: These costs should be considered when evaluating current and alternative breast cancer screening strategies.

Background: The benefits and harms of breast screening may be better balanced through a risk-stratified approach. We conducted a systematic review assessing the accuracy of questionnaire-based risk assessment tools for this purpose. Methods: Population: asymptomatic women aged ≥40 years; Intervention: questionnaire-based risk assessment tool (incorporating breast density and polygenic risk where available); Comparison: different tool applied to the same population; Primary outcome: breast cancer incidence; Scope: external validation studies identified from databases including Medline and Embase (period 1 January 2008–20 July 2021). We assessed calibration (goodness-of-fit) between expected and observed cancers and compared observed cancer rates by risk group. Risk of bias was assessed with PROBAST. Results: Of 5124 records, 13 were included examining 11 tools across 15 cohorts. The Gail tool was most represented (n = 11), followed by Tyrer-Cuzick (n = 5), BRCAPRO and iCARE-Lit (n = 3). No tool was consistently well-calibrated across multiple studies and breast density or polygenic risk scores did not improve calibration. Most tools identified a risk group with higher rates of observed cancers, but few tools identified lower-risk groups across different settings. All tools demonstrated a high risk of bias. Conclusion: Some risk tools can identify groups of women at higher or lower breast cancer risk, but this is highly dependent on the setting and population.

There is growing interest in more risk-based approaches to breast cancer screening in Australia. This would require more detailed reporting of BreastScreen data for factors of interest in the assessment and monitoring of risk-based screening. This review assesses the current and potential availability and reporting of BreastScreen data for this purpose.We systematically searched governmental BreastScreen reports and peer-reviewed literature to assess current and potential availability of outcomes for predetermined factors including breast cancer risk factors and factors important for implementing, monitoring or evaluating risk-based screening. Outcomes evaluated were BreastScreen Performance Indicators routinely included in BreastScreen Australia monitoring reports, and key tumour characteristics.All outcomes were reported annually by age group, except for tumour hormone receptor status, nodal involvement and grade. Screening participation was reported nationally for many factors important for risk-based screening; other reporting was ad hoc or unavailable.There is potential to build on BreastScreen's existing high-quality national data collection and reporting systems to inform and support risk-based breast screening.Enhanced BreastScreen data collection and reporting would improve the evidence base and support evaluation of risk-based screening and improve the detail available for benchmarking any future changes to the program.

Background There is significant interest in personalised, risk-based breast cancer screening. This requires high quality risk assessment. The ‘Gail model’ risk assessment tool has been validated on over 40,000 BreastScreen Australia participants. We assess whether adding mammographic density (MD) information improves risk stratification on that cohort. Methods We used questionnaire data, baseline MD readings (using AutoDensity) and linked screening and cancer registry records from 40,158 BreastScreen Australia participants aged 50–69 years (via the lifepool cohort). We investigated incident invasive breast cancer rates by quintiles of Gail model scores, MD, and combinations of Gail and MD. Results Gail scores and MD values were weakly correlated (r≤0.02). Gail and MD were each strong predictors of incident breast cancer, but stronger predictors when used in combination. For example, the odds ratio for incident invasive breast cancer was 3.6 (95%CI 2.5-6.3) for the 17% of women in the upper two quintiles of both Gail and MD scores compared to the 17% of women in the lower two quintiles of both scores. In comparison, the odds ratio for breast cancer between same-size (each 17%) upper and lower groups for Gail score alone was 2.5 (95%CI 1.8-3.4), and for MD 1.9 (95%CI 1.2-2.9). Conclusions Combining Gail and MD categories improves risk stratification on BreastScreen Australia participants, compared to using Gail or MD alone. Key messages While questionnaire data and MD measures are each strong predictors of future invasive breast cancer among BreastScreen Australia participants, risk prediction is stronger when questionnaire and MD measures are combined.

Background There is increasing interest in risk-based breast cancer screening, including interventions to improve outcomes for women with mammographically dense breasts. Methods Policy1-Breast is a continuous-time, multiple-cohort micro-simulation whole-population model which incorporates breast cancer risk, life-course breast density, menopause, hormone therapy use and screening participation. Outcomes include cancer diagnoses and characteristics (invasive/DCIS, tumour size, grade), mode of detection (screen-detected/interval/other) and mortality (breast cancer and other cause). Policy1-Breast validates well against key observed clinical outcomes in Australia. We estimate changes in outcomes within and outside the BreastScreen program upon the introduction of a hypothetical screening test with improved sensitivity for women with dense breasts. Results We estimate that introducing in year 2020 a screening test for women in the highest quintile of breast density at age 50 that halves the masking effect of their breast density would, by 2026-2030, increase diagnosis rates of population-level invasive cancers ( 10%) and screen-detected cancers (20%) and decrease rates of interval cancers (17%) and community-detected cancers (6%). Conclusions Targeted screening tests with improved sensitivity for women with dense breasts are expected to markedly reduce interval cancers and other cancers diagnosed outside the BreastScreen program, while increasing all cancer diagnoses due to increased rates of screen-detected cancers. Key messages Specialised breast cancer screening tests directed at women with very high breast density are expected to reduce interval cancers and increase overall cancer diagnoses. Population simulation models such as Policy1-Breast can complement trial evidence by evaluating a range of scenarios and estimating short and long-term implications.

The COVID-19 pandemic affects mortality and morbidity, with disruptions expected to continue for some time, with access to timely cancer-related services a concern. For breast cancer, early detection and treatment is key to improved survival and longer-term quality of life. Health services generally have been strained and in many settings with population breast mammography screening, efforts to diagnose and treat breast cancers earlier have been paused or have had reduced capacity. The resulting delays to diagnosis and treatment may lead to more intensive treatment requirements and, potentially, increased mortality. Modelled evaluations can support responses to the pandemic by estimating short- and long-term outcomes for various scenarios. Multiple calibrated and validated models exist for breast cancer screening, and some have been applied in 2020 to estimate the impact of breast screening disruptions and compare options for recovery, in a range of international settings. On behalf of the Covid and Cancer Modelling Consortium (CCGMC) Working Group 2 (Breast Cancer), we summarize and provide examples of such in a range of settings internationally, and propose priorities for future modelling exercises. International expert collaborations from the CCGMC Working Group 2 (Breast Cancer) will conduct analyses and modelling studies needed to inform key stakeholders recovery efforts in order to mitigate the impact of the pandemic on early diagnosis and treatment of breast cancer.

Policy decisions regarding breast cancer screening and treatment programmes may be misplaced unless the decision process includes the appropriate utilities and disutilities of mammography screening and its sequelae. The objectives of this study were to critically review how economic evaluations have valued the health states associated with breast cancer screening, and appraise the primary evidence informing health state utility values (cardinal measures of quality of life). A systematic review was conducted up to September 2018 of studies that elicited or used utilities relevant to mammography screening. The methods used to elicit utilities and the quality of the reported values were tabulated and analysed narratively. 40 economic evaluations of breast cancer screening programmes and 10 primary studies measuring utilities for health states associated with mammography were reviewed in full. The economic evaluations made different assumptions about the measures used, duration applied and the sequalae included in each health state. 22 evaluations referenced utilities based on assumptions or used measures that were not methodologically appropriate. There was significant heterogeneity in the utilities generated by the 10 primary studies, including the methods and population used to derive them. No study asked women to explicitly consider the risk of overdiagnosis when valuing the health states described. Utilities informing breast screening policy are restricted in their ability to reflect the full benefits and harms. Evaluating the true cost-effectiveness of breast cancer screening will remain problematic, unless the methodological challenges associated with valuing the disutilities of screening are adequately addressed.

Breast cancer (BC) diagnosed after a negative mammogram but prior to the next screening episode is termed an 'interval BC' (IBC). Understanding the molecular differences between IBC and screen-detected BCs (SDBC) could improve mammographic screening and management options. Therefore, we assessed both germline and somatic genomic aberrations in a prospective cohort. Utilising the Lifepool cohort of >54 000 women attending mammographic screening programs, 930 BC cases with screening status were identified (726 SDBC and 204 IBC). Clinico-pathological and family history information were recorded. Germline and tumour DNA were collected where available and sequenced for BC predisposition and driver gene mutations. Compared to SDBC, IBCs were significantly associated with a younger age at diagnosis and tumour characteristics associated with worse prognosis. Germline DNA assessment of BC cases that developed post-enrolment (276 SDBCs and 77 IBCs) for pathogenic mutations in 12 hereditary BC predisposition genes identified 8 carriers (2.27%). The germline mutation frequency was higher in IBC versus SDBC, although not statistically significant (3.90% versus 1.81%, p = 0.174). Comparing somatic genetic features of IBC and SDBC matched for grade, histological subtype and hormone receptor revealed no significant differences, with the exception of higher homologous recombination deficiency scores in IBC, and copy number changes on chromosome Xq in triple negative SDBCs. Our data demonstrates that while IBCs are clinically more aggressive than SDBC, when matched for confounding clinico-pathological features they do not represent a unique molecular class of invasive BC, but could be a consequence of timing of tumour initiation and mammographic screening. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Overdiagnosis is a harmful consequence of screening which is particularly challenging to estimate. An unbiased setting to measure overdiagnosis in breast cancer screening requires comparative data from a screened and an unscreened cohort for at least 30 years. Such randomised data will not become available, leaving us with observational data over shorter time periods and outcomes of modelling. This collaborative effort of the International Cancer Screening Network quantified the variation in estimated breast cancer overdiagnosis in organised programmes with evaluation of both observed and simulated data, and presented examples of how modelling can provide additional insights. Reliable observational data, analysed with study design accounting for methodological pitfalls, and modelling studies with different approaches, indicate that overdiagnosis accounts for less than 10% of invasive breast cancer cases in a screening target population of women aged 50 to 69. Estimates above this level are likely to derive from inaccuracies in study design. The widely discrepant estimates of overdiagnosis reported from observational data could substantially be reduced by use of a cohort study design with at least 10 years of follow-up after screening stops. In contexts where concomitant opportunistic screening or gradual implementation of screening occurs, and data on valid comparison groups are not readily available, modelling of screening intervention becomes an advantageous option to obtain reliable estimates of breast cancer overdiagnosis.

Background:Although evaluations of breast cancer screening programs frequently estimate quality-adjusted life-year (QALY) losses by stage, other breast cancer characteristics influence treatment and vary by mode of detection - i.e. whether the cancer is detected through screening (screen-detected), between screening rounds (interval-detected) or outside screening (community-detected). Here, we estimate the association between early-stage invasive breast cancer (ESIBC) characteristics and treatment-related QALY losses.Methods:Using clinicopathological and treatment information from 675 women managed for ESIBC, we estimated the average five-year treatment-related QALY loss by detection group. We then used regression analysis to estimate the extent to which known cancer characteristics and the detection mode, are associated with treatment and treatment-related QALY losses.Results:Community-detected cancers had the largest QALY loss (0.76 QALYs [95% CI 0.73;0.80]), followed by interval-detected cancers (0.75 QALYs [95% CI 0.68;0.82]) and screen-detected cancers (0.69 QALYs [95%CI 0.67;0.71]). Adverse prognostic factors more common in community-detected and interval-detected breast cancers (large tumours, lymph node involvement, high grade) were largely associated with QALY losses from mastectomies and chemotherapy. Receptor-positive subtypes, more common in screen-detected cancers, were associated with QALY losses related to endocrine therapy.Conclusions:The associations between ESIBC characteristics and treatment-related QALY losses should be considered when evaluating breast cancer screening and treatment strategies.

The coronavirus disease 2019 (COVID-19) pandemic has caused major disruptions to many aspects of life in Australia and globally. This includes actual and potential future impacts on Australia’s three national screening programs for breast, bowel and cervical cancer. These programs aim to improve cancer outcomes through an organised approach to the early detection of cancer and precancer in asymptomatic populations. The design of each program varies according to biological differences in the three cancers, the available screening technology, the target population, and variations in their administration of Australia’s federal, state and territory jurisdictions. The observed and potential impacts of COVID-19 on these programs, and on related activities such as the current national enquiry into lung cancer screening feasibility, therefore vary significantly. This article focuses on observed short-term impacts, adaptations and the longer-term outlook for cancer screening in relation to COVID-19. It summarises potential responses to minimise the harms of disruptions caused by COVID-19, and highlights research and policy opportunities in the pandemic response and recovery which could inform and accelerate optimisation of cancer screening in the long term.

IntroductionFor women of the same age and body mass index, increased mammographic density is one of the strongest predictors of breast cancer risk. There are multiple methods of measuring mammographic density and other features in a mammogram that could potentially be used in a screening setting to identify and target women at high risk of developing breast cancer. However, it is unclear which measurement method provides the strongest predictor of breast cancer risk.Methods and analysisThe measurement challenge has been established as an international resource to offer a common set of anonymised mammogram images for measurement and analysis. To date, full field digital mammogram images and core data from 1650 cases and 1929 controls from five countries have been collated. The measurement challenge is an ongoing collaboration and we are continuing to expand the resource to include additional image sets across different populations (from contributors) and to compare additional measurement methods (by challengers). The intended use of the measurement challenge resource is for refinement and validation of new and existing mammographic measurement methods. The measurement challenge resource provides a standardised dataset of mammographic images and core data that enables investigators to directly compare methods of measuring mammographic density or other mammographic features in case/control sets of both raw and processed images, for the purposes of the comparing their predictions of breast cancer risk.Ethics and disseminationChallengers and contributors are required to enter a Research Collaboration Agreement with the University of Melbourne prior to participation in the measurement challenge. The Challenge database of collated data and images are stored in a secure data repository at the University of Melbourne. Ethics approval for the measurement challenge is held at University of Melbourne (HREC ID 0931343.3).

Background The value of population-based mammographic screening has been questioned by those who believe that the reduction in mortality from earlier diagnosis is outweighed by harms including overdiagnosis and overtreatment. Much of these commentaries assume that all Early-Stage Breast Cancer (ESBC) is treated the same way after diagnosis; with extensive therapies including surgery, radiotherapy and chemotherapy being standard. Intensity of treatment received is rarely mentioned in the debate. We hypothesised that those diagnosed through a screening program (Active Screeners (AS)) would receive less extensive surgical treatment and less intense adjuvant therapies than those not recently screened (NRS). If demonstrated, these differences would form an important component of the debate over the role of mammographic screening. Methods Retrospective analysis of a consecutive cohort of female patients aged 50-69 and managed for ESBC (invasive or DCIS) during 2007-2013 within a large metropolitan Breast Service, diagnosed either via a population screening program (AS) or outside of the program (NRS). Data on patient characteristics, symptoms, mode of detection, tumour pathology, surgical intervention and adjuvant treatment recommendations were derived from prospectively collected Multi-Disciplinary Meeting (MDM) records. Patients with metastatic disease or prior treatment for breast cancer were excluded. Results 791 cases were identified (569 with screen-detected cancer, 53 with interval cancers and 169 cancers diagnosed in women not recently screened). Invasive cancers in the AS group were much smaller than in the NRS group – mean 17mm versus 26mm. The AS group had lower grade invasive cancer – grade 1, 2 and 3 were 27%, 42%, 31% - compared with 10%, 39% and 52% in the NRS group. The AS group were more likely to have ER+ve cancers (88% vs 80%) and less likely to have nodal involvement (26% vs 48%). For invasive breast cancer, the NRS group were more than twice as likely to undergo mastectomy than cancers in the AS group (35% vs 16%). Axillary dissections were more common in the NRS than the AS group (43% vs 19%). Adjuvant chemotherapy was recommended more frequently for the NRS group compared to the AS group (65% vs 37%), as was post mastectomy radiotherapy (58% vs 39%). Endocrine therapy was less often recommended to the NRS group (86% versus 77%). Conclusion Women diagnosed with early stage breast cancer who are participating in a population based screening program are less likely to receive mastectomy and/or axillary dissection, less likely to receive adjuvant chemotherapy and less likely to receive post-mastectomy radiotherapy. These differences in treatment intensity should be considered in the debate surrounding mammographic screening. Citation Format: Elder KJ, Nickson C, Cooke S, Machalek D, Rose A, Mou A, Collins JP, Park A, De Boer R, Phillips C, Pridmore V, Farrugia H, Mann GB. Benefits to breast screening beyond mortality reduction [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD2-13.

BACKGROUND: Adjuvant therapy for breast cancer is routinely discussed and recommended in multi-disciplinary meetings (MDMs). Current literature explores how treatments received by patients differ from national guidelines; however, it does not explore whether treatment is concordant with MDMs. This study provides an Australian perspective on the uptake of MDM recommendations and reasons for non-concordance. METHODS: A retrospective cohort study of patients with breast cancer presented at The Royal Melbourne Hospital MDM in 2010 and 2014 to investigate the concordance between MDM recommendations and treatment received. RESULTS: The study group comprised 441 patients (161 from 2010 and 280 from 2014). A total of 375 patients were included in the analyses. Overall, 82% of patients had perfect concordance between recommended and received treatment for all modes of adjuvant therapy. Concordance to endocrine therapy was higher for invasive cancers than ductal carcinoma in situ (97% versus 81%, P

The aim of this study was to optimise the experimental protocol and data analysis for in-vivo breast cancer x-ray imaging. Results are presented of the experiment at the SYRMEP beamline of Elettra Synchrotron using the propagation-based phase-contrast mammographic tomography method, which incorporates not only absorption, but also x-ray phase information. In this study the images of breast tissue samples, of a size corresponding to a full human breast, with radiologically acceptable x-ray doses were obtained, and the degree of improvement of the image quality (from the diagnostic point of view) achievable using propagation-based phase-contrast image acquisition protocols with proper incorporation of x-ray phase retrieval into the reconstruction pipeline was investigated. Parameters such as the x-ray energy, sample-to-detector distance and data processing methods were tested, evaluated and optimized with respect to the estimated diagnostic value using a mastectomy sample with a malignant lesion. The results of quantitative evaluation of images were obtained by means of radiological assessment carried out by 13 experienced specialists. A comparative analysis was performed between the x-ray and the histological images of the specimen. The results of the analysis indicate that, within the investigated range of parameters, both the objective image quality characteristics and the subjective radiological scores of propagation-based phase-contrast images of breast tissues monotonically increase with the strength of phase contrast which in turn is directly proportional to the product of the radiation wavelength and the sample-to-detector distance. The outcomes of this study serve to define the practical imaging conditions and the CT reconstruction procedures appropriate for low-dose phase-contrast mammographic imaging of live patients at specially designed synchrotron beamlines.

Background Mammographic screening reduces breast cancer mortality but may lead to the overdiagnosis and overtreatment of low-risk breast cancers. Conservative management may reduce the potential harm of overtreatment, yet little is known about the impact upon quality of life. Objectives To quantify women's preferences for managing low-risk screen detected ductal carcinoma in situ (DCIS), including the acceptability of active monitoring as an alternative treatment. Methods Utilities (cardinal measures of quality of life) were elicited from 172 women using visual analogue scales (VASs), standard gambles, and the Euro-Qol-5D-5L questionnaire for seven health states describing treatments for low-risk DCIS. Sociodemographics and breast cancer history were examined as predictors of utility. Results Both patients and non-patients valued active monitoring more favourably on average than conventional treatment. Utilities were lowest for DCIS treated with mastectomy (VAS: 0.454) or breast conserving surgery (BCS) with adjuvant radiotherapy (VAS: 0.575). The utility of active monitoring was comparable to BCS alone but was rated more favourably as progression risk was reduced from 40% to 10%. Disutility for active monitoring was likely driven by anxiety around progression, whereas conventional management impacted other dimensions of quality of life. The heterogeneity between individual preferences could not be explained by sociodemographic variables, suggesting that the factors influencing women's preferences are complex. Conclusions Active monitoring of low-risk DCIS is likely to be an acceptable alternative for reducing the impact of overdiagnosis and overtreatment in terms of quality of life. Further research is required to determine subgroups more likely to opt for conservative management.

There are currently no single disruptors to breast cancer screening akin to the impact of human papillomavirus testing and vaccination on cervical cancer screening. However, there is a groundswell of interest to review the BreastScreen Australia program to consider more risk-based screening protocols and to establish whether to routinely inform women about their breast density. We propose a framework for a considered, evidence-based review. Population-level effectiveness of breast cancer screening is ultimately measured through its impact on breast cancer mortality, and this has been realised in Australia. Effectiveness can also be measured through treatment intensity, estimated overdiagnosis, false-positive screens and health economics measures. Key levers to improve such population-level outcomes include screening participation, screening test sensitivity and specificity, risk assessment and screening protocols. We propose that the review of the program should fall under an evidence-based, consensus-guided framework comprising four complementary elements: improved evidence on current program performance for population risk subgroups; regularly updated evidence on key levers for change; clinical trials and population simulation modelling working in tandem; and consensus-based decision making about the degree of improvement required to justify change. Informing women about their breast density is feasible and would be valued by some BreastScreen clients to help understand the accuracy of their screening test. However, without agreed protocols for screening women with dense breasts, increases in supplemental screening as observed in other settings would, in Australia, shift screening costs to clients and Medicare. This would reduce equity of access to population screening, and maintaining BreastScreen’s usual standard of monitoring and quality management (such as screen-detected and interval cancer diagnoses, and imaging and biopsy rates) would require data linkage between BreastScreen and other services. The proposed framework assesses screening effectiveness in the era of personalised medicine, allows review of multiple factors that may together warrant change, and gives full, evidence-based consideration of the benefits, harms and costs of various approaches to breast cancer screening. To be effective, the framework requires a coordinated approach to generating the evidence required for policy makers, with time to prepare appropriate health services.

Background. Characteristics of mammographic density for Chinese women are understudied. This study aims to identify factors associated with mammographic density in China using a quantitative method.Methods. Mammographic density was measured for a total of 1071 (84 with and 987 without breast cancer) women using an automatic algorithm AutoDensity. Pearson tests examined relationships between density and continuous variables and t-tests compared differences of mean density values between groupings of categorical variables. Linear models were built using multiple regression.Results. Percentage density and dense area were positively associated with each other for cancer-free (r=0.487, pConclusion. This is the first time that mammographic density was measured by a quantitative method for women in China and identified associations should be useful to health policy makers who are responsible for introducing effective models of breast cancer prevention and diagnosis.

Background There is a growing interest in delivering more personalised, risk-based breast cancer screening protocols. This requires population-level validation of practical models that can stratify women into breast cancer risk groups. Few studies have evaluated the Gail model (NCI Breast Cancer Risk Assessment Tool) in a population screening setting; we validated this tool in a large, screened population. Methods We used data from 40,158 women aged 50–69 years (via the lifepool cohort) participating in Australia’s BreastScreen programme. We investigated the association between Gail scores and future invasive breast cancer, comparing observed and expected outcomes by Gail score ranked groups. We also used machine learning to rank Gail model input variables by importance and then assessed the incremental benefit in risk prediction obtained by adding variables in order of diminishing importance. Results Over a median of 4.3 years, the Gail model predicted 612 invasive breast cancers compared with 564 observed cancers (expected/observed (E/O) = 1.09, 95% confidence interval (CI) 1.00–1.18). There was good agreement across decile groups of Gail scores (χ2 = 7.1, p = 0.6) although there was some overestimation of cancer risk in the top decile of our study group (E/O = 1.65, 95% CI 1.33–2.07). Women in the highest quintile (Q5) of Gail scores had a 2.28-fold increased risk of breast cancer (95% CI 1.73–3.02, p

Rationale and Objectives This study employs clinical/radiological evaluation in establishing the optimum imaging conditions for breast cancer imaging using the X-ray propagation-based phase-contrast tomography. Materials and Methods Two series of experiments were conducted and in total 161 synchrotron-based computed tomography (CT) reconstructions of one breast mastectomy specimen were produced at different imaging conditions. Imaging factors include sample-to-detector distance, X-ray energy, CT reconstruction method, phase retrieval algorithm applied to the CT projection images and maximum intensity projection. Observers including breast radiologists and medical imaging experts compared the quality of the reconstructed images with reference images approximating the conventional (absorption) CT. Various radiological image quality attributes in a visual grading analysis design were used for the radiological assessments. Results The results show that the application of the longest achievable sample-to-detector distance (9.31 m), the lowest employed X-ray energy (32 keV), the full phase retrieval, and the maximum intensity projection can significantly improve the radiological quality of the image. Several combinations of imaging variables resulted in images with very high-quality scores. Conclusion The results of the present study will support future experimental and clinical attempts to further optimize this innovative approach to breast cancer imaging.

Background While population mammographic screening identifies early-stage breast cancers (ESBCs; ductal carcinoma in situ [DCIS] and invasive disease stages 1–3A), commentaries suggest that harms from overdiagnosis and overtreatment may outweigh the benefits. Apparent benefits to patients with screen-detected cancers may be due to selection bias from exclusion of interval cancers (ICs). Treatment intensity is rarely discussed, with an assumption that all ESBCs are treated similarly. We hypothesized that women diagnosed while in a screening program would receive less-intense treatment than those never or not recently screened (NRS). Methods This was a retrospective analysis of all women aged 50–69 years managed for ESBC (invasive or DCIS) during the period 2007–2013 within a single service, comparing treatment according to screening status. Data on demographics, detection, pathology, and treatment were derived from hospital, cancer registry, and screening service records. Results Overall, 622 patients were active screeners (AS) at diagnosis (569 screen-detected and 53 ICs) and 169 patients were NRS. AS cancers were smaller (17 mm vs. 26 mm, p

ASO Author Reflections is a brief invited commentary on the article, “Treatment Intensity Differences After Early-Stage Breast Cancer Diagnosis Depending on Participation in a Screening Program.” Ann Surg Oncol. 2018;25:2563–72.

The aim of this work is to investigate how radiologist expertise and image appearance may have an impact on inter-reader variability of mammographic density (MD) identification. Seventeen radiologists, divided into three expertise groups, were asked to manually segment the areas they consider to be MD in 40 clinical images. The variation in identification of MD for each image was quantified by finding the range of segmentation areas. The impact of radiologist expertise and image appearance on this variation was explored. The range of areas chosen by participating radiologists varied from 7 to 73 % across the 40 images, with a mean range of 35 ± 13 %. Participants with high expertise were more likely to choose similar areas to one another, compared to participants with medium and low expertise levels (mean range were 19 ± 10 %, 29 ± 13 % and 25 ± 14 %, respectively, p

Background: High mammographic density (MD) is a known risk factor for breast cancer, but it is currently unknown whether this altered microenvironment leads to the development of genomically different tumours. Method: We used lifepool, an Australian prospective population-based cohort of over 53,000 women currently in a mammographic screening program, to identify >1000 cases of breast carcinoma (in situ and invasive breast cancer) for analysis. Pathology reports, detection modality (screen-detected/interval), MD data (AutoDensity, Nickson et al., 2013 DOI:10.1186/bcr3474), germline DNA and tumor tissue were available for a subset of cases. Tumours were classified into quintiles, depending on the relative MD ranking of the most recent normal mammogram. Tumour DNA was analysed using Affymetrix OncoScan MIP arrays or using a targeted Agilent SureSelect and Illumina sequencing panel of 105 genes relevant to breast cancer. Copy number and mutation data were compared between tumours from the highest (high-MD) and lowest (low-MD) quintiles of MD. Results: Preliminary analysis found no significant differences in clinico-pathological features between tumours from breasts with high-MD (n=38) and low-MD (n=35). Genomic analysis of 8 high-MD tumours and 8 low-MD tumours identified chromosome 15 loss as being significantly enriched in low-MD tumours. Only Low-MD tumours to date contained TP53 mutation (3/8). Data will be presented from at least an additional 9 low-MD and 15 high-MD tumours currently undergoing genomic assays. Conclusion: When complete, our data will be the first to evaluate the somatic genetic events in tumours arising in low-MD and high-MD breasts. Although our cohort to date is small, it may be possible that tumours from extremes of MD have different genomic characteristics. Citation Format: Gorringe KL, Hughes S, Nickson C, Devereux L, Pridmore V, Rowley SM, Byrne DJ, Cheasley D, Kavanagh AM, Mann GB, Fox SB, Campbell IG. Genomic analysis of cancers arising in breasts with different mammographic density [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-06.

There is a lack of evidence regarding the optimal age at which to cease mammographic screening for breast cancer. This ecological study compared Australian state and territory level screening participation rates and cancer outcomes from 1996 to 2005 to identify the extent to which screening women aged 70–74 results in smaller, earlier stage breast cancers. With each 10 % absolute increase in screening participation, there was no significant difference in cancer incidence, but the incidence of large cancers was 8 % lower (IRR = 0.92, 95 % CI 0.90–0.94, p 15 mm) cancers—and possibly cancers with nodal involvement—without a concomitant increase in overall cancer incidence.

Australia implemented a National HPV Vaccination Program in 2007, with routine vaccination of 12-13 year old females and catch-up in females aged 13-26 years to 2009. The aim of this study was to estimate the impact of the current female-only national vaccination program on males, and then to estimate the incremental benefits to males from being included in the program. We used preliminary data to estimate vaccination coverage in females. We then fitted a dynamic model of sexual behaviour and HPV transmission in Australia to local data on female pre-vaccination age-specific HPV prevalence, predicted the corresponding pre-vaccination prevalence in males due to heterosexual transmission, and modelled the short and long term impact of female-only versus female-and-male vaccination programs. The estimated 3-dose female coverage rates were 78% (range 70-80%) for ongoing coverage in 12-13 year old girls; and from 74% (range 70-80%) in 14 year olds, to 25% (range 15-35%) for women aged 26 years old in 2007. The median estimate for age-standardised pre-vaccination HPV 16 prevalence in females and males aged 15-59 years was 3.2% (95% range: 2.4-4.1%) and 3.1% (95% range: 2.2-4.2%), respectively. The current program in females is predicted to result in a 68% reduction in male HPV 16 infections by 2050, leading to an estimated long term reduction of 14% in rates of cancers of the head, neck and anogenital area. The estimated proportion of the maximum possible vaccine-conferred benefit to males from a female-and-male program which will be achieved by female-only vaccination is 73% (range in probabilistic sensitivity analysis: 53-78%). In conclusion, up to three-quarters of the maximum possible vaccination-conferred benefit to males due to reduced heterosexual transmission will be achieved by the existing female-only program.

Comprehensive evaluation of the cost-effectiveness of HPV vaccination in China has not previously been performed. The objective of this study was to evaluate vaccination as an alternative or addition to primary HPV screening with careHPV (Qiagen, Gaithersburg, USA), and to assess the threshold total cost per vaccinated girl (CVG) at which strategies involving vaccination would become viable compared to screening-only strategies in rural China. We used data from field studies in Shanxi Province to support modelling of HPV vaccination and screening, including local information on sexual behaviour, HPV prevalence, test accuracy, treatment protocols and costs. We evaluated several strategies involving screening once or twice per lifetime or at regular 5-yearly intervals, with or without vaccination of young females at age 15 years, assuming 70% coverage for both screening and vaccination. We also predicted cross-sectional cancer incidence each year to the year 2050 for a range of strategies. We found that strategies involving vaccination would be cost-effective at CVGs of US$50-54 or less, but at CVGs >$54, screening-only strategies would be more cost-effective. If vaccination of young cohorts is combined with two rounds of careHPV screening for women aged 30-59 years in 2012 and 2027, a predicted indicative 33% reduction in cervical cancer incidence by 2030 would be sustained until 2050, with incidence rates decreasing thereafter. In conclusion, taking into account estimated vaccine delivery costs (for 3 doses), a per-dose HPV vaccine cost of approximately

Background: Breast cancer screening is effective in reducing breast cancer mortality, but there is increasing concern that it may also lead to overdiagnosis; the detection and treatment of a cancer that would never have presented symptomatically during the woman's lifetime. Conservative management of low-risk breast cancer may reduce the harm of overdiagnosis resulting from mammographic screening programs, yet little is known about how such strategies might impact upon quality of life. Aim: To quantify women's preferences for managing low risk breast cancers identified by breast cancer screening. Methods: Utilities (measures of preference) were obtained from women with and without a history of breast cancer for seven health states reflecting low risk screen detected ductal carcinoma in situ (DCIS) using standard gambles. Demographics and a history of prior screening participation or breast cancer diagnosis were examined as predictors of screening and treatment pathway preferences. Results: Utilities were lower for breast cancers treated with mastectomy or invasive adjuvant treatment. The impact of active monitoring on quality of life was comparable to breast conserving surgery, although women in both patient and general population groups rated active monitoring more favorably as the risk of disease spread was decreased. There was some variation in ratings across patients suggesting that individual risk aversion does affect preferences for the type of conservative management valued. Conclusion: Overdiagnosis remains a challenge for improving the current breast cancer screening program. Active monitoring of low risk ductal carcinoma in situ may provide an acceptable solution for reducing the impact of overdiagnosis and overtreatment resulting from breast cancer screening on quality of life.

Background: Controversy persists about the overdiagnosis of low risk breast cancers identified by breast cancer screening programs. Low risk ductal carcinoma in situ (DCIS) is a noninvasive breast condition with an uncertain risk of invasive progression. Standard management consists of immediate surgical treatment, with or without radiotherapy and adjuvant therapy. Active monitoring of low risk DCIS via annual mammography is proposed as an alternative strategy to immediate surgery to reduce the harm of overdiagnosis, whereby the disease is only treated upon disease progression. However, the costs and benefits of active monitoring are not well researched in the breast cancer setting. Aim: To assess the cost-effectiveness of active monitoring versus immediate surgical management in women diagnosed with low grade ductal carcinoma in situ (DCIS). Methods: A Markov state transition model was constructed for a theoretical cohort of women aged 50 years and over with low risk DCIS over a lifetime horizon. A cost-utility analysis was performed to compare a strategy of observation (active monitoring) versus immediate surgical treatment using an annual time cycle. Transition probabilities, costs and utilities were obtained from national mortality and cost data, published meta-analyses, primary data collection of utilities and expert opinion. A healthcare perspective was adopted to present the results. Primary outcomes were assessed in terms of cost per quality-adjusted-life-year (cost per QALY). Multiple sensitivity analyses were undertaken to determine effect of parameter uncertainty on results. Results: The cumulative costs and QALYs for each age cohort are presented. Active monitoring is a cost-effective strategy for the management of low risk breast cancer in older women with comorbid conditions. Sensitivity analyses revealed the ICERs for all women to be affected by baseline probability of disease progression, age, cost of surgery and utility. Conclusion: Conservative management of ductal carcinoma in situ via active monitoring may be cost-effective compared with immediate surgical treatment in a selected cohort of older women with low risk disease.

Aims: The study aims to assess variation in appearance between mammographic projections (conspicuity variation) for invasive breast cancers (IBCs) compared with radial scars (RS). Conspicuity variation has been previously described as characteristic of RS. The lesions were also compared with respect to breast density and the proportion of cases detected by one of two readers and required a third (consensus) read. Materials and methods: The study was approved by the BreastScreen Victoria research committee. Mammograms of 75 randomly selected invasive breast cancers, with histological diameter 10 mm (IBC), were mixed with 67 consecutively detected RS, all from a double-reading population-based breast cancer screening programme. On blinded review, these 142 lesions were classified for mammographic findings and assessed for marked or minor conspicuity variation between views. We assessed the associations between lesion type, lesion spicules and centres, breast density, conspicuity variation and proportion detected by one reader only. Results: Marked conspicuity variation was common, but not statistically different for IBC and RS (64% vs. 66%, c

To compare double reading plus arbitration for discordance, (currently best practice, (BP)) with computer-aided-detection (CAD)-assisted single reading (CAD-R) for detection of invasive cancers detected within BreastScreen Australia. Secondarily, to examine characteristics of cancers detected/rejected using each method. Mammograms of 157 randomly selected double-read invasive cancers were mixed 1:9 with normal cancers (total 1569), all detected in a BreastScreen service. Cancers were detected by two readers or one reader (C2 and C1 cancers, ratio 70:30%) in the program. The 1569 film-screen mammograms were read by two radiologists (reader A (RA) and reader B(RB)), with findings recorded before and after CAD. Discordant findings with BP were resolved by arbitration. We compared CAD-assisted reading (CAD-RA, CAD-RB) with BP, and CAD and arbitration contribution to findings. We correlated cancer size, sensitivity and mammographic density with detection methods. BP sensitivity 90.4% compared with CAD-RA sensitivity 86.6% (P = 0.12) and CAD-RB 94.3% (P = 0.14). CAD-RB specificity was less than BP (P = 0.01). CAD sensitivity was 93%, but readers rejected most positive CAD prompts. After CAD, reader's sensitivity increased 1.9% and specificity dropped 0.2% and 0.8%. Arbitration decreased specificity 4.7%. Receiving operator curves analysis demonstrated BP accuracy better than CAD-RA, borderline significance (P = 0.07), but not CAD-RB. Secondarily, cancer size was similar for BP and CAD-R. Cancers recalled after arbitration (P = 0.01) and CAD-R (P = 0.10) were smaller. No difference in cancer size or sensitivity between reading methods was found with increasing breast density. CAD-R and BP sensitivity and cancer detection size were not significantly different. CAD-R specificity was significantly lower for one reader.

Objectives Breast cancer prognosis is better for smaller tumours. Women with high breast density are at higher risk of breast cancer and have larger screen-detected and interval cancers in mammographic screening programmes. We assess which continuous measures of breast density are the strongest predictors of breast tumour size at detection and therefore the best measures to identify women who might benefit from more intensive mammographic screening or alternative screening strategies. Setting and methods We compared the association between breast density and tumour size for 1007 screen-detected and 341 interval cancers diagnosed in an Australian mammographic screening programme between 1994 and 1996, for three semi-automated continuous measures of breast density: per cent density, dense area and dense area adjusted for non-dense area. Results After adjustment for age, hormone therapy use, family history of breast cancer and mode of detection (screen-detected or interval cancers), all measures of breast density shared a similar positive and significant association with tumour size. For example, tumours increased in size with dense area from an estimated mean 2.2 mm larger in the second quintile (β = 2.2; 95% Cl 0.4–3.9, P < 0.001) to mean 6.6 mm larger in the highest decile of dense area (β = 6.6; 95% Cl 4.4–8.9, P < 0.001), when compared with first quintile of breast density. Conclusions Of the breast density measures assessed, either dense area or per cent density are suitable measures for identifying women who might benefit from more intensive mammographic screening or alternative screening strategies.