Digital Breast Tomosynthesis : - the future screening tool for breast cancer?

Bakgrunn: Brystkreft er den vanligste kreftformen blant kvinner og en av de hyppigste årsakene til kreftdødsfall i Norge og globalt. Målsettingen med mammografiscreening er å oppdage brystkreft i et tidlig stadium og redusere dødeligheten av sykdommen. Studier har vist høyere deteksjon av screeningoppdagede krefttilfeller med digital brysttomosyntese som inkluderer ~200-250 bilder sammenlignet med standard digital mammografi (DM) med fire bilder. Vi utførte en randomisert kontrollert studie (RCT), Tomosyntese-studien i Bergen (To-Be1). Målsettingen med studien var å sammenligne tidligindikatorer i screening ved bruk av digital brysttomosyntese i kombinasjon med syntetiske 2D-bilder (DBT) versus standard DM. Avhandlingen inkluderer tre studier med følgende mål: Studie 1: Å sammenligne lesetid, stråledose, konsensus og tilbakekalling ved bruk av DBT og DM etter det første året av To-Be1. Studie 2: Å sammenligne tilbakekalling, falske positive screeningsresultater og screeningoppdaget kreft for kvinner med ulik mammografisk tetthet målt automatisk (Volpara tetthetsgrad, VDG 1-4) og med ulike screeningteknikker (DBT versus DM). Studie 3: Å undersøke fordeling av mammografiske funn hos kvinner tilbakekalt etter screening med DBT versus DM og analysere sammenhenger mellom mammografiske funn og det endelige resultatet av screeningundersøkelsen. Metode: Alle kvinner som deltok i screening utført i Bergen i løpet av 2016-2017 som en del av Mammografiprogrammet (n=32 976) ble invitert til å delta i To-Be1. Totalt aksepterte 89,3 % av kvinnene invitasjonen og ble randomisert til DBT eller DM. Etter uavhengig dobbelttyding med konsensus ble resultater etter DBT sammenlignet med DM. Mammografisk tetthet ble oppgitt som VDG 1-4, som er analog til kategoriene i BI-RADS´ 5. utgave. Radiologene klassifiserte mammografiske funn hos etterinnkalte kvinner etter en modifisert BI-RADS skala. Vi brukte deskriptive analyser og t-test for å sammenligne gjennomsnittsverdier, samt kji-kvadrat-test med tilhørende 95% konfidensintervall (KI) for å sammenligne kategorier. Log-binominale regresjonsmodeller ble brukt for å estimere relativ risiko. En p-verdi lavere enn 0,05 ble definert som statistisk signifikant. Vi brukte statistikkprogrammet STATA. Resultater: Studie 1: Gjennomsnittlig lesetid var 1:11 min:sek for DBT og 0:41 min:sek for DM i det første året av To-Be1. Det var ingen statistiske forskjeller i gjennomsnittlig stråledose for noen av tetthetskategoriene for DBT (2,96 mGy) versus DM (2,95 mGy). Tilbakekallingen var 3,0 % for DBT og 3,6 % for DM etter det første året med To-Be1. Studie 2: Etterundersøkelsesraten for kvinner med VDG 1 var 2,1% for DBT og 3,3% for DM, mens den var 3,2% for DBT og 4,3% for DM for de med VDG 2. Raten av falske positive screening resultater var 1,6% for DBT og 2,8% for DM for kvinner med VDG 1. For kvinner med VDG 2 var den 2,4% for DBT og 3,6 for DM. Ingen statistiske forskjeller i screeningoppdaget kreft ble funnet mellom DBT og DM for noen av tetthetskategoriene. Justert relativ risiko for tilbakekalling, falskt positivt screeningsresultat og screeningoppdaget kreft økte med VDG i DBT, mens det ikke ble funnet forskjeller i DM. Studie 3: Studien inkluderte 182 screeningdetekterte krefttilfeller (n=95 for DBT og n=87 for DM). Blant disse var 36,8% spikulerte masser for DBT mens det var 18,4% for DM. Kalk var det hyppigste mammografiske funnet for brystkrefttilfeller for de som var screenet med DM (23%). For DBT var andelen på 13,7%. Asymmetri, uskarp og skjult masse var mindre hyppig hos kvinner med et falsk positiv screening resultat etter screening med DBT versus DM. Konklusjon: Resultater fra To-Be1 indikerte at DBT var minst like god som DM når det gjelder etterundersøkelser og deteksjon av brystkreft, som betyr at DBT er trygt å bruke i screening. DBT var bedre egnet enn DM for kvinner med VDG 1 og 2 med hensyn til etterundersøkelsesrate og falske positive, mens deteksjon av brystkreft ikke var forskjellig. Det tok lengre tid å lese DBT enn DM bilder, og konsensus tok lengre tid med DBT. Mer kunnskap om forskjeller i mammografiske funn og sammenheng med screeningsresultater for DBT versus DM kan bidra til å ytterligere forbedre fordelene med DBT som et screeningverktøy.Background: Breast cancer is the most common cancer and one of the leading causes of cancer deaths in Norway and globally. Mammographic screening aims for early detection of breast cancer and reduced mortality from the disease. Studies have shown higher rates of screen-detected cancers for digital breast tomosynthesis including ~200-250 images compared to standard digital mammography (DM) including four images. We performed a randomized controlled trial (RCT), the Tomosynthesis trial in Bergen (To-Be1), were the aim was to compare early performance measures for digital breast tomosynthesis including synthesised 2D images (DBT) versus DM in screening. This thesis includes three studies with the following aims: Study 1: To compare preliminary results of reading time, radiation dose, consensus and recall for DBT and DM after the first year of To-Be1. Study 2: To compare recall, false positive screening results and screen-detected cancers by automated mammographic density (Volpara density grade, VDG 1-4) and screening technique (DBT versus DM). Study 3: To investigate distribution of mammographic features in women recalled after screening with DBT versus DM and assess associations between mammographic features and final outcome of the screening examination. Method: All women who attended the screening unit in Bergen during 2016-2017 as part of BreastScreen Norway (n=32 976) were invited to participate in To-Be1. In total, 89.3% of the women accepted the invitation and were randomized to undergo either DBT or DM. After independent double reading with consensus, results for DBT were compared with DM. Mammographic density were described by VDG 1-4 which are analogue to the categories in the BI-RADS 5th edition. The radiologists classified the mammographic features of recalled women according to a modified BI-RADS scale. We presented descriptive results and used t-tests to test for means, and chi-squared tests for categories with corresponding 95% confidence intervals (CI). Log-binominal regression models were used to estimate relative risks. A p-value lower than 0.05 was defined as statistically significant. We used STATA software. Results: Study 1: Mean reading time was 1:11 min:sec for DBT versus 0:41 min:sec for DM in the first year of To-Be1. Mean glandular dose did not differ statistically for women screened with DBT (2.96 mGy) versus DM (2.95 mGy). Recall was 3.0% for DBT and 3.6% for DM in the first year of To-Be1. Study 2: Recall rate for women with VDG 1 was 2.1% for DBT and 3.3% for DM, while it was 3.2% for DBT and 4.3% for DM for women with VDG 2. The rate of false positive screening results was 1.6% for DBT and 2.8% for DM for women with VDG 1. For women with VDG 2 it was 2.4% for DBT and 3.6% for DM. No statistical difference in screen-detected cancers was observed between DBT and DM in any density categories. Adjusted relative risk of recall, false positives and screen-detected cancers increased with VDG for DBT. No difference was found for DM. Study 3: The study included 182 screen detected cancers (n=95 DBT and n= 87 DM). 36.8% of those detected with DBT was spiculated mass, while it was 18.4 % for DM. Calcifications was the most frequent feature for breast cancer among those screened with DM (23.0%), which did not differ statistically from the 13.7% for DBT. Asymmetry, indistinct and obscured mass was less frequent in women with a false positive screening result after screening with DBT versus DM. Conclusion: Results from To-Be1 indicated DBT to be as least as good as DM in terms of recall and cancer detection, which means that DBT is safe for the women. DBT was superior to DM in women with VDG 1 and 2 (lower recall, fewer false positives, no difference in cancer detection). However, time spent on initial screen reading and on consensus was longer for DBT compared with DM. More knowledge of the differences in distribution of mammographic features and their association with screening outcome, might contribute to further improve the benefits of DBT as a screening tool for breast cancer.Doktorgradsavhandlin

Volumetric Mammographic Density, Age-Related Decline, and Breast Cancer Risk Factors in a National Breast Cancer Screening Program.

Background: Volumetric mammographic density (VMD) measures can be obtained automatically, but it is not clear how these relate to breast cancer risk factors.Methods: The cohort consisted of 46,428 women (ages 49-71 years) who participated in BreastScreen Norway between 2007 and 2014 and had information on VMD and breast cancer risk factors. We estimated means of percent and absolute VMD associated with age, menopausal status, body mass index (BMI), and other factors.Results: The associations between VMD and most breast cancer risk factors were modest, although highly significant. BMI was positively associated with absolute VMD, whereas inversely associated with percent VMD. Percent VMD was inversely associated with a 5-year older age at screening in premenopausal and postmenopausal women (-0.18% vs. -0.08% for percent VMD and -0.11 cm3 vs. -0.03 cm3 for absolute VMD). This difference was largest among postmenopausal women with BMI < 25 kg/m2 (P for interaction with percent VMD < 0.0001), never users of postmenopausal hormone therapy (P for interaction < 0.0001), and premenopausal women with a family history of breast cancer (P for interaction with absolute VMD = 0.054).Conclusions: VMD is associated with several breast cancer risk factors, the strongest being BMI, where the direction of the association differs for percent and absolute VMD. The inverse association with age appears modified by menopausal status and other breast cancer risk factors.Impact: Because VMD methods are becoming widely available in screening and clinical settings, the association between VMD measures and breast cancer risk factors should be investigated further in longitudinal studies. Cancer Epidemiol Biomarkers Prev; 27(9); 1065-74. ©2018 AACR

A randomized controlled trial of digital breast tomosynthesis versus digital mammography in population-based screening in Bergen: interim analysis of performance indicators from the To-Be trial

Objectives To describe a randomized controlled trial (RCT) of digital breast tomosynthesis including synthesized two-dimensional mammograms (DBT) versus digital mammography (DM) in a population-based screening program for breast cancer and to compare selected secondary screening outcomes for the two techniques. Methods This RCT, performed in Bergen as part of BreastScreen Norway, was approved by the Regional Committees for Medical Health Research Ethics. All screening attendees in Bergen were invited to participate, of which 89% (14,274/15,976) concented during the first year, and were randomized to DBT (n = 7155) or DM (n = 7119). Secondary screening outcomes were stratified by mammographic density and compared using two-sample t-tests, chi-square tests, ANOVA, negative binomial regression and tests of proportions (z tests). Results Mean reading time was 1 min 11 s for DBT and 41 s for DM (p < 0.01). Mean time spent at consensus was 3 min 12 s for DBT and 2 min 12 s for DM (p < 0.01), while the rate of cases discussed at consensus was 6.4% and 7.4%, respectively for DBT and DM (p = 0.03). The recall rate was 3.0% for DBT and 3.6% for DM (p = 0.03). For women with non-dense breasts, recall rate was 2.2% for DBT versus 3.4% for DM (p = 0.04). The rate did not differ for women with dense breasts (3.6% for both). Mean glandular dose per examination was 2.96 mGy for DBT and 2.95 mGy for DM (p = 0.433). Conclusions Interim analysis of a screening RCT showed that DBT took longer to read than DM, but had significantly lower recall rate than DM. We found no differences in radiation dose between the two techniques. Key Points • In this RCT, DBT was associated with longer interpretation time than DM • Recall rates were lower for DBT than for DM • Mean glandular radiation dose did not differ between DBT and DMpublishedVersio

Recall Rates in Screening Mammography: Variability in Performance and Decisions

Having a high recall rate may increase the probability of cancer being detected earlier, however it also has been related to increased false positive decisions, causing significant psychological and economical costs for both screened women and the mammography screening service. Therefore, the purpose of this thesis is to explore the impact of various recall rates on breast radiologists’ performance in a laboratory setting. Methods This study was designed to encompass two aspects 1) the effect of setting varying recall rates on the performance of breast radiologists in screening mammography 2) types of mammographic appearances of breast cancer are more likely to be missed at different recall rates. Five Australian breast radiologists were recruited to read one single test set of 200 mammographic cases (180 normal and 20 abnormal cases) over three different recall rate conditions: free recall, 15% and 10%. These radiologists were tasked with marking the location of suspicious lesions and providing a confidence. Results A significant decrease in radiologists’ performance was observed when reading at lower recall rates, with lower sensitivity (P=0.002), case location sensitivity (P=0.002) and ROC AUC (P=0.003). Reading at a lower recall rate had a significant increase in specificity (P=0.002). The second study of this thesis showed that breast radiologists demonstrated lower sensitivity and receiver ROC AUC for non-specific density (NSD) (P=0.04 and P=0.03 respectively) and mixed features (P=0.01 and P=0.04 respectively) when reading at 15% and 10% recall rates. No significant change was observed on cancer characterized with stellate masses (P=0.18 and P=0.54 respectively) and architectural distortion (P=1.00 and P=0.37 respectively). Conclusion Reducing the number of recalled cases to 10% significantly reduced breast radiologists’ performance. Stellate masses were likely to be recalled (90.0%) while NSDs were likely to be missed (45.6%) at reduced recall rates

The benefits and harms of breast cancer screening in Australia

The introduction of screening mammography in Australia has been associated with an increase in the incidence of early-stage breast cancer. Concern is growing about the problems caused when women are diagnosed with breast cancer and undergo treatments that do not benefit them because their cancer would not progress, or would progress, but would not become symptomatic within the remaining lifetime of the patient. This is known as overdiagnosis. Screening mammography aims to decrease breast cancer morbidity and mortality by advancing in time the diagnosis and thereby increasing the chance of successful treatment. But overdiagnosis and the consequent overtreatment can cause serious lifelong harm and are therefore considered the major downsides of breast screening. Mounting evidence of the extent of overdiagnosis has led to the recognition that the benefits and harms of breast screening are finely balanced, and women need to know the magnitude of the trade-offs. The extent of overdiagnosis due to breast screening is contested, with published estimates ranging from 1% to 57%. There is a critical need for research investigating the harm to benefit ratio in Australia and quantification of the effects of screening mammography on the incidence of stage-specific breast cancer and overdiagnosis. Individual women require information about the impact of regularly attending screening mammography on breast cancer mortality and overdiagnosis to make informed decisions. A challenge to estimating this in a randomised controlled trial is nonadherence to the trial protocol. Previous systematic reviews have provided estimates of the effect of receiving an invitation to screening on the risk of dying due to breast cancer. Chapter 2 presents a meta-analysis of the screening mammography trials using a simple adjustment that estimates the probability of a reduction in breast cancer mortality and risk of overdiagnosis due to the effect of receiving screening by regularly participating in a breast screening program. Adjustment for nonadherence increased the size of the size of the effect by up to 50%. The prevented fraction of breast cancer mortality at 13-year follow-up increased from 0.22 to 0.30 with deattenuation. The percentage risk of overdiagnosis during the screening period in women invited to screening increased from 19.0% to 29.7%. From 2013 through 2017, the Australian national breast cancer screening programme gradually invited women aged 70 to 74 years to attend screening, following a policy decision to extend invitations to older women. Yet no formal evaluation of the effects of the change in policy on outcomes for women was undertaken. Building on my meta-analysis, in Chapter 3 I used a Markov model and applied the breast cancer mortality reduction and overdiagnosis estimates reported in Chapter 2 to Australian breast cancer incidence and mortality data to estimate the benefits and harms of the new package of biennial screening from age 50 to 74 compared with the previous programme of screening from age 50 to 69. I found that the extra five years of screening results in approximately seven more overdiagnosed cancers to avert one more breast cancer death. Thus extending screening mammography in Australia to older women results in a less favourable harm to benefit ratio than stopping at age 69. To identify temporal trends in stage-specific breast cancer in Australia, I used an observational study design to analyse data on women who received a diagnosis of breast cancer from 1972 to 2012 as recorded in the New South Wales Cancer Registry (Chapter 4). I explored trends in stage-specific incidence before screening and compared them to periods after screening began. I found that screening was not associated with lower incidence of late-stage breast cancer at diagnosis and incidence for all stages remained higher than prescreening levels. In women aged 50 to 69 years, the incidence of carcinoma in situ, localised and regional breast cancer has more than doubled compared to the prescreening era. The data presented in Chapter 4 indicate that excess detection of breast cancer is a problem in New South Wales. Thus I designed an ecological study to quantify overdiagnosis. I estimated the background trend of increasing incidence using two approaches, the first based on the prescreening trend in women of screening age (50 years and older), and the second based on the contemporary trend in women too young to be screened (40 to 44 years of age). From these trends, I estimated the expected age-standardised incidence of breast cancer, by stage at diagnosis, in the absence of screening, for women aged 50 years and over in the years since the national screening mammography program, BreastScreen, was introduced (1988 to 2012). I then calculated the difference in observed and expected incidence rates to determine the excess incidence of early-stage breast cancer and reduction in the incidence of late-stage disease. I found that screening mammography has resulted in overdiagnosis of early-stage and regional breast cancer. I estimate that around six additional cases of early and regional breast cancer are detected for every distant metastatic breast cancer prevented. Due to the substantial increase in detection of carcinoma in situ of the breast observed in Chapter 4, I explored sub-types and causes of this. Chapter 6 presents a descriptive analysis of temporal trends in the incidence of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) in women who received a diagnosis from 1972 to 2012, recorded in the NSW Cancer Registry. Carcinoma in situ as a proportion of all breast cancer increased dramatically, and incidence of DCIS across all ages rose from 0.15 per 100,000 during 1972 to 1983 to 16.81 per 100,000 over 2006 to 2012, with the greatest increase seen among women in the target age group for screening (50 to 69 years). DCIS incidence has not stabilized despite screening being well established for over 20 years, and participation rates in the target age range remaining stable. Our observational estimate of overdiagnosis from Chapter 5 is different to those from meta-analyses of randomised controlled trials of screening mammography and some other observational studies. Thus the final paper in this thesis presents a Cochrane Protocol on Overdiagnosis due to screening mammography for women aged 40 years and older (Chapter 7). We present methodology to identify and evaluate all primary epidemiological studies that have quantified overdiagnosis resulting from screening mammography and provide estimates of its frequency (including randomised and observational studies). An approach to assessing the risk of bias due to lead time is also discussed. Trying to quantify the benefits and harms of screening mammography and present them to women using natural frequencies should better enable informed choice, and is consistent with the international shift towards promoting and supporting shared decision making for screening. This thesis provides valuable new evidence about the trade-offs of screening mammography in Australia. The finding that risk of harm is greater than the chance of benefit is consistent with international studies of breast screening and demonstrates the importance of continuing this work to better quantify overdiagnosis for women, clinicians, and policymakers

BreastScreen Australia evaluation : a review of methodological options for evaluating the effect of BreastScreen Australia on breast cancer mortality

This report provides evidence-based recommendations for appropriate and cost-effective methods that could be used to evaluate the impact of the national BreastScreen Australia population-based mammographic screening program on mortality from female breast cancer. The report represents a significant collaboration between the Australian Government, the National Breast Cancer Centre as well as Australian and international experts in mammography research and evaluation, epidemiology and health services research.The recommendations are based on a review of national and international evidence on approaches used to assess the impact of mammography screening programs on breast cancer mortality in other settings. The review has used a systematic approach to assessing the strategic and methodological approaches taken in each of the studies identified and their potential limitations.The national evaluation of the BreastScreen Australia Program aims to assess the appropriateness, efficiency and effectiveness of the BreastScreen Program. The completion of this report marks an important first step in that process. In addition, the review and recommendations in this report may have broader application at an international level.<br /