Comparing accuracy of tomosynthesis plus digital mammography or synthetic 2D mammography in breast cancer screening: baseline results of the MAITA RCT consortium.

AIM: The analyses here reported aim to compare the screening performance of digital tomosynthesis (DBT) versus mammography (DM). METHODS: MAITA is a consortium of four Italian trials, REtomo, Proteus, Impeto, and MAITA trial. The trials adopted a two-arm randomised design comparing DBT plus DM (REtomo and Proteus) or synthetic-2D (Impeto and MAITA trial) versus DM; multiple vendors were included. Women aged 45 to 69 years were individually randomised to one round of DBT or DM. FINDINGS: From March 2014 to February 2022, 50,856 and 63,295 women were randomised to the DBT and DM arm, respectively. In the DBT arm, 6656 women were screened with DBT plus synthetic-2D. Recall was higher in the DBT arm (5·84% versus 4·96%), with differences between centres. With DBT, 0·8/1000 (95% CI 0·3 to 1·3) more women received surgical treatment for a benign lesion. The detection rate was 51% higher with DBT, ie. 2·6/1000 (95% CI 1·7 to 3·6) more cancers detected, with a similar relative increase for invasive cancers and ductal carcinoma in situ. The results were similar below and over the age of 50, at first and subsequent rounds, and with DBT plus DM and DBT plus synthetic-2D. No learning curve was appreciable. Detection of cancers >= 20 mm, with 2 or more positive lymph nodes, grade III, HER2-positive, or triple-negative was similar in the two arms. INTERPRETATION: Results from MAITA confirm that DBT is superior to DM for the detection of cancers, with a possible increase in recall rate. DBT performance in screening should be assessed locally while waiting for long-term follow-up results on the impact of advanced cancer incidence.

Testing behavioral economics messages to increase non-responders' participation in organized colorectal cancer-screening programs: A randomized controlled trial.

This study aimed to evaluate the impact of behavioral economic-inspired messages on participation in colorectal cancer (CRC) screening programs. We conducted a randomized-controlled trial involving 11,505 non-responders to the CRC screening programs in Florence, Rome, and Turin in 2020. Participants aged 54-70 years were randomly assigned to four conditions. Individuals in the control conditions received a standard invitation letter while the three intervention groups included an additional paragraph featuring either i. normative feedback [F] message (giving feedback that invited subjects did not participate); ii. Minority norm [MN] message (only a minority did not participate); iii. F+ MN message (combining both messages). The primary outcome was the screening participation rate 90 days after the invitation was completed. A multivariate analysis was conducted adjusting for gender, age and birthplace. Overall, screening participation rates were 5.3% in the control condition, 7.0% in the F, 8.2% in the MN, and 7.4% in the F + MN arms (p = 0.002). Invited subjects in the MN arm were more likely to participate (adjusted Odds Ratio[aOR] = 1.38; 95% Confidence Interval [95%CI,1.13-1.68]), particularly those aged 54-59 years (aOR = 1.52; 95%CI:1.16-1.98), and 60-64 (aOR = 1.57; 95%CI:1.62-; 95%CI: 1.06-2.48). Additionally, individuals aged 60-64 invited in F and F + MN arms demonstrated a higher likelihood of participation (aOR for F arm = 1.60; 95%CI: 1.06-2.41; aOR for F + MN arm = 1.99; 95%CI: 1.35-2.92). The inclusion of MN and/or F messages in the invitation letter increased participation among previous non-responders <65 years. Behavioral economics is a promising area of interest for enhancing CRC screening participation. TRIAL REGISTRATION: ISRCTN registration number: ISRCTN11841256.

The impact of the COVID-19 pandemic on Italian population-based cancer screening activities and test coverage: Results from national cross-sectional repeated surveys in 2020.

Background: In Italy, regions have the mandate to implement population-based screening programs for breast, cervical, and colorectal cancer. From March to May 2020, a severe lockdown was imposed due to the COVID-19 pandemic by the Italian Ministry of Health, with the suspension of screening programs. This paper describes the impact of the pandemic on Italian screening activities and test coverage in 2020 overall and by socioeconomic characteristics. Methods: The regional number of subjects invited and of screening tests performed in 2020 were compared with those in 2019. Invitation and examination coverage were also calculated. PASSI surveillance system, through telephone interviews, collects information about screening test uptake by test provider (public screening and private opportunistic). Test coverage and test uptake in the last year were computed by educational attainment, perceived economic difficulties, and citizenship. Results: A reduction of subjects invited and tests performed, with differences between periods and geographical macro areas, was observed in 2020 vs. 2019. The reduction in examination coverage was larger than that in invitation coverage for all screening programs. From the second half of 2020, the trend for test coverage showed a decrease in all the macro areas for all the screening programs. Compared with the pre-pandemic period, there was a greater difference according to the level of education in the odds of having had a test last year vs. never having been screened or not being up to date with screening tests. Conclusions: The lockdown and the ongoing COVID-19 emergency caused an important delay in screening activities. This increased the preexisting individual and geographical inequalities in access. The opportunistic screening did not mitigate the impact of the pandemic. Funding: This study was partially supported by Italian Ministry of Health - Ricerca Corrente Annual Program 2023 and by the Emilian Region DGR 839/22.

Key performance indicators of breast cancer screening programmes in Italy, 2011-2019.

INTRODUCTION: Performance indicators for organised breast cancer screening programmes in Italy, 2011-2019, were evaluated. MATERIALS AND METHODS: Aggregated data were gathered by the National Centre for Screening Monitoring from over 150 regional or sub-regional screening programmes in Italy. Invitation and examination coverage, participation rate (PR), recall rate (RR), detection rate, positive predictive value (PPV) for the target population as a whole (women aged 50-69), by 5-year age-class, geographical macro-area (North, Centre, South-Islands with the exception of three Regions for missing/uncomplete data) and Region were estimated. RESULTS: Coverage showed an increasing positive trend, especially in the South-Islands, and PR was stable all over Italy. On the other hand, an increasing RR and decreasing PPV were recorded, especially at the first screening test and in some regions. DISCUSSION AND CONCLUSIONS: The positive increase in coverage is accompanied by a worsening of some performance indicators for which a better resource allocation and staff training are required. For this reason, further and continuous monitoring is mandatory.

Cancer screening programmes in Italy during the COVID-19 pandemic: an update of a nationwide survey on activity volumes and delayed diagnoses.

INTRODUCTION: In Italy, regional governments are in charge of implementing cervical, breast and colorectal cancer screening programmes. The 2020 Coronavirus pandemic led to a national lockdown and the temporary suspension of several non-urgent healthcare activities, including cancer screening. This paper aims to describe the results of a national survey carried out by the National Centre for Screening Monitoring (ONS) on cervical, breast and colorectal cancer screening activities in 2020. MATERIALS AND METHODS: A national survey was conducted by ONS in 2020 to assess: the number of screening invitations by Region; the volumes of screening tests and the attitude to attend the screening programme compared to 2019; the number of delayed diagnoses of malignant or pre-malignant lesions caused by the slowing down of screening programmes, based on the average Region-specific screening detection rate for cervical, breast and colorectal cancers. RESULTS: Screening tests for breast, colorectal and cervical cancer decreased by 37.6%, 45.5% and 43.4% in 2020 compared with 2019. In 2020 the estimated numbers of undiagnosed lesions are: 3,324 breast cancers, 1,299 colorectal cancers, 7,474 colorectal advanced adenomas and 2,782 CIN2 or more severe cervical lesions. Participation in cancer screening programmes decreased by 15%, 15% and 20%, for cervical, breast and CRC screening, respectively. DISCUSSION AND CONCLUSIONS: An urgent call to action is needed to prevent further delays and to limit the impact of the pandemic on cancer diagnosis and prevention.

A dynamic web-based decision aid to improve informed choice in organised breast cancer screening. A pragmatic randomised trial in Italy.

BACKGROUND: Improving the quality of information and communication is a priority in organised breast cancer screening and an ethical duty. Programmes must offer the information each woman is looking for, promoting informed decision-making. This study aimed to develop and evaluate a web-based dynamic decision aid (DA). METHODS: A pragmatic randomised trial carried out in six regional organised screening programmes recruited women at the first invitation receiving DA or a web-based standard brochure (SB). The primary outcome was informed choice measured on knowledge, attitudes, and intentions. Follow-up period: 7-10 days. Secondary outcomes included participation rate, satisfaction, decisional conflict, and acceptability of DA. RESULTS: Two thousand one hundred and nineteen women were randomised and 1001 completed the study. Respectively, 43.9% and 36.9% in the DA and SB reached the informed choice. The DA gave a 13-point higher proportion of women aware about overdiagnosis compared to SB (38.3% versus 25.2%, p < 0.0001). The percentage of women attending screening was the same: 84% versus 83%. Decisional conflict was significantly lower in the DA group (14.4%) than in the SB group (19.3%). CONCLUSION: DA increases informed choice. Complete information including the pros, cons, controversies, and overdiagnosis-overtreatment issues boost a woman's knowledge without reducing the rate of actual screening participation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT03097653.

[Tailored Breast Screening Trial (TBST)]. / Tailored Breast Screening Trial (TBST).

BACKGROUND: mammography screening in premenopausal women is still the object of controversy and the cost and harms-benefit balance is lower than the one observed for women aged 50 years or more. The reasons are the lower screening sensitivity and the lower risk of occurrence of breast cancer at younger ages. For these reasons, an annual interval is suggested for this age group, and a lower positive predictive value of the recall rate is observed in screening practice. Harms of screening are false positive rates and overdiagnosis (that is an exceeding number of cases over the women's lifetime ascribable to early diagnosis). A tailored approach to screening could both contribute to a reduction of possible harms and reduce the costs of the service screening programmes, which started to offer screening mammography to 45- 49-year-old women also in Italy, according with the suggestions of the Italian Group for Mammography Screening. Higher breast density is considered a marker of risk and, at the same time, it brings about a masking effect that decreases the screening mammography sensitivity at younger ages. AIM: the Tailored Breast Screening Trial (TBST) is a population-based, non-inferiority randomised trial aimed at evaluating the impact of a change in the screening protocol in a service screening practice. "Tailored" means that the use of a breast density classification allocates women to a longer interval, decreasing the number of screening rounds in the 45- 50-year age range. Density of the breast at the baseline is considered as an indicator of risk and also as a masking factor. The aim of this study is to assess the impact of a longer interval and the reduction of side effects for women allocated to the intervention group. In this study, any further intervention is offered to high-density women who are followed-up according to the usual care interval, since the study aimed at decreasing the screening burden. METHODS: 45-year-old women resident in the screening centre catchment area will be invited to attend for mammography screening and will be asked for informed consent in order to be included in the study. After the enrolment, they will receive a high quality digital mammography; two views and breast density will be classified according with the BI-RADS classification. Women are randomly allocated either to an usual care group or to the intervention group. In the intervention group, women with a dense breast (3-4 categories in BI-RADS)will be invited again after 1 year, while the lower-density group in the intervention arm will be invited after 2 years. After the age of 50, all women will continue to be screened in the usual service screening programme. Density of the breast will be read by 2 readers, and controversies will be solved by a consensus. Allocation of women is blinded to the mammography readers. EXPECTED RESULTS: the outcomes are: A. cumulative incidence of interval-cancer cases by intention to treat (ITT) grouping and by density group, aimed at assessing the non inferiority of screening performance; B. cumulative incidence of T2+/node-positive status breast cancer cases between arms and by protocol. Screening performance parameters will be evaluated at each screening round. Interim and outcome analysis are expected at 3 and 6 years average follow- up, respectively, starting from the beginning of the screening. SAMPLE SIZE: the non-inferiority limit is derived from the accepted level of interval cancers in women 50-69 years, which was considered acceptable by the European Community Guidelines. Assuming a 70%BI-RADS 1-2 at the baseline on the basis of the digital mammography experience, the estimated sample size with a power of 90% is 16,596 women per arm. RESULTS OF THE FEASIBILITY STUDY: the background of the study, that uses data from cancer registries and screening centres, describes the most relevant characteristics of breast cancer occurring in the Italian regions where the study will be conducted. The description of stage distribution in the 40-54-year-old group and the coverage by spontaneous screening, as available by outpatient current data, showed the modification of stage at presentation, according with the implementation of service screening in women 50-54 years. In Emilia-Romagna and Piedmont Regions, service screening is already active for women aged 45 years and more, even though different invitation protocols were used. In Tuscany Region the extension of screening has already been planned for the next few years. Performance data are reported: they show the recall and the detection rates at first and at repeated screening rounds in Emilia-Romagna Region. In order to assess the feasibility and the interobserver reproducibility of breast density visual classification by BI-RADS, two testing sets of 80 digital mammograms for screened women aged 50-52 years were made available by the ISPO (Institute for oncological study and prevention) service screening tests. The test was performed by 11 radiologists, which are members of the working group. Concordance was moderate with a BI-RADS classification in 4 categories (kappa=0.46;95%CI 0.41-0.53), and substantial using 1-2 vs.3-4 (kappa=0.68;95%CI 0.59-0.79). The retest performed using the second mammography test did not change the results. CONCLUSION: the TBST was authorised by the Ethical Committee in Florence (Tuscany Region, Central Italy) and the recruitment is still in progress through the invitation of the target population in the participating screening centres. In Florence and Veneto Region, the first round is almost completed and it confirmed the feasibility of the study and of the randomisation process.

Direct mailing of faecal occult blood tests for colorectal cancer screening: a randomized population study from Central Italy.

BACKGROUND: Sending faecal occult blood tests (FOBT) by mail has been proposed both as a method to increase participation and a way to reduce staff costs in colorectal cancer screening. METHODS: Two multicentre randomized controlled trials (ISRCTN10351276) were performed: one randomly assigned 3196 individuals who had previously participated in colorectal screening to receive a FOBT kit at home or a standard invitation; in the second, 4219 people aged 50-69 years who did not respond to a screening invitation were either sent a FOBT or a standard recall letter. The cost per returned kit was calculated in each arm. RESULTS: Participation was higher with direct FOBT mailing in both trials: relative risk 1.11 (95% CI 1.06-1.17) and 1.36 (95% CI 1.16-1.60) for previous responders and non-responders, respectively. The cost per returned kit for previous responders ranged from 4.24€ to 16.10€, and from 3.29€ to 7.36€ with FOBT mailing and standard invitation, respectively, not including staff costs; for non-responders it ranged from 17.13€ to 46.80€, and from 7.36€ to 18.30€ with FOBT mailing and standard recall, respectively. CONCLUSIONS: The FOBT mailing strategy modestly increased participation. This method can be used on a population of previous responders to reduce personnel costs and workload. When used as a reminder to non-responders, this method increases costs.

Molecular profile in body fluids in subjects enrolled in a randomised trial for lung cancer screening: Perspectives of integrated strategies for early diagnosis.

The aim of this study was to evaluate the diagnostic value of a grid of molecular genetic markers detectable in sputum and plasma samples of individuals enrolled in a lung cancer screening program with low-dose CT. Subjects enrolled in the baseline screening round of the ITALUNG (randomised) screening trial were invited to provide biological specimens for molecular analysis (1356 subjects out of 1406). We included 98 subjects in this analysis. There was a highly statistically significant difference between proportion of subjects with a negative baseline CT screening test who were positive to allelic imbalance, and those with a non-calcified nodule (NCN greater than or equal to 5mm), the reason of recall for all suspects at CT Scan (chi(2): 22.9; P<0.0001). Allelic imbalance showed good performance for screening of NCN > or = 5 mm. In subjects recalled for NCN > or = 5 mm, LOH, K-ras mutations and high levels of free plasma DNA (>5ng/ml plasma) might be important to support clinical decision making for further follow-up and repeated screening. This study, embedded in an early diagnosis randomised trial, suggests that a multi-screening approach integrating imaging technique and a biomolecular marker panel is worth of further investigation.

An estimate of overdiagnosis 15 years after the start of mammographic screening in Florence.

AIM: Several studies have tried to quantify overdiagnosis of breast cancer with mammography screening, but estimates vary widely. The aim of this study is to evaluate the degree of overdiagnosis of breast cancer 15 years after the introduction of service screening in Florence (Italy). METHODS: We selected 61,568 women aged 50-69 years at the beginning of service screening (1990) and we used the cancer registry data to follow up them for breast cancer incidence. The measure of overdiagnosis is the ratio of cumulative incidence of breast cancer in the invited group (observed) at least 5 years after the last screening to that expected in the absence of screening. RESULTS: Under the assumption of a 1.2% annual trend in pre-screening incidence in women aged 60-69 years at the start of service screening, the ratio of observed to expected cumulative cases was 1.01 (95%CI: 0.95-1.07), but assuming no incidence trend, an unlikely scenario, the estimate of overdiagnosis rose to 1.13 (95%CI: 1.07-1.19). CONCLUSION: Overdiagnosis of breast cancer in Florentine service screening can be estimated only for women aged 60-69 years at the start of service screening, for it is only for this group that a sufficient follow-up period is available after the last screening. Although the estimate of overdiagnosis is very sensitive to pre-screening trend estimates, our data show that 15 years after the introduction of mammographic service screening the degree of overdiagnosis was nearly zero and more than likely lower than 13% in this age group.

Early diagnosis, not differential treatment, explains better survival in service screening.

Italian population-based breast cancer screening programmes with 2-year, high-quality mammography started in the cities of Florence and Turin in the early 1990s. Breast cancer cases from the local Tumour Registry were classified by method of detection and tumour characteristics (size, nodal-status and grade). Follow-up was at December 2001. In total, 4444 breast cancer cases were analysed. The Hazard Ratio comparing before and after-invitation breast cancer cases indicated a 27% reduction (HR=0.73; 95%CI: 0.61-0.87) in the risk of dying for the disease. After adjustment for tumour characteristics, survival rate was comparable by invitation status, whereas the proportion of early cancer was 33.7% and 46.6% in the before and after-invitation group. Survival rates by tumour characteristic subgroups was comparable by invitation status. Late stage and grade 3 were indicators of poor prognosis. Adjustment for tumour characteristics confirmed screening and not differential treatment as the most important reason for the observed survival benefit. The survival analysis by specific subgroups did not support the hypothesis that the difference in prognosis was attributable to differential treatment.