The Upgrade Risk of B3 Lesions to (Pre)Invasive Breast Cancer After Diagnosis on Core Needle or Vacuum Assisted Biopsy. A Belgian National Cohort Study.

INTRODUCTION: Flat epithelial atypia (FEA), lobular neoplasia (LN), papillary lesions (PL), radial scar (RS) and atypical ductal hyperplasia (ADH) are lesions of uncertain malignant potential and classified as B3 lesions by the European guidelines for quality assurance in breast cancer screening and diagnosis. Current management is usually wide local excision (WE), surveillance may be sufficient for some. We investigated the upgrade rate of B3 lesions to breast malignancy in a subsequent resection specimen after diagnosis on core needle-or vacuum assisted biopsy (CNB-VAB) in a national population-based series. METHODS: Using data from the Belgian Cancer Registry (BCR) between January 1, 2013 and December 31, 2016, inclusion criteria were new diagnosis of a B3 lesion on CNB or VAB with subsequent histological assessment on a wider excision specimen. Histological agreement between first- and follow-up investigation was analyzed to determine the upgrade risk to ductal adenocarcinoma in situ (DCIS) or invasive breast cancer (IC) according to the type of B3 lesion. RESULTS: Of 1855 diagnosed B3 lesions, 812 were included in this study: 551 after CNB-261 after VAB. After diagnosis on CNB and VAB, we found 19.0% and 14.9% upgrade to malignancy respectively. Upgrade risks after CNB and VAB were: FEA 39.5% and 17.6%; LN 40.5% and 4.3%; PL 10.4% and 12.5%; RS 25.7%and 0.0%; ADH 29.5% and 20.0%. CONCLUSION: Based on the observed upgrade rate we propose three recommendations: first, resection of ADH, and FEA with WE; second, resection of RS and classical LN with therapeutic VAB and further surveillance when radio-pathological correlation is concordant; third, surveillance of PL.

Tumour characteristics of screen-detected and interval cancers in the Flemish Breast Cancer Screening Programme: A mammographic breast density study.

OBJECTIVE: The objective is to investigate tumour prognostic factors versus breast density in screen-detected cancers and interval cancers. The results may highlight the need for more personalised screening protocols based on breast density in organized screening programmes. STUDY DESIGN: A retrospective study was performed of tumour characteristics of screen-detected cancers (n=468) and interval cancers (n=515) of 983 women who participated in the Flemish Breast Cancer Screening Programme in 2009-2010. Breast density was obtained from the screening programme data. Information on nodal invasion and histological grading was taken from the Belgian Cancer Registry. Tumour size and proliferation and receptor expression status were retrieved from pathology reports. The differences in tumour characteristics between screen-detected and interval cancers as well as the variation in these variables with breast density in both groups were studied by logistic regression. RESULTS: A comparison of tumour characteristics between screen-detected cancers and interval cancers systematically showed features of more aggressive tumours in interval cancers: larger tumour size, nodal invasion, grade 3 tumours, and hormone receptor negative phenotype (p<0.05). The analysis of tumour characteristics versus breast density in screen-detected cancers showed higher numbers of aggressive grade 3 tumours in low-density breasts and of the luminal A subtype with good prognosis in high-density breasts (p<0.05). This analysis for interval cancers highlights a high proportion of the difficult-to-treat triple-negative subtype in low-density breasts compared with high-density breasts. In conclusion, the study data support arguments against changes in breast cancer screening programmes with prolongation of screening intervals in low-density breasts.

Occurrence and characteristics of faecal immunochemical screen-detected cancers vs non-screen-detected cancers: Results from a Flemish colorectal cancer screening programme.

BACKGROUND: Colorectal cancer (CRC) and its precursor lesions are detected at an early stage by CRC screening programmes, which reduce CRC-related mortality. An important quality indicator for CRC screening is the occurrence of interval CRC (IC) between screening rounds. Currently there is no guideline regarding acceptable levels of ICs in CRC screening programmes, and ICs reported in prior work vary considerably. METHODS: This study describes the occurrence of screen-detected (SD) CRC and non-screen-detected CRC within the population-based CRC screening programme of Flanders, stratified by multiple variables such as sex, age, tumour location and tumour stage between October 2013 and July 2017. In addition, faecal immunochemical test (FIT) IC proportions over the sum of SD-CRCs and FIT-ICs are calculated, together with FIT sensitivity and programme sensitivity to display the effectiveness of detecting CRC by the screening programme. RESULTS: Of 1,212,354 FIT participants, 4094 were diagnosed with SD-CRC, whereas 772 participants were diagnosed with CRC between FIT-screening rounds. Significant associations were shown between people not being SD for CRC and women, older individuals, right-sided tumour location and more advanced tumour stage. Furthermore, a clear distinction was shown between the right-sided and the left-sided colorectum concerning all above-mentioned variables and distributions of tumour stages. CONCLUSION: The Flemish FIT-interval CRC proportion of 15.9% was within the limits of previously published results. In addition, calculations show that the effectiveness of the screening programme is dependent on tumour location, suggesting that future research should report results stratified by location.

Benefits of switching from guaiac-based faecal occult blood to faecal immunochemical testing: experience from the Wallonia-Brussels colorectal cancer screening programme.

BACKGROUND: Faecal immunochemical tests (FITs) have replaced guaiac-based faecal occult blood test (gFOBTs) in several colorectal cancer (CRC) screening programmes. We aimed to evaluate the benefits of this transition based on the Wallonia-Brussels-organised CRC screening programme. METHODS: A total of 1,569,868 individuals aged 50-74 years, who were invited to screening during 2009-2017, were studied by linking their screening records with insurance, pathology and cancer data in the Belgian Cancer Registry. We compared neoplasm detection rates and positive predictive values (PPVs) of gFOBT and FIT at 15 µg haemoglobin per gram cut-off in screen-naive individuals. We furthermore examined the incidence rates of interval cancer in gFOBT- and FIT-based screening programme. RESULTS: Advanced neoplasms were detected less frequently by gFOBT (0.8%) than by FIT (1.3%), with a difference of 0.5% (P < 0.01). PPVs were lower for gFOBT (15.1%) than for FIT (21.7%) for advanced neoplasms (difference 6.6%, P < 0.01). Compared to participants with negative gFOBT, those with negative FIT were 77% less likely to develop interval cancer (incidence rate ratio 0.23, 95% confidence interval 0.16-0.33). CONCLUSION: Our study demonstrated that in an organised CRC screening programme, replacing gFOBT with FIT improved neoplasm detection rate and substantially reduced interval cancer incidence.

Participation in faecal immunochemical testing-based colorectal cancer screening programmes in the northwest of Europe.

OBJECTIVE: This study compared the participation in four faecal immunochemical testing-based screening programmes for colorectal cancer in Flanders, France, Basque country and the Netherlands, to identify factors to further optimize faecal immunochemical testing programmes. METHOD: Background information and data on performance indicators were collected and compared for the four programmes. RESULTS: Invitation method, reminders, funding, faecal immunochemical testing cut-off and follow-up after positive faecal immunochemical testing differed in the four programmes. In France, only an invitation letter is sent by mail, while the sample kit must be collected from the general practitioner. In the other programmes, an invitation letter including the sample kit is sent by mail. Participation rates vary substantially according to the method of invitation, with the highest participation rates in the Netherlands (73.0%) and Basque country (72.4%), followed by Flanders (54.5%) and France (28.6%). Basque country (92.8%) and France (88.4%), the two programmes with most active involvement of general practitioners in referral for colonoscopy, had the highest participation rates for colonoscopy. CONCLUSIONS: Large differences in screening participation observed between programmes according to the invitation method used suggest that changes to the design of the programme, such as including the sample kit with the invitation, or active involvement of GPs, might increase participation.

Post-colonoscopy colorectal cancer in Belgium: characteristics and influencing factors.

Background and study aims Post-colonoscopy colorectal cancer (PCCRC) is an important quality parameter of colonoscopy. Most studies have shown that the risk for colorectal cancer is reduced after an index colonoscopy for screening or diagnostic purposes with or without polypectomy. In this study, we aimed to quantify and describe PCCRC in Belgium, including the possible relationships with patient, physician, and colonoscopy characteristics. Patients and methods Reimbursement data on colorectal related medical procedures from the Intermutualistic Agency (IMA-AIM) were linked with data on clinical and pathological staging of colorectal cancer (CRC) available at the Belgian Cancer Registry (BCR) over a period covering 9 years (2002 - 2010). Results In total, 63 518 colorectal cancers were identified in 61 616 patients between 2002 and 2010. We calculated a mean PCCRC rate of 7.6 %. PCCRC was significantly higher in older people and correlated significantly with polyp detection rate and the number of resections and procedures performed per year per physician. Conditional observed survival, given still alive 3 years since first colonoscopy, for PCCRC was worse than for CRC. Older patients and patients with invasive carcinomas had a worse outcome. Conclusions Although no quality register exists in Belgium, we were able to demonstrate that PCCRC in Belgium is directly related to the experience of the physician performing the procedure. In the absence of a quality register, utilization of population-based data sources proved to be a valuable tool to identify quality parameters.

Risk stratification for colorectal neoplasia detection in the Flemish colorectal cancer screening programme.

BACKGROUND: The quantitative faecal immunochemical test (FIT) detects pre-cancerous lesions and colorectal cancer (CRC). Current CRC screening programmes are based upon a binary FIT result. This study evaluates the possibility of personalised risk prediction, based on FIT, age and gender to gain more insight into improving discrimination between normal outcomes, pre-cancerous lesions, carcinoma in situ and CRC working towards a more tailored screening approach. METHODS: In this retrospective study, from October 2013 until July 2016, data from 57,421 participants who underwent a colonoscopy after a positive FIT in the Flemish CRC screening programme were analysed using a multinomial multivariable logistic regression model. RESULTS: A significant difference in risk of detecting neoplasia was found between the established risk profiles based on the combination of the quantitative FIT, age and gender. The odds for detecting CRC in men aged 74, with a FIT result of ≥1000 ng/ml, was higher by a factor of 58.43 than that for women aged 56, with a FIT result of 75 ng/ml. CONCLUSION: A large difference in risk with regard to the detection of colorectal neoplasia was found, based on demographics of the population. For some participants, the chance of finding no anomalies was more than 60%. Including additional variables in a prediction model could further increase discrimination between outcomes and practicality.

Screen-detected versus interval cancers: Effect of imaging modality and breast density in the Flemish Breast Cancer Screening Programme.

OBJECTIVES: To investigate if direct radiography (DR) performs better than screen-film mammography (SF) and computed radiography (CR) in dense breasts in a decentralized organised Breast Cancer Screening Programme. To this end, screen-detected versus interval cancers were studied in different BI-RADS density classes for these imaging modalities. METHODS: The study cohort consisted of 351,532 women who participated in the Flemish Breast Cancer Screening Programme in 2009 and 2010. Information on screen-detected and interval cancers, breast density scores of radiologist second readers, and imaging modality was obtained by linkage of the databases of the Centre of Cancer Detection and the Belgian Cancer Registry. RESULTS: Overall, 67% of occurring breast cancers are screen detected and 33% are interval cancers, with DR performing better than SF and CR. The interval cancer rate increases gradually with breast density, regardless of modality. In the high-density class, the interval cancer rate exceeds the cancer detection rate for SF and CR, but not for DR. CONCLUSIONS: DR is superior to SF and CR with respect to cancer detection rates for high-density breasts. To reduce the high interval cancer rate in dense breasts, use of an additional imaging technique in screening can be taken into consideration. KEY POINTS: • Interval cancer rate increases gradually with breast density, regardless of modality. • Cancer detection rate in high-density breasts is superior in DR. • IC rate exceeds CDR for SF and CR in high-density breasts. • DR performs better in high-density breasts for third readings and false-positives.

Breast cancer risk is increased in the years following false-positive breast cancer screening.

A small number of studies have investigated breast cancer (BC) risk among women with a history of false-positive recall (FPR) in BC screening, but none of them has used time-to-event analysis while at the same time quantifying the effect of false-negative diagnostic assessment (FNDA). FNDA occurs when screening detects BC, but this BC is missed on diagnostic assessment (DA). As a result of FNDA, screenings that detected cancer are incorrectly classified as FPR. Our study linked data recorded in the Flemish BC screening program (women aged 50-69 years) to data from the national cancer registry. We used Cox proportional hazards models on a retrospective cohort of 298 738 women to assess the association between FPR and subsequent BC, while adjusting for potential confounders. The mean follow-up was 6.9 years. Compared with women without recall, women with a history of FPR were at an increased risk of developing BC [hazard ratio=2.10 (95% confidence interval: 1.92-2.31)]. However, 22% of BC after FPR was due to FNDA. The hazard ratio dropped to 1.69 (95% confidence interval: 1.52-1.87) when FNDA was excluded. Women with FPR have a subsequently increased BC risk compared with women without recall. The risk is higher for women who have a FPR BI-RADS 4 or 5 compared with FPR BI-RADS 3. There is room for improvement of diagnostic assessment: 41% of the excess risk is explained by FNDA after baseline screening.

Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young.

OBJECTIVE: In the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients presenting with cerebrovascular disease. However, the clinical relevance was unclear in all cases. We report on detailed phenotyping in subjects identified with α-galactosidase A (α-Gal A) enzyme deficiency or GLA mutations identified in the BeFaS (n=10), and on the results of family screening in this population. METHODS: Family screening was performed to identify additional mutation carriers. Biochemical and/or clinical evaluation of all subjects (BeFaS index patients and relatives carrying a GLA mutation) was performed. RESULTS: Genetic family screening revealed 18 additional GLA mutation carriers. Bloodspot α-Gal A enzyme activity was normal in all GLA mutation carriers, even in 2 males with the p.A143T mutation. Plasma Gb3 and lyso-Gb3 levels were normal in all subjects. Elevated Gb3 in urine was detected in 2 subjects. Some classic clinical signs of Fabry disease, like angiokeratoma or cornea verticillata, could not be detected in our population. Cardiac symptoms of Fabry disease were found in 6 out of 10 p.A143T carriers. No signs of cerebrovascular disease were found in the relatives with a GLA mutation. CONCLUSIONS: We could not identify mutations causing the classical clinical phenotype of Fabry disease in our cerebrovascular disease population. Enzyme activity analysis in bloodspots and plasma may fail to identify late-onset variants of Fabry disease. We recommend genetic testing when an atypical, late-onset variant of Fabry disease is suspected in a male cerebrovascular disease patient. However, this may lead to the identification of non-disease causing or controversial genetic variants.