The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 mm in size)-results from the UK Sloane Project.

BACKGROUND: The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial. METHODS: We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the Sloane project. RESULTS: Microinvasion was recorded in 521 of 11,285 patients (4.6%), with considerable variation in reported incidence among screening units (0-25%). Microinvasion was associated with high-grade DCIS, larger DCIS size, comedo necrosis and solid, cribriform architecture (all P < 0.001). Microinvasion was more frequent in patients who underwent mastectomy compared with breast-conserving surgery (BCS) (6.9% vs 3.6%, P < 0.001), and in those undergoing axillary nodal surgery (60.4% vs 30.3%, P < 0.001) including the subset undergoing BCS (43.4% vs 8.5%, P < 0.001). Nodal metastasis rate was low and not statistically significant difference from the DCIS only group (P = 0.68). Following median follow-up of 110 months, 3% of patients had recurrent ipsilateral high-grade DCIS, and 4.2% developed invasive carcinoma. The subsequent ipsilateral invasion was of Grade 3 in 71.4% of patients with microinvasion vs 30.4% in DCIS without microinvasion (P = 0.02). Distant metastasis and breast cancer mortality were higher with microinvasion compared with DCIS only (1.2% vs 0.3%, P = 0.01 and 2.1% vs 0.8%; P = 0.005). CONCLUSIONS: The higher breast cancer mortality with microinvasion indicates a more aggressive disease.

Pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane Project.

BACKGROUND: The Sloane audit compares screen-detected ductal carcinoma in situ (DCIS) pathology with subsequent management and outcomes. METHODS: This was a national, prospective cohort study of DCIS diagnosed during 2003-2012. RESULTS: Among 11,337 patients, 7204 (64%) had high-grade DCIS. Over time, the proportion of high-grade disease increased (from 60 to 65%), low-grade DCIS decreased (from 10 to 6%) and mean size increased (from 21.4 to 24.1 mm). Mastectomy was more common for high-grade (36%) than for low-grade DCIS (15%). Few (6%) patients treated with breast-conserving surgery (BCS) had a surgical margin <1 mm. Of the 9191 women diagnosed in England (median follow-up 9.4 years), 7% developed DCIS or invasive malignancy in the ipsilateral and 5% in the contralateral breast. The commonest ipsilateral event was invasive carcinoma (n = 413), median time 62 months, followed by DCIS (n = 225), at median 37 months. Radiotherapy (RT) was most protective against recurrence for high-grade DCIS (3.2% for high-grade DCIS with RT compared to 6.9% without, compared with 2.3 and 3.0%, respectively, for low/intermediate-grade DCIS). Ipsilateral DCIS events lessened after 5 years, while the risk of ipsilateral invasive cancer remained consistent to beyond 10 years. CONCLUSION: DCIS pathology informs patient management and highlights the need for prolonged follow-up of screen-detected DCIS.

Effect of general practice characteristics and antibiotic prescribing on Escherichia coli antibiotic non-susceptibility in the West Midlands region of England: a 4 year ecological study.

Objectives: To assess the effect of general practice characteristics and antibiotic prescribing on the number of non-susceptible Escherichia coli isolated from urine specimens submitted from community settings, we undertook an ecological study of the general practice population in the West Midlands. Methods: Descriptive analysis and multilevel modelling of temporal trends in antibiotic prescribing and non-susceptibility of E. coli urine isolates to a range of antibiotics prescribed in the community over a 4 year period. Results: Nine of the 16 antibiotic prescribing/non-susceptibility combinations demonstrated a significant statistical linear correlation with non-susceptibility either for prescribing in a quarter or for prescribing within the previous 12 months. The magnitude of the effect varied, from a 0.3% increase in the odds of non-susceptibility to ampicillin/amoxicillin (when prescribing ampicillin/amoxicillin) to a 6.3% increase in the odds of non-susceptibility to nitrofurantoin (when prescribing nitrofurantoin) for an increase of 50 DDDs per 1000 practice population within a quarter (equivalent to ∼10 courses of antibiotics). In all 16 models, single-handed general practices were shown to have a significant association with increased numbers of non-susceptible E. coli urine isolates (adjusted ORs 1.083-1.657). Increased prescribing of ampicillin/amoxicillin in winter periods was associated with increased non-susceptibility of E. coli isolated from urine specimens. Conclusions: Small increases in antibiotic prescribing in individual general practices reduce the number of susceptible bacteria in the practice population. To maintain the effectiveness of available treatment, antibiotic stewardship should be encouraged and supported within each practice.

Atypia detected during breast screening and subsequent development of cancer: observational analysis of the Sloane atypia prospective cohort in England.

OBJECTIVE: To explore how the number and type of breast cancers developed after screen detected atypia compare with the anticipated 11.3 cancers detected per 1000 women screened within one three year screening round in the United Kingdom. DESIGN: Observational analysis of the Sloane atypia prospective cohort in England. SETTING: Atypia diagnoses through the English NHS breast screening programme reported to the Sloane cohort study. This cohort is linked to the English Cancer Registry and the Mortality and Birth Information System for information on subsequent breast cancer and mortality. PARTICIPANTS: 3238 women diagnosed as having epithelial atypia between 1 April 2003 and 30 June 2018. MAIN OUTCOME MEASURES: Number and type of invasive breast cancers detected at one, three, and six years after atypia diagnosis by atypia type, age, and year of diagnosis. RESULTS: There was a fourfold increase in detection of atypia after the introduction of digital mammography between 2010 (n=119) and 2015 (n=502). During 19 088 person years of follow-up after atypia diagnosis (until December 2018), 141 women developed breast cancer. Cumulative incidence of cancer per 1000 women with atypia was 0.95 (95% confidence interval 0.28 to 2.69), 14.2 (10.3 to 19.1), and 45.0 (36.3 to 55.1) at one, three, and six years after atypia diagnosis, respectively. Women with atypia detected more recently have lower rates of subsequent cancers detected within three years (6.0 invasive cancers per 1000 women (95% confidence interval 3.1 to 10.9) in 2013-18 v 24.3 (13.7 to 40.1) in 2003-07, and 24.6 (14.9 to 38.3) in 2008-12). Grade, size, and nodal involvement of subsequent invasive cancers were similar to those of cancers detected in the general screening population, with equal numbers of ipsilateral and contralateral cancers. CONCLUSIONS: Many atypia could represent risk factors rather than precursors of invasive cancer requiring surgery in the short term. Women with atypia detected more recently have lower rates of subsequent cancers detected, which might be associated with changes to mammography and biopsy techniques identifying forms of atypia that are more likely to represent overdiagnosis. Annual mammography in the short term after atypia diagnosis might not be beneficial. More evidence is needed about longer term risks.

Evidence-informed recommendations on managing breast screening atypia: perspectives from an expert panel consensus meeting reviewing results from the Sloane atypia project.

Evidence-based clinical guidelines are essential to maximize patient benefit and to reduce clinical uncertainty and inconsistency in clinical practice. Gaps in the evidence base can be addressed by data acquired in routine practice. At present, there is no international consensus on management of women diagnosed with atypical lesions in breast screening programmes. Here, we describe how routine NHS breast screening data collected by the Sloane atypia project was used to inform a management pathway that maximizes early detection of cancer and minimizes over-investigation of lesions with uncertain malignant potential. A half-day consensus meeting with 11 clinical experts, 1 representative from Independent Cancer Patients' Voice, 6 representatives from NHS England (NHSE) including from Commissioning, and 2 researchers was held to facilitate discussions of findings from an analysis of the Sloane atypia project. Key considerations of the expert group in terms of the management of women with screen detected atypia were: (1) frequency and purpose of follow-up; (2) communication to patients; (3) generalizability of study results; and (4) workforce challenges. The group concurred that the new evidence does not support annual surveillance mammography for women with atypia, irrespective of type of lesion, or woman's age. Continued data collection is paramount to monitor and audit the change in recommendations.

Laboratory diagnosed microbial infection in English UK Biobank participants in comparison to the general population.

Understanding the genetic and environmental risk factors for serious bacterial infections in ageing populations remains incomplete. Utilising the UK Biobank (UKB), a prospective cohort study of 500,000 adults aged 40-69 years at recruitment (2006-2010), can help address this. Partial implementation of such a system helped groups around the world make rapid progress understanding risk factors for SARS-CoV-2 infection and COVID-19, with insights appearing as early as May 2020. In principle, such approaches could also to be used for bacterial isolations. Here we report feasibility testing of linking an England-wide dataset of microbial reporting to UKB participants, to enable characterisation of microbial infections within the UKB Cohort. These records pertain mainly to bacterial isolations; SARS-CoV-2 isolations were not included. Microbiological infections occurring in patients in England, as recorded in the Public Health England second generation surveillance system (SGSS), were linked to UKB participants using pseudonymised identifiers. By January 2015, ascertainment of laboratory reports from UKB participants by SGSS was estimated at 98%. 4.5% of English UKB participants had a positive microbiological isolate in 2015. Half of UKB isolates came from 12 laboratories, and 70% from 21 laboratories. Incidence rate ratios for microbial isolation, which is indicative of serious infection, from the UKB cohort relative to the comparably aged general population ranged from 0.6 to 1, compatible with the previously described healthy participant bias in UKB. Data on microbial isolations can be linked to UKB participants from January 2015 onwards. This linked data would offer new opportunities for research into the role of bacterial agents on health and disease in middle to-old age.

Unresected screen-detected ductal carcinoma in situ: Outcomes of 311 women in the Forget-Me-Not 2 study.

BACKGROUND AND AIM: The natural history of ductal carcinoma in situ (DCIS) is poorly understood. The aim of this cohort study was to determine the outcomes of women who had no surgery for screen-detected DCIS in the 6 months following diagnosis. METHODS: English breast screening databases were retrospectively searched for women diagnosed with DCIS without invasive cancer at screening and who had no record of surgery within 6 months of diagnosis. These were cross-referenced with cancer registry data. Details of the potentially eligible women were sent to the relevant breast screening units for verification and for completion of data forms detailing clinical, radiological and pathological findings, non-surgical treatment and subsequent clinical course. RESULTS: Data for 311 eligible women (median age 62 years) were available. 60 women developed invasive cancer, 56 ipsilateral and 4 contralateral. Ipsilateral invasion risk increased approximately linearly with time for at least 10 years. The 10-year cumulative risk of ipsilateral invasion was 9% (95% CI 4-21%), 39% (24-58%) and 36% (24-50%) for low, intermediate and high grade DCIS respectively and was higher in younger women, in those with larger DCIS lesions and in those with microinvasion. Most invasive cancers that developed were grade 2 or 3. CONCLUSION: The findings suggest that active surveillance may be a reasonable alternative to surgery in patients with low grade DCIS but that women with intermediate or high grade disease should continue to be offered surgery. This highlights the importance of reproducible grading of DCIS to ensure patients receive appropriate treatment.

Breast screening atypia and subsequent development of cancer: protocol for an observational analysis of the Sloane database in England (Sloane atypia cohort study).

INTRODUCTION: The National Health Service (NHS) Breast Screening Programme aims to detect cancer earlier when treatment is more effective but can harm women by over diagnosing and overtreating cancers which would never have become symptomatic. As well as breast cancer, a spectrum of atypical epithelial proliferations (atypia) can also be detected as part of screening. This spectrum of changes, while not cancer, may mean that a woman is more likely to develop breast cancer in the future. Follow-up of atypia is not evidence based. We currently do not know which atypia should be detected to avoid future cancer. This study will explore how atypia develops into breast cancer in terms of number of women, time of cancer development, cancer type and severity, and whether this varies for different types of atypia. METHODS AND ANALYSIS: The Sloane cohort study began in April 2003 with ongoing data collection including atypia diagnosed through screening at screening units in the UK. The database for England has 3645 cases (24 September 2020) of epithelial atypia, with follow-up from 1 to 15 years. The outcomes include subsequent invasive breast cancer and the nature of subsequent cancer. Descriptive statistics will be produced. The observed rates of breast cancer at 1, 3 and 6 years for types of atypia will be reported with CIs, to enable comparison to women in the general population. Time to event methods will be used to describe the time to breast cancer diagnosis for the types of atypia, including flexible parametric modelling if appropriate. Patient representatives from Independent Cancer Patients' Voice are included at every stage of the research. ETHICS AND DISSEMINATION: The study has received research ethics approval from the University of Warwick Biomedical and Scientific Research Ethics Committee (BSREC 10/20-21, 8 October 2020), Public Health England office for data release approvals (ODR1718_313) and approval from the English Breast Research Advisory Committee (BSPRAC_031). The findings will be disseminated to breast screening clinicians (via journal publication and conference presentation), to the NHS Breast Screening Programme to update their guidelines on how women with atypia should be followed up, and to the general public.

Cohort profile of the Sloane Project: methodology for a prospective UK cohort study of >15 000 women with screen-detected non-invasive breast neoplasia.

PURPOSE: The introduction of breast screening in the UK led to an increase in the detection of non-invasive breast neoplasia, predominantly ductal carcinoma in situ (DCIS), a non-obligatory precursor of invasive breast cancer. The Sloane Project, a UK prospective cohort study of screen-detected non-invasive breast neoplasia, commenced in 2003 to evaluate the radiological assessment, surgical management, pathology, adjuvant therapy and outcomes for non-invasive breast neoplasia. Long-term follow-up and accurate data collection are essential to examine the clinical impact. Here, we describe the establishment, development and analytical processes for this large UK cohort study. PARTICIPANTS: Women diagnosed with non-invasive breast neoplasia via the UK National Health Service Breast Screening Programme (NHSBSP) from 01 April 2003 are eligible, with a minimum age of 46 years. Diagnostic, therapeutic and follow-up data collected via proformas, complement date and cause of death from national data sources. Accrual for patients with DCIS ceased in 2012 but is ongoing for patients with epithelial atypia/in situ neoplasia, while follow-up for all continues long term. FINDINGS TO DATE: To date, patients within the Sloane cohort comprise one-third of those diagnosed with DCIS within the NHSBSP and are representative of UK practice. DCIS has a variable outcome and confirms the need for longer-term follow-up for screen-detected DCIS. However, the radiology and pathology features of DCIS can be used to inform patient management. We demonstrate validation of follow-up information collected from national datasets against traditional, manual methods. FUTURE PLANS: Conclusions derived from the Sloane Project are generalisable to women in the UK with screen-detected DCIS. The follow-up methodology may be extended to other UK cohort studies and routine clinical follow-up. Data from English patients entered into the Sloane Project are available on request to researchers under data sharing agreement. Annual follow-up data collection will continue for a minimum of 20 years.

Risk factors for the development of invasive cancer in unresected ductal carcinoma in situ.

BACKGROUND: The natural history of ductal carcinoma in situ (DCIS) remains uncertain. The risk factors for the development of invasive cancer in unresected DCIS are unclear. METHODS: Women diagnosed with DCIS on needle biopsy after 1997 who did not undergo surgical resection for ≥1 year after diagnosis were identified by breast centres and the cancer registry and outcomes were reviewed. RESULTS: Eighty-nine women with DCIS diagnosed 1998-2010 were identified. The median age at diagnosis was 75 (range 44-94) years with median follow-up (diagnosis to death, invasive disease or last review) of 59 (12-180) months. Twenty-nine women (33%) developed invasive breast cancer after a median interval of 45 (12-144) months. 14/29 (48%) with high grade, 10/31 (32%) with intermediate grade and 3/17 (18%) with low grade DCIS developed invasive cancer after median intervals of 38, 60 and 51 months. The cumulative incidence of invasion was significantly higher in high grade DCIS than other grades (p = .0016, log-rank test). Invasion was more frequent in lesions with calcification as the predominant feature (23/50 v. 5/25; p = .042) and in younger women (p = .0002). Endocrine therapy was associated with a lower rate of invasive breast cancer (p = .048). CONCLUSIONS: High cytonuclear grade, mammographic microcalcification, young age and lack of endocrine therapy were risk factors for DCIS progression to invasive cancer. Surgical excision of high grade DCIS remains the treatment of choice. Given the uncertain long-term natural history of non-high grade DCIS, the option of active surveillance of women with this condition should be offered within a clinical trial.