Disease Registration Service Research Articles

Implementation of a national rapid prenatal exome sequencing service in England: evaluation of service outcomes and factors associated with regional variation

IntroductionPrenatal exome sequencing (pES) can enhance genetic diagnosis of fetuses with structural anomalies and has recently been introduced as a national service in England. We aimed to examine service outcomes such as diagnostic yield (definite final diagnosis), referral rate, and sources of referral, and explore variation in outcomes of pES by individual or service level factors between 01 October 2021 and 30 June 2022.MethodspES testing results from the National Health Service laboratories performing testing were linked to National Congenital Anomaly and Rare Disease Registration Service data and the Maternity Services Data Set and descriptive statistics computed.ResultsThere were 475,089 women who gave birth in England during the study period. The referral rate for pES was 8.6 (95% CI 7.8, 9.4) per 10,000 maternities. About 59% of those referred proceeded with pES testing and 35% of women who proceeded received a definite final diagnosis with a median turnaround time of 15 days. Of those who had pES testing, 64.6% had a live birth, 25.3% underwent termination of pregnancy (median gestational age at termination: 26 weeks), and 9.3% had a stillbirth. Among the 85 women who had a definite final diagnosis, 40% had a termination of pregnancy, 18% had a stillbirth, and 42% had a live birth. The corresponding figures among women without a definite final diagnosis were 18%, 5%, and 78%, respectively. Among women who had a termination of pregnancy, the median gestational age at final report was 24.9 weeks and 26.2 weeks at termination. Variation observed in some of the characteristics and outcomes between regional services were limited by small sample size.ConclusionThis study showed that of those referred, pES testing provided a diagnosis for one in three pregnancies with a fetal anomaly across England during the study period when other tests had been non-informative. Women who opted for a termination of pregnancy underwent the procedure at relatively late gestations. Earlier referral for pES, streamlining pathways, and faster turnaround times may help results to be available at an earlier gestation to allow families more time to make decisions around continuing or terminating their pregnancy. The variation in service outcomes between regional services needs to be investigated further to understand the reasons for these differences.

Second Primary Cancer Risks After Breast Cancer in BRCA1 and BRCA2 Pathogenic Variant Carriers.

Second primary cancer (SPC) risks after breast cancer (BC) in BRCA1/BRCA2 pathogenic variant (PV) carriers are uncertain. We estimated relative and absolute risks using a novel linkage of genetic testing data to population-scale National Disease Registration Service and Hospital Episode Statistics electronic health records. We followed 25,811 females and 480 males diagnosed with BC and tested for germline BRCA1/BRCA2 PVs in NHS Clinical Genetics centers in England between 1995 and 2019 until SPC diagnosis, death, migration, contralateral breast/ovarian surgery plus 1 year, or the 31st of December 2020. We estimated standardized incidence ratios (SIRs) using English population incidences, hazard ratios (HRs) comparing carriers to noncarriers using Cox regression, and Kaplan-Meier 10-year cumulative risks. There were 1,840 BRCA1 and 1,750 BRCA2 female PV carriers. Compared with population incidences, BRCA1 carriers had elevated contralateral BC (CBC; SIR, 15.6 [95% CI, 11.8 to 20.2]), ovarian (SIR, 44.0 [95% CI, 31.4 to 59.9]), combined nonbreast/ovarian (SIR, 2.18 [95% CI, 1.59 to 2.92]), colorectal (SIR, 4.80 [95% CI, 2.62 to 8.05]), and endometrial (SIR, 2.92 [95% CI, 1.07 to 6.35]) SPC risks. BRCA2 carriers had elevated CBC (SIR, 7.70 [95% CI, 5.45 to 10.6]), ovarian (SIR, 16.8 [95% CI, 10.3 to 26.0]), pancreatic (SIR, 5.42 [95% CI, 2.09 to 12.5]), and combined nonbreast/ovarian (SIR, 1.68 [95% CI, 1.24 to 2.23]) SPC risks. Compared with females without BRCA1/BRCA2 PVs on testing, BRCA1 carriers had elevated CBC (HR, 3.60 [95% CI, 2.65 to 4.90]), ovarian (HR, 33.0 [95% CI, 19.1 to 57.1]), combined nonbreast/ovarian (HR, 1.45 [95% CI, 1.05 to 2.01]), and colorectal (HR, 2.93 [95% CI, 1.53 to 5.62]) SPC risks. BRCA2 carriers had elevated CBC (HR, 2.40 [95% CI, 1.70 to 3.40]), ovarian (HR, 12.0 [95% CI, 6.70 to 21.5]), and pancreatic (HR, 3.56 [95% CI, 1.34 to 9.48]) SPC risks. Ten-year cumulative CBC, ovarian, and combined nonbreast/ovarian cancer risks were 16%/6.3%/7.8% (BRCA1 carriers), 12%/3.0%/6.2% (BRCA2 carriers), and 3.6%/0.4%/4.9% (noncarriers). Male BRCA2 carriers had higher CBC (HR, 13.1 [95% CI, 1.19 to 146]) and prostate (HR, 5.61 [95% CI, 1.96 to 16.0]) SPC risks than noncarriers. Survivors of BC carrying BRCA1 and BRCA2 PVs are at high SPC risk. They may benefit from enhanced surveillance and risk-reduction measures.

Abstract PO4-17-05: Patterns of care: radiotherapy after breast conserving surgery and the use of endocrine therapy for screen-detected ductal carcinoma in situ (DCIS) in the UK

Abstract Background The use of adjuvant radiotherapy (RT) and endocrine therapy (ET) in the management of pure ductal carcinoma in situ (DCIS) remains controversial. We investigate how the use of adjuvant RT after breast conserving surgery (BCS) and use of adjuvant ET (in BCS and mastectomy patients) has changed over time. Methods A prospective cohort SQL database of 11,284 patients (the Sloane Project) diagnosed 2003-2012 with screen-detected DCIS in the UK was interrogated for use of adjuvant RT and ET over time and association with factors reported to be predictive of recurrence (patient age, DCIS nuclear grade, size, comedo necrosis, resection margins), as well as institution of surgery, travel time to radiotherapy facility, Index of Multiple Deprivation and outcome (provided by the National Disease Registration Service, NDRS). RT data by site were confirmed with more recent data from the National Audit of Breast Cancer in Older Patients (NABCOP), which looked at patterns of care and outcomes for women aged 70 years and over, compared with those aged 50-64 in England and Wales. Results Among the 7,949 women (70.6%) treated by BCS, post-operative adjuvant RT was given to 4,939 (62.1%); RT use after BCS increased over time (R2 =0.92; p< 0.01). RT use was associated with year of diagnosis (p < 0.01), younger age at diagnosis (p < 0.01), larger DCIS size (p < 0.01), presence of comedo necrosis (p < 0.01), higher nuclear grade (p < 0.01) and presence of microinvasion (p < 0.01). Adjusted analyses showed the most significant factor for RT after BCS was the surgery institution. Travel time to RT facility, Index of Multiple Deprivation and final radial margin were not associated with RT use. When compared with the more recent data from the NABCOP, a marked variation in radiotherapy use across hospitals remains. Ipsilateral recurrence rate varied significantly by hospital, with some of the difference associated with RT utilisation. ET was prescribed in 1313 women (12%), more often following BCS than mastectomy (p < 0.001), with significant variation by institution and a decline in the use of ET over time. Conclusion Marked geographic variation in the use of RT and ET after surgery for DCIS persists in the UK and is likely due to physician choice rather than other factors such as travel times to RT facilities. This is contributing to geographic variation in ipsilateral recurrence rates, suggesting the need for adoption of more authoritative guidelines to support clinical decision-making. Consistent national practice could provide auditable performance standards for adjuvant therapy of screen detected DCIS and contribute to more uniform patient care. Citation Format: Karen Clements, David Dodwell, Elinor Sawyer, Ramsey Cutress, Nisha Sharma, Abeer Shaaban, Alastair Thompson. Patterns of care: radiotherapy after breast conserving surgery and the use of endocrine therapy for screen-detected ductal carcinoma in situ (DCIS) in the UK [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-05.

Abstract 7321: Second primary cancer risks following breast cancer in BRCA1/2 pathogenic variant carriers

Abstract Background: Second primary cancer (SPC) risk estimates in breast cancer (BC) survivors carrying germline BRCA1/2 pathogenic variants (PVs) remain uncertain. We estimated relative and absolute SPC risks following BC in BRCA1/2 PV carriers using genetic testing laboratory data in England, linked for the first time to population-scale electronic health records data from the National Disease Registration Service and Hospital Episode Statistics. Material and methods: The cohort contained 27,154 women diagnosed with primary BC and tested for germline BRCA1/2 PVs between 1995-2019. Follow-up began at the latest of the genetic test dates and one year following the BC diagnosis and continued until the first SPC diagnosis, death, migration, relevant surgery, and the end of 2020, whichever came first. We estimated overall and site-specific standardized incidence ratios (SIRs) by comparing observed and expected SPC counts, with expected counts calculated using incidences for the general English population accounting for calendar year, SPC site, age, and gender. We stratified the SIRs by age, estrogen-receptor status, and cancer site. We further assessed associations using Cox regression adjusted for age at BC diagnosis and estrogen-receptor status of the first BC, and estimated 10-year absolute SPC risks with Kaplan-Meier analysis. Results: There were 1909 BRCA1 (138 with SPCs) and 1926 BRCA2 (101 with SPCs) PV carriers, with mean follow-up lengths of 4.2 and 4.4y and median follow-up lengths of 3.4 and 3.6y. In BRCA1 PV carriers, there were elevated contralateral BC (SIR:15.3, 95%CI:11.5-19.8), ovarian (SIR:43.3, 95%CI:30.9-58.9), non-breast and non-ovarian combined (SIR:2.23, 95%CI:1.63-2.98), colorectal (SIR:4.72, 95%CI:2.58-7.92) and uterine (SIR:3.42, 95%CI:1.25-7.44) SPC risks. In BRCA2 PV carriers, there were increased contralateral BC (SIR:7.53, 95%CI:5.33-10.3), ovarian (SIR:16.5, 95%CI:10.1-25.5), non-breast and non-ovarian (SIR:1.72, 95%CI:1.27-2.27) and pancreatic (SIR:6.57, 95%CI:2.63-13.5) SPC risks. Consistently, when we compared BC survivors carrying a BRCA1 PV to BC survivors without a PV in either gene, they were at elevated contralateral BC (HR:3.94, 95%CI:2.91-5.33), ovarian (HR:35.7, 95%CI:21.3-60.0), non-breast and non-ovarian (HR:1.53, 95%CI:1.11-2.12) and colorectal (HR:2.95, 95%CI:1.56-5.55) SPC risks, whereas BRCA2 PV carriers were at increased contralateral BC (HR:2.59, 95%CI:1.83-3.65), ovarian (HR:12.3, 95%CI:6.93-21.9) and pancreatic (HR:5.32, 95%CI:2.30-12.3) SPC risks. We estimated 10-year cumulative contralateral BC, ovarian, and non-breast and non-ovarian SPC risks of 15%, 6.3%, and 7.8% in BRCA1 PV carriers and 12%, 2.9%, and 6.2% in BRCA2 PV carriers. Conclusions: Cancer risks were increased, at combined and specific sites, following BC in BRCA1/2 PV carriers. These findings could aid the clinical management of BC survivors carrying BRCA1/2 PVs. Citation Format: Isaac Allen, Hend Hassan, Yvonne Walburga, Catherine Huntley, Lucy Loong, Tameera Rahman, Beth Torr, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Margreet Lüchtenborg, Joanna Pethick, Francesco Santaniello, Shilpi Goel, Sophie Allen, Katrina Lavelle, Fiona McRonald, Diana M. Eccles, Eva Morris, Steven Hardy, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou. Second primary cancer risks following breast cancer in BRCA1/2 pathogenic variant carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7321.

The comprehensive English National Lynch Syndrome Registry: development and description of a new genomics data resource

Lynch Syndrome (LS) is a cancer predisposition syndrome caused by constitutional pathogenic variants in the mismatch repair (MMR) genes. To date, fragmentation of clinical and genomic data has restricted understanding of national LS ascertainment and outcomes, and precluded evaluation of NICE guidance on testing and management. To address this, via collaboration between researchers, the National Disease Registration Service (NDRS), NHS Genomic Medicine Service Alliances (GMSAs), and NHS Regional Clinical Genetics Services, a comprehensive registry of LS carriers in England has been established. For comprehensive ascertainment of retrospectively identified MMR pathogenic variant (PV) carriers (diagnosed prior to January 1, 2023), information was retrieved from all clinical genetics services across England, then restructured, amalgamated, and validated via a team of trained experts in NDRS. An online submission portal was established for prospective ascertainment from January 1, 2023. The resulting data, stored in a secure database in NDRS, were used to investigate the demographic and genetic characteristics of the cohort, censored at July 25, 2023. Cancer outcomes were investigated via linkage to the National Cancer Registration Dataset (NCRD). A total of 11,722 retrospective and 570 prospective data submissions were received, resulting in a comprehensive English National Lynch Syndrome Registry (ENLSR) comprising 9030 unique individuals. The most frequently identified pathogenic MMR genes were MSH2 and MLH1 at 37.2% (n=3362) and 29.1% (n=2624), respectively. 35.9% (n=3239) of the ENLSR cohort received their LS diagnosis before their first cancer diagnosis (presumptive predictive germline test). Of these, 6.3% (n=204) developed colorectal cancer, at a median age of initial diagnosis of 51 (IQR 40-62), compared to 73 years (IQR 64-80) in the general population (p<0.0001). The ENLSR represents the first comprehensive national registry of PV carriers in England and one of the largest cohorts of MMR PV carriers worldwide. The establishment of a secure, centralised infrastructure and mechanism for routine registration of newly identified carriers ensures sustainability of the data resource. This work was funded by the Wellcome Trust, Cancer Research UK and Bowel Cancer UK. The funder of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Cohort profile: the National Congenital Anomaly Registration Dataset in England

PurposeThe National Congenital Anomaly and Rare Disease Registration Service (NCARDRS), part of National Disease Registration Service in National Health Service England, quality assures, curates and analyses individual data on the...

Recommendations for laboratory workflow that better support centralised amalgamation of genomic variant data: findings from CanVIG-UK national molecular laboratory survey.

National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission. In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4). Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored. The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation.

Prevalence of neural tube defects in England prior to the mandatory fortification of non-wholemeal wheat flour with folic acid: a population-based cohort study

ObjectivesTo determine the baseline trends in the total birth prevalence of neural tube defects (NTDs) in England (2000–2019) to enable the impact of folic acid fortification of non-wholemeal wheat flour...

Equity of Access to Proton Beam Therapy in England: A National NHS analysis

Policies to improve population health have often focused on equitable access to health services. While new technologies have an enormous potential in improving health outcomes, they may not always be equally accessible across diverse geographical areas and socio-economic backgrounds. Between 2008 and 2018, 1352 patients with eligible indications for Proton Beam Therapy (PBT) were treated overseas within the NHS Proton Overseas Programme (POP) and 947 patients have been treated at the Christie since the National NHS PBT service started in December 2018. The 8 most common PBT cancer indications cover more than 80% of the referrals and referral rates depend on several factors. Aim of this study is to evaluate equity of access to PBT throughout the country and how this has changed since the national PBT service inception. Incidence data were available for 7/8 of the most common PBT cancer indications. These data were provided by the National Disease Registration Service (NDRS) by diagnosis, age group and by the 7 NHS regions in England. The incidence data referred to the time period 2013-2019. The first national NHS PBT center started accepting referrals in October 2018, therefore this time period was split in pre-NHS PBT (1/1/13-30/9/18) and post-NHS PBT (1/10/18-31/12/19). Demographics and clinical characteristics of patients referred for PBT were extracted from the national NHS PBT registry for matching clinical diagnoses and time period. The ratio between the referred (observed) and newly diagnosed (expected) patients is the Proton Utilization Proportion (PUP), which tracks the proportion of eligible patients using the technology. For the 7 common PBT indications examined, the total number of newly diagnosed patients was 2134 in the pre-NHS PBT period and 461 in the post-NHS PBT period. The (accepted) referrals were 587 and 300 in the pre-and post-NHS PBT period, respectively. An increase in the PUP between the pre-NHS PBT and the post-NHS PBT is noted for any diagnostic category, age group and NHS region. The most noticeable increase is noticed for Medulloblastoma, which became a commissioned indication for PBT only in 2016.The PUP in England increased post-NHS PBT by 137% overall. Of note, post-NHS PBT, 99% of the patients aged 0-15 with these 7 common indications for PBT were referred and treated with PBT. Promoting equality of access to cutting-edge radiotherapy technologies is at the heart of NHS England's values. Throughout the development of the policies and processes related to PBT access in the UK, the NHS has given regard to the need to reduce geographical variation which may contribute to health inequalities. The PUP has increased since the opening of a National PBT service in England, which uses a central web-based Proton Referral Pathway managed by a National Proton Office. Further analysis will follow to examine whether socio-economic or geographical barriers exist within each region.

RF05 A national report on incidence, patient demographics and tumour characteristics of melanoma by BRAF, NRAS and KIT genotype: England 2016–2019

Abstract Although studies have shown variation between countries in the incidence and characteristics of patients and tumours associated with melanoma BRAF, NRAS and KIT mutations, no national molecular genetics data from England have been published. In 2022, the National Institute for Health and Care Excellence highlighted the need for national cohort studies to evaluate the role of biomarkers. This descriptive national observational study used National Disease Registration Service (NDRS) data to identify all site melanoma cases that were diagnosed and underwent molecular genetic testing in England between 2016 and 2019. The NDRS collects molecular genetics data from most genomic laboratories nationally but does not routinely receive results for BRAF testing by immunohistochemistry (IHC) done at local pathology laboratories. Molecular genetic testing and incidence of wild-type (WT), BRAF mutant (+), NRAS+ and KIT+ melanomas were described. Demographic (sex, age, ethnicity, deprivation, geographical region) and tumour factors (site, stage) of BRAF+, NRAS+, KIT+ and WT tumours were described. In total, 61 514 new melanomas were registered in England between 2016 and 2019. Thirteen per cent (n = 7925), 5.0% (n = 3084) and 1.2% (n = 743) of tumours underwent BRAF, NRAS and KIT testing, respectively. BRAF testing rates varied across regions from 19.9% (n = 1040/5217) in the West Midlands to 5.5% (n = 227/4114) in the North East. Thirty-four per cent (n = 2674/7925), 30.5% (n = 942/3084) and 8.6% (n = 64/743) of tumours were BRAF+, NRAS+ and KIT+, respectively. Thirty-four per cent (n = 1523/4479) of males and 37.6% (n = 1132/3014) of females with cutaneous melanomas were BRAF+. Forty-six per cent (n = 1693/3712) of patients aged &amp;lt; 70 years and 20.5% (n = 332/1622) aged ≥ 80 years were BRAF+. The highest proportion of BRAF+ cutaneous melanoma were identified in the North East (46.7%, n = 106/227) and the lowest in the West Midlands (32.6%, n = 339/1040). Thirty-two per cent (n = 560/1760) of males and 30.0% (n = 349/1167) of females with cutaneous melanoma were NRAS+. Twenty-six per cent (n = 356/1354) of patients aged &amp;lt; 70 years and 31.8% (n = 229/718) aged ≥ 80 years were NRAS+. The highest proportion of NRAS+ cutaneous melanoma were in the West Midlands (40%, n = 14/35) and the lowest in the North East (28.3%, n = 36/127). We report the largest and most complete dataset for national molecular genetics of melanoma ever published. Regional differences in BRAF testing may be explained by variations in local practice and methods used, and differences in population age, but could impact on treatment options. Lack of IHC, testing nonuniformity and lack of whole melanoma population data (early-stage nonrecurrent tumours and tumours in frail elderly patients may be excluded) were limitations.

P49 Epidemiology of skin cancer by ethnicity in England, 2013–2020: a cohort study

Abstract Skin cancer rates are increasing worldwide and predominantly affect people of white ethnicity. Although less common, skin cancers in people with skin of colour (SOC) are more likely to experience diagnostic delays and higher mortality. High-quality epidemiological data on skin cancers in SOC are limited. SOC and skin phototype are not recorded in registry data; however, the ethnic group can be used as a somewhat limited proxy. The aim of this retrospective national cancer registry cohort study was to describe skin cancer epidemiology by the ethnic group. We identified a cohort of patients diagnosed with skin cancer in England (2013–2020) from the National Disease Registration Service (NDRS). The ethnic group is routinely recorded as self-reported during hospital visits in Patient Administration System and Hospital Episode Statistics datasets collected by the NDRS. We analysed data by the broad ethnic group [White, Asian (excluding Chinese), Black, Chinese, mixed, other, unknown]. We report counts, incidence, stage at presentation (melanoma only), referral pathway, anatomical location and geographical variation. The first basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) per patient were reported. More cases of skin cancers were diagnosed in Asian ethnicities than in Black and Chinese ethnicities, except for melanoma, which was more frequently diagnosed in Black ethnicities. Of 713 615 BCCs, 571 396 (80.1%) were reported in White, 799 (0.1%) in Asian, 634 (0.1%) in mixed, 413 (0.1%) in Black, 156 (0.02%) in Chinese and 3122 (0.4%) in people of ‘other’ ethnicities; 137 095 (19.2%) were of ‘unknown’ ethnicity. Of 244 072 cSCCs, 225 534 (92.4%) were in White, 609 (0.2%) in Asian, 354 (0.1%) in Black, 279 (0.1%) in mixed, 66 (0.03%) in Chinese and 1137 (0.5%) in people of ‘other’ ethnicity; 16 093 (6.6%) were of ‘unknown’ ethnicity. Of 111 676 melanomas, 102 273 (91.6%) were in White, 199 (0.2%) in Black, 180 (0.2%) in Asian, 125 (0.1%) in mixed, 25 (0.02%) in Chinese and 695 (0.6%) in ‘other’ ethnicities; 8179 (7.3%) were of ‘unknown’ ethnicity. This is the first national study of skin cancer types by ethnicity in England. National datasets allow for the better evaluation of rare subgroups of patients. The main limitation is the high proportion of unknown ethnicity reporting, which is higher for keratinocyte cancers than for other cancers, presumably due to their automated processing and lack of data sources (i.e. inpatient or multidisciplinary team datasets). These data will support a better understanding of unmet clinical needs in underserved populations.

RF03 Lentigo maligna 2013–2019 in England: incidence and survival of 18,377 cases

Abstract Lentigo maligna (LM) is a common melanoma in situ with limited national epidemiological data. National data on LM incidence, age groups and 5-year survival in England from 2013 to 2019 were explored using report-level data published openly on the ‘Get Data Out’ National Disease Registration Service (NDRS) programme. In total, 18 377 new cases (49% male, 51% female) of LM were registered in England, with a mean of 2625 new diagnoses per year. The crude incidence rate of LM increased from 4.33/100 000 [95% confidence interval (CI) 4.16–4.51] in 2013 to 4.69/100 000 (95% CI 4.52–4.87) in 2019. The average crude incidence rate of LM per year was 23.4/100 000 [95% CI 22.7–24.9; 35.2 male (95% CI 33.2–37.4), 15.4 female (95% CI 15.2–17.5)] in those aged &amp;gt; 80 years vs. 0.59/100 000 [95% CI 0.55–0.62; 0.65 male (95% CI 0.59–0.71), 0.53 female (95% CI 0.47–0.59)] in those aged &amp;lt; 60 years. Overall, 5-year Kaplan–Meier survival was 83.1% (95% CI 81.5–84.6) for LM diagnosed in 2013, while 5-year overall net survival was 103.7% (95% CI 101.2–106.2) in 2014. By comparison, for invasive melanoma, 5-year overall Kaplan–Meier survival was 79.1% (95% CI 78.3–79.8) and 5-year overall net survival was 88.6% (95% CI 87.6–89.6) for 2013 diagnoses. Important limitations are that registered LM is based on histopathological data or multidisciplinary team discussions; hence, LM treated topically without biopsy or untreated LM were not included. Privately treated patients were also under-represented, as there was no requirement for private laboratory data to be submitted to NDRS, unlike data from National Health Service laboratories. The apparent 5-year LM-specific survival advantage is likely due to fewer frail patients seeking medical attention, being referred or undergoing histological confirmation. We report the largest series of data on LM in Europe to date. The observed increase in the incidence of LM and its excellent 5-year net survival supports further discussion on current clinical practice and treatment options.

008 How often and how quickly do people with a first cutaneous squamous cell carcinoma develop further tumours? Analysis of national registry data between 2013 and 2020 in England

Abstract In England, cutaneous squamous cell carcinoma (cSCC) has an incidence rate of 85.2 per 100 000 person-years and over 30 000 new incident patients annually. Subsequent cSCC are common. Improved understanding of the frequency and time frames is important for cancer prevention, management guidelines and service provision. The aim of this study was to describe national cSCC accrual data in England. This retrospective cancer registry cohort study used data provided by the National Disease Registration Service. Cancer registrations are created from National Health Service (NHS) data feeds, primarily pathology reports from NHS laboratories. Patients with a first-ever registered cSCC during 2013–2015 were identified. All cSCC pathology reports from 2013 to 2020 were analysed in the 5 years following the first cSCC diagnosis date. To account for supplemental reporting and the possibility that two reports within a short time frame double count the same tumour (e.g. diagnostic biopsy followed by therapeutic excision), a washout period of 112 days (16 weeks) was used (i.e. cSCC was designated as a separate tumour when registration exceeded this period after the preceding cSCC diagnosis date). Sensitivity analysis assessed effects of several washout periods. Pathology reports were not reviewed, and a proportion of subsequent tumours may represent recurrences beyond the washout period or delayed treatment. A total of 79 301 first-ever cSCC tumours were registered. After applying the 112-day washout period, 22 225 subsequent tumours remained for analysis up to 2020. In total, 15 544 (19.6%), 4437 (5.6%) and 1426 (1.8%) of people developed a second, third and fourth cSCC tumour within 5 years, respectively. Within 1 year of the first-ever cSCC, 5676 (7.2%) patients had a second cSCC, increasing to 15.1% (n = 11 968) and 19.6% (n = 15 544) by years 3 and 5, respectively. The median interval between first and second cSCC was 550 days [interquartile range (IQR) 256–1046], second-to-third cSCC interval 392 days (IQR 219–708), third-to-fourth 283 days (IQR 175–492) and fourth-to-fifth 235 days (IQR 160–398). The accrual estimates are sensitive to the washout period. However, even with a 365-day washout period, 3.4% and 5.1% had developed a second cSCC by years 3 and 5, respectively. These data show that one in five patients will develop another cSCC within 5 years of their first-ever cSCC. Data on cSCC accrual rates are limited globally to single-centre or regional datasets. This national study provides detailed information on accrual rates in England, which are important for informing all aspects of clinical care, health service provision and design of future clinical trials for cSCC prevention.

Cohort profile: radiotherapy dataset (RTDS) in England

PurposeThe purpose of the Radiotherapy Dataset (RTDS) is to collect consistent and comparable data across all providers of National Health Service (NHS)-funded radiotherapy and to provide intelligence for service planning,...

Epidemiology of porocarcinoma in England 2013-2018: apopulation-based registry study.

Porocarcinoma (PC) is a cutaneous malignancy that differentiates towards (possibly arises from) the sweat ducts and glands. Lack of histological diagnostic markers makes clinical and pathological diagnosis complex. The limited data available suggest the incidence is increasing; however, this remains to be established in national epidemiological studies. To report the incidence, treatment and survival of patients with PC in England from 1 January 2013 to 31 December 2018 using national cancer registry data. PC diagnoses in England during 2013-2018 were identified from the National Disease Registration Service using morphology and behaviour codes. These were registered from routinely collected pathology reports and cancer outcomes and services datasets. The 2013 European age standardized incidence rates (EASRs), Kaplan-Meier all-cause survival and log-rank test were calculated. In total, 738 tumours (396 in males and 342 in females) were diagnosed. The median age at diagnosis was 82 years old (interquartile range 74-88). The most frequently affected site were lower limbs (35.4%), followed by the face (16%). The majority of the cohort received surgical excision (73.0%). The Kaplan-Meier all-cause survival was 45.4% at 5 years, which was lower than in previous studies. The EASR for the whole population was 0.25 [95% confidence interval (CI) 0.23-0.27] per 100 000 person-years (PY)]. PC incidence rates in the East of England (EASR of 0.54, 95% CI 0.47-0.63 per 100 000 PY) were three times higher than the South West (EASR of 0.14, 95% CI 0.10-0.19 per 100 000 PY) where the regional rates were the lowest. This study shows that there is large variation in the EASRs of PC across England. This may reflect differences in how PC is diagnosed and registered in different regions in England. These data support national assessment of the management of PC, which will inform future studies and guideline development.

Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996–2020: development of a national resource of patient-level genomics laboratory records

ObjectiveTo describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the...

Trends in incidence, treatment and survival of Merkel cell carcinoma in England 2004-2018: a cohort study.

Merkel cell carcinoma (MCC) is a rare tumour with neuroendocrine differentiation and high associated mortality. Studies that describe the epidemiology of MCC are often limited by small sample size, short duration of follow-up, absence of nationwide data and paucity of data on different risk factors. To determine the incidence, demographics and survival for MCC in England between 2004 and 2018. This national retrospective cohort study identified all cases of MCC in England from 2004 to 2018 using national population-based data from the National Disease Registration Service. Crude counts, European age-standardized incidence rates (EASRs) and joinpoint analysis were conducted. Patient demographics and treatments received were described. Multivariable Cox regression analysis was used to study risk factors for MCC-specific mortality, by including a priori defined demographic factors, tumour characteristics and immunosuppression. Treatment data were not included in the Cox regression analysis. A total of 3775 MCC tumours were registered. The median age at diagnosis was 81 years (interquartile range 74-87). Overall, 96·6% of patients identified as White ethnicity, and 8·3% of patients were immunosuppressed. The most common site was the face (27·4%). Patients most often presented with stage one disease (22·8%); however, stage was unknown in 31·0%. In total, 80·7% of patients underwent surgical excision, 43·5% radiotherapy and 9·2% systemic therapy. The EASR increased from 0·43 per 100 000 person-years (PYs) to 0·65 per 100 000 person-years between 2004 and 2018, representing a significant annual percentage change of 3·9%. The EASR was greater in men than in women for all years, with an overall male-to-female ratio of 1·41 : 1. The highest EASR was in South West England. Five-year disease-specific survival was 65·6% [95% confidence interval (CI) 63·8-67·4], with a median follow-up of 767 days. MCC-specific mortality increased with age [hazard ratio (HR) 1·02, 95% CI 1·02-1·03], deprivation (HR 1·43, 95% CI 1·16-1·76), immunosuppression (HR 2·80, 95% CI 2·34-3·34) and stage at diagnosis (HR 8·24, 95% CI 5·84-11·6). This study presents the largest national MCC dataset in Europe, and the most complete reporting of MCC incidence and survival ever published. With the EASR of MCC increasing and high associated mortality, this study encourages further research into the pathology, diagnosis and therapeutic options for MCC to support management guidelines.

Factors Influencing 1-Year Survival in Haemphagocytic Lymphohistiocytosis: A National Cohort Study in England

Background: Haemophagocytic lymphohistiocytosis (HLH) is a rapidly progressive, life-threatening clinical syndrome of excessive immune activation. Multiple predisposing factors influence the likelihood of any individual developing HLH at any time, encompassing genetic, auto-immune disease, immunosuppression and malignancy. In partnership with the National Congenital Anomalies and Rare Disease Registration Service (NCARDRS) we have undertaken a nationwide study in England of all cases of HLH diagnosed between 2003 and 2018, and modeled interactions of demographics and comorbidities with survival. Methods: Using national linked electronic health data from hospital admissions and death certification we identified cases of HLH that were diagnosed in England between 1st January 2003 and 31st December 2018 using a previously validated approach (Bishton et al Brit J Haem 2021). Patients of all ages admitted to hospital with an admission coded with HLH ICD-10 codes D76.1 and D76.2, or who died with a death code of D76.1, D76.2 or D76.3 provided in the latter situation there was confirmatory free text on the death certificate indicating HLH, were included. We calculated 1-year survival using Kaplan-Meier methods by calendar year, age group, sex and comorbidity (haematological malignancy, inflammatory rheumatological or bowel diseases (IBD). We modelled 1-year survival and the interactions between age and associated comorbidity using Cox regression. Results: There were 1628 people with HLH included in the analysis. 706 (68.6%) patients were aged ≥15 years, 920 (56.5%) were male and 855 (52.5%) had at least one associated comorbidities recorded. The most common comorbidities were lymphoma (n=270 [16.6%]), leukaemia (n=125 [7.7%]), systemic juvenile idiopathic arthritis (SJIA) (n=78 [4.8%]), IBD (n=70 [4.3%]), vasculitis (n=64 [3.9%]) and systemic lupus erythematosus (SLE) (n=47 [2.9%]). Overall, crude 1-year survival was 50% (95% CI 48-53%) with no improvement observed over the study period. Survival varied significantly with age (0-4, 61%; 5-14 76%; 15-54 61%; >55 24% p<0.01)(figure 1), sex (males, 46%, females, 55% p<0.01) and associated comorbidity (rheumatological/IBD, 69%, haematological malignancy 28%, other malignancy, 37% p <0.01). Those aged 0-14 and 15-54 years had a 3-fold increased risk of death at 1-year among HLH associated with haematological or non-haematological malignancy compared to rheumatological disease/IBD. Predicted 1-year survival decreased markedly with age in those with rheumatological disease/IBD (age 0-14, 84%; 15-54, 73%; >55, 27%) meaning survival for those aged >55 years was poor regardless of the underlying disease process. Notably there was no difference in outcomes by lymphoma subtype (B-cell, T-cell or Hodgkin lymphoma) in contrast to the auto-immune sub-groups, where outcomes for adult onset Stills disease and SJIA were excellent (77% and 89% respectively) whilst survival in rheumatoid arthritis (35%) and vasculitis (39%) were similar to non-haematological malignancy driven HLH. Conclusion: We provide the first estimates of survival for HLH by the associated trigger factors (vasculitis, rheumatoid arthritis, IBD, malignancy), on a national scale, and make the critical observation that outcomes have remained static for the study period. Furthermore outcomes for haematological malignancies are dismal regardless of disease subtype, whilst significant variation in outcomes for different auto-immune disease subtypes are seen indicating that the severe impact of this syndrome is not limited to those with underlying malignancy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

673 The Role of the First Postnatal Ultrasound Scan to Predict Outcome in Children with Antenatally Diagnosed Hydronephrosis

Abstract Aim We aimed to determine if the renal pelvic diameter on the first postnatal scan can predict the need for surgical intervention in children with antenatally diagnosed hydronephrosis. Method Data of all babies with antenatal hydronephrosis born in our centre from 2009–2015 were obtained from the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS). The medical records were analysed retrospectively for diagnosis, investigations, and interventions. Mean follow-up was 7 (4–10) years. The results were expressed as mean and percentage. Statistical data analysis was performed on GraphPad. Results 224 babies were included in the study. 162 (72%) were males, and 92 (39%) had bilateral hydronephrosis. 163 (73%) had spontaneous resolution of hydronephrosis. The resolution rates were similar for unilateral and bilateral cases. The mean renal pelvic diameter was 6.2mm in the resolved group and 16.2mm in the persistent group (p&amp;lt;0.01). The highest renal pelvic diameter undergoing spontaneous resolution was 24mm. Of the 61 (27%) children with persistent hydronephrosis, 38 (17%) children required surgery. Pyeloplasty for pelviureteric junction obstruction was the most common procedure. 23 (10%) patients continued to have persistent dilatation but needed no intervention. Renal duplex was the most common diagnosis in this group, followed by vesicoureteric reflux. All babies with a pelvic diameter of 25mm or above on their first postnatal ultrasound required surgical intervention. Conclusion The majority of antenatal hydronephrosis resolves spontaneously. However, interventions are necessary if the pelvic diameter is above 25mm.

An Update to the Malthus Model for Radiotherapy Utilisation in England

AimsThe Malthus Programme predicts national and local radiotherapy demand by combining cancer incidence data with decision trees detailing the indications, and appropriate dose fractionation, for radiotherapy. Since the last model update in 2017, technological advancements and the COVID-19 pandemic have led to increasing hypofractionation of radiotherapy schedules. Indications for radiotherapy have also evolved, particularly in the context of oligometastatic disease. Here we present a brief update on the model for 2021. We have updated the decision trees for breast, prostate, lung and head and neck cancers, and incorporated recent cancer incidence data into our model, generating a current estimate of fraction demand for these four cancer sites across England. Materials and methodsThe decision tree update was based on evidence from practice-changing randomised controlled trials, published guidelines, audit data and expert opinion. Site- and stage-specific incidence data were taken from the National Disease Registration Service. We used the updated model to estimate the proportion of patients who would receive radiotherapy (appropriate rate of radiotherapy) and the fraction demand per million population at a national and Clinical Commissioning Group level in 2021. ResultsThe total predicted fraction demand has decreased by 11.4% across all four cancer sites in our new model, compared with the 2017 version. This reduction can be explained primarily by greater use of hypofractionated treatments (including stereotactic ablative radiotherapy) and a shift towards earlier stage presentation. The only large change in appropriate rate of radiotherapy was an absolute decrease of 3% for lung cancer. ConclusionsCompared with our previous model, the current version predicts a reduction in fraction demand across England. This is driven principally by hypofractionation of radiotherapy regimens, using technology that requires increasingly complex planning. Treatment complexity and local service factors need to be taken into account when translating fraction burden into linear accelerator demand or throughput.