Diana Eccles

Background: genetic testing has increased without corresponding growth in genetics/oncology workforces. Resources including Patient Decision Aids (PtDA) are useful and valued by patients and clinicians to provide information and complement shared decision-making. Despite their promise, few PtDA have been developed for patients with genetic cancer susceptibility facing difficult decisions about risk management. We aimed to fill this gap in care, partnering with patients from the earliest stages of project conception. Methods: we codesigned Lynch Choices, a PtDA (interactive, personalised website/booklet) for families with Lynch Syndrome. This will later be adapted for other conditions. In addition to a Patient Reference Panel, we purposively invited a large, international stakeholder panel including patient groups, charities, public bodies, clinical and academic experts. Implementation strategies and frameworks were employed to identify barriers and facilitators and maximise uptake potential. Patient/stakeholder feedback was incorporated in a transparent Table of Changes using the Person-Based Approach. Patient funding was provided, and a publication policy agreed with stakeholders. Additional grant funding facilitated partnerships with underserved communities. Conclusions: Creating an effective, engaging PtDA is not enough. Systematic uptake in real world clinical practice, with its challenges and resource limitations, is needed to optimise benefit to patients and clinicians. Implementation science methods should be applied from the earliest stages of codesign of a PtDA, involving patients who will use the resource and a wide range of …

The 313-variant polygenic risk score (PRS313) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 225,105 female participants from the UK Biobank. The mean PRS313 differed markedly across European countries, being highest in south-eastern Europe and lowest in north-western Europe. Using the overall European PRS313 distribution to categorise individuals leads to overestimation and underestimation of risk in some individuals from south-eastern and north-western countries, respectively. Adjustment for principal components explained most of the observed heterogeneity in mean PRS. Country-specific PRS distributions may be used to calibrate risk categories in individuals from different countries.

Background Resources including Patient Decision Aids (PtDA) are useful and valued by patients and clinicians to provide information and complement shared decision‐making. Despite their promise, few PtDA exist for patients with genetic cancer susceptibility facing difficult decisions about risk management. We aimed to fill this gap, partnering with patients to codesign Lynch ChoicesTM, a PtDA website for families with Lynch Syndrome. In addition to a Patient Reference Panel, we purposively invited an international stakeholder panel including charities, public bodies, clinical and academic experts. Implementation strategies and frameworks were employed to optimise translation of research findings to improve care. Methods Patient/stakeholder suggestions were incorporated in a transparent Table of Changes and prioritised using the Person‐Based Approach throughout planning and codesign of Lynch …

BackgroundNational 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.MethodsIn 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 …

BackgroundTesting for germline pathogenic variants (GPVs) in cancer predisposition genes is increasingly offered as part of routine care for patients with cancer. This is often urgent in oncology clinics due to potential implications on treatment and surgical decisions. This also allows identification of family members who should be offered predictive genetic testing. In the UK, it is common practice for healthcare professionals to provide a patient information leaflet (PIL) at point of care for diagnostic genetic testing in patients with cancer, after results disclosure when a GPV is identified, and for predictive testing of at-risk relatives. Services usually create their own PIL, resulting in duplication of effort and wide variability regarding format, content, signposting and patient input in co-design and evaluation.MethodsRepresentatives from UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene …

BackgroundSecond primary cancers (SPCs) after breast cancer (BC) present an increasing public health burden, with little existing research on socio-demographic, tumour, and treatment effects. We addressed this in the largest BC survivor cohort to date, using a novel linkage of National Disease Registration Service datasets.MethodsThe cohort included 581,403 female and 3562 male BC survivors diagnosed between 1995 and 2019. We estimated standardized incidence ratios (SIRs) for combined and site-specific SPCs using incidences for England, overall and by age at BC and socioeconomic status. We estimated incidences and Kaplan–Meier cumulative risks stratified by age at BC, and assessed risk variation by socio-demographic, tumour, and treatment characteristics using Cox regression.FindingsBoth genders were at elevated contralateral breast (SIR: 2.02 (95% CI: 1.99–2.06) females; 55.4 (35.5–82.4 …

Introduction Patient decision aids (PtDA) complement shared decision‐making with healthcare professionals and improve decision quality. However, PtDA often lack theoretical underpinning. We are codesigning a PtDA to help people with increased genetic cancer risks manage choices. The aim of an innovative workshop described here was to engage with the people who will use the PtDA regarding the theoretical underpinning and logic model outlining our hypothesis of how the PtDA would lead to more informed decision‐making. Methods Short presentations about psychological and behavioural theories by an expert were interspersed with facilitated, small‐group discussions led by patients. Patients were asked what is important to them when they make health decisions, what theoretical constructs are most meaningful and how this should be applied to codesign of a PtDA. An artist created a visual summary …

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 …

BackgroundBreast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility.Patients and methodsWe included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. Eligibility criteria: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer.We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD.Results159/2135 (7.4%) cases had a qualifying variant in an …

Tamoxifen is widely used in patients with hormone receptor‐positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z‐endoxifen. The Z‐endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z‐endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z‐endoxifen concentration and tamoxifen treatment outcomes, and identify a Z‐endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from …

Full responses from the 2023 UK CSG Diagnostic Laboratory Survey component focused on centralised data submission to PHE/NHSD and LIMS system organisation. To preserve anonymity, free-text comments are not provided.

The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4-hydroxy-tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 CYP2D6. Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross-ancestry genome-wide association study with well-characterized patients of European, Middle-Eastern and Asian descent (N= 497) to identify genetic factors impacting active and parent metabolite formation. Genome-wide significant variants were functionally evaluated in an independent liver cohort (N= 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (N= 287, N= 189). Within a single 1-Mb region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and MR endoxifen/N-desmethyltamoxifen (minimal P= 5.4 E-35 and 2.5 E-65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (rho= 0.35 to-0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (N= 12) plus CYP2D6 activity score (AS) increased the explained variability (~ 9%) compared to AS alone, explaining up to 49%(median R 2) and 72% of the variability in endoxifen and MR endoxifen/N-desmethyltamoxifen, respectively. Our findings …

The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4‐hydroxy‐tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6). Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross‐ancestry genome‐wide association study with well‐characterized patients of European, Middle‐Eastern, and Asian descent (n = 497) to identify genetic factors impacting active and parent metabolite formation. Genome‐wide significant variants were functionally evaluated in an independent liver cohort (n = 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (n = 287, n = 189). Within a single 1‐megabase (Mb) region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with …

Background: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC.Methods: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan–Meier survival curves.Results: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients’ median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage …

Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association …

Background Many cancer survivors following primary treatment have prolonged poor quality of life. Aim To determine the effectiveness of a bespoke digital intervention to support cancer survivors. Design Pragmatic parallel open randomised trial. Setting UK general practices. Methods People having finished primary treatment (<= 10 years previously) for colo-rectal, breast or prostate cancers, with European-Organization-for-Research-and-Treatment-of-Cancer QLQ-C30 score <85, were randomised by online software to: 1)detailed ‘generic’ digital NHS support (‘LiveWell’;n=906), 2) a bespoke complex digital intervention (‘Renewed’;n=903) addressing symptom management, physical activity, diet, weight loss, distress, or 3) ‘Renewed-with-support’ (n=903): ‘Renewed’ with additional brief email and telephone support. Results Mixed linear regression provided estimates of the differences between each intervention …

Genetic testing for cancer susceptibility is a cornerstone of precision cancer prevention and care. Major communication hurdles remain for the differently specialized professionals involved in the identification, counselling, and clinical management of at-risk individuals. This may be ascribed to gaps in the genetic/genomic literacy of health care providers and to an ambiguous lexicon used for variant description. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) international consortium endorses controlled terminology and a framework for interpretation and reporting of germline variants in cancer susceptibility genes (PMID: 30962250). However, for most ENIGMA affiliates a language other than English is used for written and verbal communication of genetic test results, potentially confounding local application of the published framework. The ENIGMA Clinical Working Group …

Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2 and MSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1, PALB2, RAD51D and RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and RAD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients …

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 NHS regional molecular genetics laboratories.DesignLaboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years’ missing data.ResultsIndividual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English …

The transforming growth factor beta receptor 1 (TGFBR1) gene is associated with two distinct clinical presentations, Multiple Self-Healing Squamous Epithelioma (MSSE) also known as Ferguson-Smith syndrome and Loeys-Dietz syndrome. MSSE is characterized by development of multiple self-healing skin tumours that may affect any part of the body. Spontaneous resolution may take several months leaving pitted scars. Most pathogenic variants in MSSE patients are truncating variants distributed throughout the gene or missense variants in the receptor domain of TGFBR1. Missense variants in the kinase domain of TGFBR1 cause LDS which is a connective tissue disorder associated with increased risk of aortic and arterial aneurysms and dissection. There are two reports in the literature of patients with both MSSE and LDS phenotype and a missense variant in the kinase domain of TGFBR1. The patient …