Digital innovation for cancer risk assessment allows large-scale service redevelopment of regional cancer genetics service delivery.

Family-history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention and Early Detection (SPED). The online patient-facing cancer Family History Questionnaire Service (cFHQS) is a digitalised, resource efficient tool for family history data capture to facilitate this. The capturing of digital data from cFHQS allows for data interrogation of patients referred to Clinical Genetics for the purposes of service improvement. Digital data from 4,044 cFHQS respondents over a three-year period was collected and interrogated with respect to the number and type of familial tumour diagnoses to enable service improvement and streamlining of referral pathways. 81% of colorectal and 71% of breast screening assessments were population- or moderate-risk. Most patients who completed cFHQS reported more than one diagnosis of cancer/tumour/polyps in their family. 2.5% of family history assessment patients had a second indication that required assessment that would have been missed if single tumour type assessment was undertaken. Implementation of an innovative, digital family history data collection pathway has allowed large scale interrogation of referral patterns and assessment outcomes to enable service development. The high volume of inappropriate referrals to Clinical Genetics for population and moderate risk patients highlighted the need for dedicated secondary care pathway provision for these patients. The use of cFHQS streamlined family history assessment allows for redistribution of resources to improve equity and access to genetic cancer risk assessment.

Codesign of Lynch ChoicesTM : Using implementation science to create a clinically deliverable patient decision support website to transform cancer genetics care pathways.

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 ChoicesTM . An interactive stakeholder meeting was convened to identify barriers and facilitators to clinical implementation of the PtDA. RESULTS: Patient and stakeholder partnerships drove the direction of the research throughout codesign, resulting in several iterative refinements to the PtDA prior to roll out including the addition of illustrations/videos, clearer presentation of cancer risks and increased accessibility for lower literacy. Barriers and facilitators identified from stakeholders were used to create an implementation process map. CONCLUSIONS: Creating an effective, engaging PtDA is not enough. Systematic uptake in real world clinical practice, with its resource limitations, is needed to optimise benefit to patients and clinicians. Assessment of speed and breadth of dissemination and usage will be collected to further evidence the benefit of embedding implementation science methods from the outset to translate research findings into clinical practice.

Co-design of patient information leaflets for germline predisposition to cancer: recommendations for clinical practice from the UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar Programme and the Association of Genetic Nurse Counsellors (AGNC).

BACKGROUND: Testing 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. METHODS: Representatives from UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar programme and Association of Genetic Nurse Counsellors (AGNC) held a 2-day meeting with the aim of making recommendations for clinical practice regarding co-design of PIL for germline cancer susceptibility genetic testing. Lynch syndrome and haematological malignancies were chosen as exemplar conditions. RESULTS: Meeting participants included patient representatives including as co-chair, multidisciplinary clinicians and other experts from across the UK. High-level consensus for UK recommendations for clinical practice was reached on several aspects of PIL using digital polling, including that PIL should be offered, accessible, co-designed and evaluated with patients. CONCLUSIONS: Recommendations from the meeting are likely to be applicable for PIL co-design for a wide range of germline genetic testing scenarios.

Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement.

The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

'A good decision is the one that feels right for me': Codesign with patients to inform theoretical underpinning of a decision aid website.

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. Notes from patient discussions and the artwork were analysed using reflexive thematic analysis. RESULTS: The overarching theme was: It's personal. Contextual factors important for decision-making were varied and changed over time. There was no one 'best fit' theory to target support needs in a PtDA, suggesting an inductive, flexible framework approach to programme theory would be most effective. The PtDA logic model was revised based on patient feedback. CONCLUSION: Meaningful codesign of PtDA including discussions about the theoretical mechanisms through which they support decision-making has the potential to lead to improved patient care through understanding the intricately personal nature of health decisions, and tailoring content and format for holistic care. PATIENT CONTRIBUTION: Patients with lived experience were involved in codesign and coproduction of this workshop and analysis as partners and coauthors. Patient discussions were the primary data source. Facilitators provided a semi-structured guide, but they did not influence the patient discussions or provide clinical advice. The premise of this workshop was to prioritise the importance of patient lived experience: to listen, learn, then reflect together to understand and propose ideas to improve patient care through codesign of a PtDA.

DCIS and LCIS: Are the Risk Factors for Developing In Situ Breast Cancer Different?

Ductal carcinoma in situ (DCIS) is widely accepted as a precursor of invasive ductal carcinoma (IDC). Lobular carcinoma in situ (LCIS) is considered a risk factor for invasive lobular carcinoma (ILC), and it is unclear whether LCIS is also a precursor. Therefore, it would be expected that similar risk factors predispose to both DCIS and IDC, but not necessarily LCIS and ILC. This study examined associations with risk factors using data from 3075 DCIS cases, 338 LCIS cases, and 1584 controls aged 35-60, recruited from the UK-based GLACIER and ICICLE case-control studies between 2007 and 2012. Analysis showed that breastfeeding in parous women was protective against DCIS and LCIS, which is consistent with research on invasive breast cancer (IBC). Additionally, long-term use of HRT in post-menopausal women increased the risk of DCIS and LCIS, with a stronger association in LCIS, similar to the association with ILC. Contrary to findings with IBC, parity and the number of births were not protective against DCIS or LCIS, while oral contraceptives showed an unexpected protective effect. These findings suggest both similarities and differences in risk factors for DCIS and LCIS compared to IBC and that there may be justification for increased breast surveillance in post-menopausal women taking long-term HRT.

Patient decision support resources inform decisions about cancer susceptibility genetic testing and risk management: a systematic review of patient impact and experience.

Background: Patients with genetic cancer susceptibility are presented with complex management options involving difficult decisions, for example about genetic testing, treatment, screening and risk-reducing surgery/medications. This review sought to explore the experience of patients using decision support resources in this context, and the impact on decision-making outcomes. Methods: Systematic review of quantitative, qualitative and mixed-methods studies involving adults with or without cancer who used a decision support resource pre- or post-genetic test for any cancer susceptibility. To gather a broad view of existing resources and gaps for development, digital or paper-based patient resources were included and not limited to decision aids. Narrative synthesis was used to summarise patient impact and experience. Results: Thirty-six publications describing 27 resources were included. Heterogeneity of resources and outcome measurements highlighted the multiple modes of resource delivery and personal tailoring acceptable to and valued by patients. Impact on cognitive, emotional, and behavioural outcomes was mixed, but mainly positive. Findings suggested clear potential for quality patient-facing resources to be acceptable and useful. Conclusions: Decision support resources about genetic cancer susceptibility are likely useful to support decision-making, but should be co-designed with patients according to evidence-based frameworks. More research is needed to study impact and outcomes, particularly in terms of longer term follow-up to identify whether patients follow through on decisions and whether any increased distress is transient. Innovative, streamlined resources are needed to scale up delivery of genetic cancer susceptibility testing for patients with cancer in mainstream oncology clinics. Tailored patient-facing decision aids should also be made available to patients identified as carriers of a pathogenic gene variant that increases future cancer risks, to complement traditional genetic counselling. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020220460, identifier: CRD42020220460.

UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2.

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 with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1, PALB2, RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting.

Person-based co-design of a decision aid template for people with a genetic predisposition to cancer.

Background: People with genetic predispositions to cancer are faced with complex health decisions about managing their risk. Decision aids can support informed, values-based decisions, alongside shared decision-making with a clinician. Whilst diagnoses of genetic predispositions to cancer are increasing, there is no scalable decision aid to support these people. This paper presents an accessible, relevant decision aid template which can be adapted for different predispositions to cancer. Methods: The decision aid template was co-developed with 12 patients affected by cancer and informed by empirical and theoretical literature. In addition, consultations were conducted with a further 19 people with Lynch syndrome; a specific genetic predisposition to cancer. Clinical stakeholders were consulted regularly. Coulter's framework for decision aid development guided the process, and these activities were complemented by the International Patient Decision Aid Standards, and the latest evidence on communicating risk in decision aids. Programme theory was developed to hypothesise how the decision aid would support decision-making and contextual factors which could influence the process. Guiding principles co-developed with the patient panel described how the decision aid could effectively engage people. Results: The in-depth co-design process led to the identification of five core components of an accessible decision aid template for people with a genetic predisposition to cancer: defining the decision; option grid showing implications of each option; optional further details such as icon arrays to show tailored risk and personal narratives; values clarification activity; and a summary to facilitate discussion with a clinician. Specific guidance was produced describing how to develop each component. The guiding principles identified that the decision aid template needed to promote trust, reduce distress, and be comprehensive, personally relevant and accessible in order to engage people. Conclusion: Adopting a co-design process helped ensure that the decision aid components were relevant and accessible to the target population. The template could have widespread application through being adapted for different genetic predispositions. The exact content should be co-designed with people from diverse backgrounds with lived experience of the specific predisposition to ensure it is as useful, engaging and relevant as possible.

A cost analysis of a cancer genetic service model in the UK.

Technological advances in DNA sequencing have made gene testing fast and more affordable. Evidence of effectiveness and cost-effectiveness of genetic service models is essential for the successful translation of sequencing improvements for patient benefit, but remain sparse in the genetics literature. In particular, there is a lack of detailed cost data related to genetic services. A detailed micro-costing of 28 possible pathways relating to breast and/or ovarian cancer and BRCA testing was carried out by defining service activities and establishing associated costs. These data were combined with patient-level data from a Royal Marsden Cancer Genetics Service audit over a 6-month period during which BRCA testing was offered to individuals at ≥10 % risk of having a mutation, in line with current NICE guidance. The average cost across all patient pathways was £2227.39 (range £376.51 to £13,553.10). The average cost per pathway for an affected person was £1897.75 compared to £2410.53 for an unaffected person. Of the women seen in the Cancer Genetics Service during the audit, 38 % were affected with breast and/or ovarian cancer, and 62 % were unaffected but concerned about their family history. The most efficient service strategy is to identify unaffected relatives from an affected individual with an identified BRCA mutation. Implementation of this strategy would require more comprehensive testing of all eligible cancer patients, which could be achieved by integrating BRCA testing into oncology services. Such integration would be also more time-efficient and deliver greater equity of access to BRCA testing than the standard service model.

Genetic predisposition to ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. METHODS: To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. RESULTS: Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10(-8). CONCLUSION: In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.

Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.

Implications for cancer genetics practice of pro-actively assessing family history in a General Practice cohort in North West London.

At present cancer genetics referrals are reactive to individuals asking for a referral and providing a family history thereafter. A previous pilot study in a single General Practice (GP) catchment area in North London showed a 1.5-fold increase in breast cancer risk in the Ashkenazi Jewish population compared with the non-Ashkenazi mixed population. The breast cancer incidence was equal in the Ashkenazim in both pre- and postmenopausal groups. We wanted to investigate the effect of proactively seeking family history data from the entire female population of the practice to determine the effect on cancer genetics referral. Objectives To determine the need for cancer genetics intervention for women in a single GP catchment area. (1) to determine the incidence and strength of family history of cancer in women aged over 18 in the practice, (2) to offer cancer genetics advice and determine the uptake of counselling in those with a positive family history, (3) to identify potential BRCA1/BRCA2 gene mutation carriers who can be offered clinical follow up with appropriate translational research studies. Design Population-based cohort study of one General Practice female population. Participants Three hundred and eighty-three women over the age of 18 from one General Practice who responded to a questionnaire about family history of cancer. The whole female adult GP population was the target and the total number sampled was 3,820. Results 10% of patients completed the questionnaire (n = 383). A family history of cancer was present in 338 cases, 95 went on to have genetic counselling or had previously had counselling and 47 were genetically tested. We identified three carriers of an Ashkenazi Jewish founder mutation in BRCA1. Conclusions Response rate to a family history questionnaire such as that used in genetics centres was low (10%) and other approaches will be needed to proactively assess family history. Although the Ashkenazim are present in 39% of the GP catchment area, 62% of those who returned a family history questionnaire were from this ethnic group and of those returned, 44% warranted referral to a cancer genetics unit. In the non Ashkenazim, the questionnaire return rate was 38% and 18% of those warranted referral to cancer genetics.

Should healthcare providers have a duty to warn family members of individuals with an HNPCC-causing mutation? A survey of patients from the Ontario Familial Colon Cancer Registry.

BACKGROUND: As genetic testing becomes more common and increasingly intertwined with medical care, the issues of genetic privacy and doctor-patient confidentiality are being examined. Hereditary non-polyposis colorectal cancer (HNPCC) is a genetic predisposition to colorectal and certain other cancers. Effective screening that can prevent colorectal cancer is an important incentive for genetic testing. METHODS: A survey regarding the duty to warn family members of the risks associated with an HNPCC-causing mutation was mailed to 227 participants in the Ontario Familial Colon Cancer Registry (OFCCR). To our knowledge, the opinions of patients on this subject have not been reported previously in the literature. Responses were analysed quantitatively using the SAS system and qualitatively by the review of written comments. RESULTS: Completed surveys were returned by 105 participants, with a response rate of 46.3%. The majority felt a personal responsibility to warn relatives, but there was no significant agreement that doctors or genetic counsellors should have a duty to warn relatives without a patient's permission. CONCLUSIONS: Patients undergoing genetic testing for HNPCC generally understand that relatives could benefit from being informed of genetic risk, but may not be willing or able to inform each family member. Healthcare professionals should engage patients in a discussion of familial implications before genetic testing. An agreement should be formulated regarding which of the relatives should be informed. Patients should be encouraged to personally disseminate the information, given the unrealistic burden on practitioners to perform this task and patients' preference for control over the information.

Cancer genetic testing and assisted reproduction.

PURPOSE: Because of increasing uptake of cancer genetic testing and the improving survival of young patients with cancer, health care practitioners including oncologists will increasingly be asked about options for assisted reproduction by members of families affected by hereditary cancer syndromes. Among these reproductive options, preimplantation genetic diagnosis (PGD) offers the opportunity to select embryos without familial cancer-predisposing mutations. METHODS: A review of the published literature supplemented by a survey of PGD centers in the United States. RESULTS: Prenatal diagnosis and/or embryo selection after genetic testing has already been performed in the context of more than a dozen familial cancer syndromes, including the common syndromes of genetic predisposition to colon and breast cancer. CONCLUSION: While constituting new reproductive options for families affected by cancer, the medical indications and ethical acceptance of assisted reproductive technologies for adult-onset cancer predisposition syndromes remain to be defined. Continued discussion of the role of PGD in the reproductive setting is needed to inform the responsible use of these technologies to decrease the burden of heritable cancers.