Understanding cancer predisposition in Singapore: what's next

Knowledge of an underlying genetic predisposition to cancer allows the use of personalised prognostic, preventive and therapeutic strategies for the patient and carries clinical implications for family members. Despite great progress, we identified six challenging areas in the management of patients with hereditary cancer predisposition syndromes and suggest recommendations to aid in their resolution. These include the potential for finding unexpected germline variants through somatic tumour testing, optimal risk management of patients with hereditary conditions involving moderate-penetrance genes, role of polygenic risk score in an under-represented Asian population, management of variants of uncertain significance, clinical trials in patients with germline pathogenic variants and technology in genetic counselling. Addressing these barriers will aid the next step forward in precision medicine in Singapore. All stakeholders in healthcare should be empowered with genetic knowledge to fully leverage the potential of novel genomic insights and implement them to provide better care for our patients.Published versio

Missed diagnosis or misdiagnosis: common pitfalls in genetic testing

Genetic testing has the power to identify individuals with increased predisposition to disease, allowing individuals the opportunity to make informed management, treatment and reproductive decisions. As genomic medicine continues to be integrated into aspects of everyday patient care and the indications for genetic testing continue to expand, genetic services are increasingly being offered by non-genetic clinicians. The current complexities of genetic testing highlight the need to support and ensure non-genetic professionals are adequately equipped with the knowledge and skills to provide services. We describe a series of misdiagnosed/mismanaged cases, highlighting the common pitfalls in genetic testing to identify the knowledge gaps and where education and support is needed. We highlight that education focusing on differential diagnoses, test selection and result interpretation is needed. Collaboration and communication between genetic and non-genetic clinicians and integration of genetic counsellors into different medical settings are important. This will minimise the risks and maximise the benefits of genetic testing, ensuring adverse outcomes are mitigated.Published versionNgeow J receives funding from AstraZeneca for cancer research

Case report: olaparib use in metastatic lung adenocarcinoma with BRCA2 pathogenic variant

Poly (ADP-ribose) polymerase (PARP) inhibitors have been approved in malignancies associated with germline BRCA1 or BRCA2 pathogenic variants, such as breast, ovarian, prostate, and pancreatic cancer. In malignancies not associated with germline BRCA1 or BRCA2 pathogenic variants, the therapeutic relevance of PARP inhibitors is less clear. Non-small-cell lung cancer (NSCLC) is known to demonstrate somatic alterations in BRCA1 or BRCA2 gene. The current report is on a gentleman with metastatic lung adenocarcinoma with a somatic BRCA2 pathogenic variant, who was effectively treated with olaparib. Furthermore, we discuss the existing data for use of PARP inhibitors in NSCLC. This study highlights the utility of next-generation sequencing in identifying gene mutations and demonstrates how such information can be used to select targeted therapies in patients with actionable molecular alterations.Published versio

Predictive testing for tumor predisposition syndromes in pediatric relatives : an Asian experience

Approximately 10% of pediatric cancer patients possess germline pathogenic/likely pathogenic variants (PV/LPV) in known tumor predisposition genes. Predictive testing is the optimal approach to identify asymptomatic at-risk relatives to guide gene-directed surveillance for early cancer detection and/or risk-reducing strategies. However, the uptake rate for predictive testing remains low in Asian countries. We aim to evaluate the uptake rate of predictive testing in a pediatric population (aged under 21-years-old) in a multi-ethnic Asian cancer center. Our retrospective analysis included families with PV/LPVs identified in genes associated with pediatric tumor predisposition. Of the 83 pediatric first-degree relatives (FDRs) from 49 unrelated families, 20 FDRs (24.1%) originating from 13 families (26.6%) underwent predictive testing. Genes tested in pediatric FDRs were APC, RB1, SBDS, SDHA, SDHB, SDHD, and TP53. All pediatric FDRs of probands with PV/LPVs in RB1 and biallelic PVs in SBDS underwent predictive testing, while <45% of pediatric FDRs had predictive testing for familial PV/LPVs identified in the APC, SDHA, SDHB, SDHD, and TP53 genes. Amongst the 13 families who underwent pre-test counseling, 80% of pediatric FDRs in these families proceeded with predictive testing. Malay pediatric FDRs and siblings of probands were more likely to undergo predictive testing. We conclude that the predictive testing rate in pediatric FDRs is higher than that of adult FDRs in Asia, but still below the global average. We postulate factors that may influence predictive testing uptake in pediatric FDRs includes a lack of genetics awareness, concerns regarding insurance, and genetic discrimination.Published versio

Understanding patients' views and willingness toward the use of telehealth in a cancer genetics service in Asia

Telehealth is a growing field, its pertinence magnified by COVID-19 causing the accelerated digitalization of the world. Given the significant global demand to provide telehealth services, it is important to explore patient receptiveness toward this alternative service model, particularly from regions where it has yet to be implemented. We conducted a cross-sectional study to understand the views and willingness of patients toward the use of telehealth for cancer genetic counseling. A survey was completed by 160 patients of the National Cancer Centre Singapore, and descriptive statistics were used to analyze the data. The study found that 95.6% (n = 153/160) of participants did not have prior telehealth experience. Most participants were willing or neutral toward having genetic counseling by phone (n = 114/160, 71.3%) and video (n = 106/160, 66.3%). However, majority prefer in-person appointments for first (n = 127/160, 79.4%) and follow-up (n = 97/160, 60.6%) visits over telehealth. Majority agreed that a phone/video consultation would meet most of their needs but voiced concerns regarding privacy and sharing of information (n = 79/160, 49.4% for phone; n = 74/160, 46.3% for video) and whether their emotional needs could be met (n = 61/160, 38.1%). Participants' age, employment status, income, mode of transportation to the appointment, and whether special arrangements were made to attend the in-person appointment were associated with receptivity to telehealth genetic counseling (p ≤ .05 for all). This study adds diversity to existing literature and demonstrates that patients from Asia are generally willing and accepting of the use of telehealth in a cancer genetics service. This will help meet increasing global demand of telehealth consultations in the post-pandemic new norm. Furthermore, it will also provide services for underserved populations and patients requiring urgent testing in a timely manner. Further studies are needed to explore the cost-effectiveness and fair billing methods, as well as willingness and acceptability of telehealth genetic counseling in post-COVID times.National Medical Research Council (NMRC)This work was supported by National Medical Research Council (NMRC)

COVID-19 vaccination uptake and safety profile among germline BRCA1 and BRCA2 pathogenic variant carriers in Singapore

Background: Although Singapore is one of the highest vaccinated countries in the world, vaccine hesitancy remains in a subpopulation, including individuals with cancer predisposition syndromes. At the Cancer Genetics Service National Cancer Centre Singapore, we see patients with germline genetic alterations, most being BRCA1/2 pathogenic/likely pathogenic variant (PV/LPV) carriers. While reported safe for cancer patients, there are limited studies addressing the safety profile and outcomes of COVID-19 vaccination among individuals with germline PV/LPV in cancer predisposition genes such as BRCA1/2. This study aims to evaluate the outcomes of COVID-19 vaccination among germline PV/LPV carriers in BRCA1/2. Methods: We conducted a phone call survey of COVID-19 vaccination uptake and toxicity in a prospective cohort of 189 participants with germline BRCA1/2 PV/LPV between 1st Sept 2021 and 30th Sept 2021. We collected demographics data including gender, race, age, history of cancer, types of cancer, and number of cancers. Statistical difference in baseline demographics between responders with history of cancer and those without were assessed using Chi-square, Fisher’s exact and independent t-test analysis. Logistic regression was used to evaluate effect of demographics on the occurrence of post-vaccination side effects. Results: Among 189 BRCA1/2 PV/LPV carriers responded, 97 carried PV/LPV in BRCA1 and 92 in BRCA2. Majority were vaccinated (89.5%) and had completed the two-dose vaccine schedule, with 7 (4.1%) received only one dose. The most common post-vaccination side effects was myalgia (56.5%) followed by fever (40.2%), headache (16.3%) and fatigue (11.2%). There were no major severe side events. Evaluation by logistic regression showed that the occurrence of side effects was not affected by PV/LPV gene (BRCA1 or BRCA2), gender, race, age or history of cancer. Conclusion: The post-vaccination side effects profile among individuals with germline PV/LPV in BRCA1/2 is consistent with the Singaporean general population, hence recommendations for COVID-19 vaccination for these individuals should not differ from non-carriers and should be encouraged by their healthcare providers.Published versio

Impact of cancer diagnoses on the outcomes of patients with COVID-19: a systematic review and meta-analysis

10.1136/bmjopen-2020-044661BMJ OPEN12

Strategies to improve implementation of cascade testing in hereditary cancer syndromes: a systematic review

Abstract Hereditary cancer syndromes constitute approximately 10% of all cancers. Cascade testing involves testing of at-risk relatives to determine if they carry the familial pathogenic variant. Despite growing efforts targeted at improving cascade testing uptake, current literature continues to reflect poor rates of uptake, typically below 30%. This study aims to systematically review current literature on intervention strategies to improve cascade testing, assess the quality of intervention descriptions and evaluate the implementation outcomes of listed interventions. We searched major databases using keywords and subject heading of “cascade testing”. Interventions proposed in each study were classified according to the Effective Practice and Organization of Care (EPOC) taxonomy. Quality of intervention description was assessed using the TIDieR checklist, and evaluation of implementation outcomes was performed using Proctor’s Implementation Outcomes Framework. Improvements in rates of genetic testing uptake was seen in interventions across the different EPOC taxonomy strategies. The average TIDieR score was 7.3 out of 12. Items least reported include modifications (18.5%), plans to assess fidelity/adherence (7.4%) and actual assessment of fidelity/adherence (7.4%). An average of 2.9 out of 8 aspects of implementation outcomes were examined. The most poorly reported outcomes were cost, fidelity and sustainability, with only 3.7% of studies reporting them. Most interventions have demonstrated success in improving cascade testing uptake. Uptake of cascade testing was highest with delivery arrangement (68%). However, the quality of description of interventions and assessment of implementation outcomes are often suboptimal, hindering their replication and implementation downstream. Therefore, further adoption of standardized guidelines in reporting of interventions and formal assessment of implementation outcomes may help promote translation of these interventions into routine practice

Impact of variant reclassification in cancer predisposition genes on clinical care

PURPOSE: Genetic testing has clinical utility in the management of patients with hereditary cancer syndromes. However, the increased likelihood of encountering a variant of uncertain significance in individuals of non- European descent such as Asians may be challenging to both clinicians and patients. This study aims to evaluate the impact of variant reclassification in an Asian country with variants of uncertain significance reported in cancer predisposition genes. METHODS: A retrospective analysis of patients seen at the Cancer Genetics Service at the National Cancer Centre Singapore between February 2014 and March 2020 was conducted. The frequency, direction, and time to variant reclassification were evaluated by comparing the reclassified report against the original report. RESULTS: A total of 1,412 variants of uncertain significance were reported in 49.9% (845 of 1,695) of patients. Over 6 years, 6.7% (94 of 1,412) of variants were reclassified. Most variants of uncertain significance (94.1%, 80 of 85) were downgraded to benign or likely benign variant, with a smaller proportion of variants of uncertain significance (5.9%, 5 of 85) upgraded to pathogenic or likely pathogenic variant. Actionable variants of uncertain significance upgrades and pathogenic or likely pathogenic variant downgrades, which resulted in management changes, happened in 31.0% (39 of 126) of patients. The median and mean time taken for reclassification were 1 and 1.62 year(s), respectively. CONCLUSION: We propose a clinical guideline to standardize management of patients reported to have variants of uncertain significance. Management should be based on the patient's personal history, family history, and variant interpretation. For clinically relevant or suspicious variants of uncertain significance, follow-up is recommended every 2 years, as actionable reclassifications may happen during this period.Ministry of Health (MOH)National Medical Research Council (NMRC)National Research Foundation (NRF)Supported by the National Research Foundation Singapore under its Clinical Scientist Award (NMRC/CSA-INV/0017/2017) and administered by the Singapore Ministry of Health’s National Medical Research Council. This project was partially funded by NCC Research Fund, NCC Cancer Fund, and Terry Fox supporting funds. J.N. was funded by the National Medical Research Council Singapore and also received research funding from AstraZeneca

An in-depth exploration of the post-test informational needs of BRCA1 and BRCA2 pathogenic variant carriers in Asia

Identification of one's status as a BRCA1/2 pathogenic variant carrier often marks the start of navigating challenging decisions related to cancer risk management and result disclosure. Carriers report unmet informational needs, but studies have yet to explore the specific aspects of and how best to fulfill these needs. This study aims to explore the informational needs of BRCA1/2 pathogenic variant carriers in Asia to inform for the design of educational materials to support risk management decision-making.Published versio