Impact of free cancer predisposition cascade genetic testing on uptake in Singapore

Cascade testing for cancer predisposition offers a highly efficient and cost-effective method for identifying individuals at increased risk for cancer, in whom targeted interventions can often improve survival. The aim of this study was to determine the impact of free cascade testing on uptake and identify other associated factors. Demographic and clinical data were gathered prospectively for 183 probands found to have a pathogenic variant associated with cancer predisposition and their 826 first-degree relatives (FDRs). The provision of free cascade testing was significantly associated with uptake (21.6% vs 6.1%; χ2, P < 0.001). Relationship type between FDR and proband and FDR age also demonstrated significant associations, suggesting greater engagement amongst younger generations. Overall, 29.0% (53/183) of families had at least 1 FDR who underwent cascade testing. Of these families, 67.9% (36/53) had an uptake rate of at least 40.0%. Cost is a significant barrier to cascade testing uptake in Singapore. Tailored interventions targeting underrepresented groups and genetic counseling approaches supporting family communication and decision-making are necessary.

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title: Aligning Policy to Promote Cascade Genetic Screening for Prevention and Early Diagnosis of Heritable Diseases
abstract: Cascade genetic screening is a methodology for identifying and testing close blood relatives of individuals at increased risk for heritable conditions and follows a sequential process, minimizing testing costs and the number of family members who need to be tested. It offers considerable potential for cost savings and increased awareness of heritable conditions within families. CDC-classified Tier 1 genomic applications for hereditary breast and ovarian cancer syndrome (HBOC), Lynch Syndrome (LS), and familial hypercholesterolemia (FH) are recommended for clinical use and support the use of cascade genetic screening. Most individuals are unaware of their increased risk for heritable conditions such as HBOC, LS, and FH. Consistent implementation of cascade genetic screening could significantly increase awareness and prevention of heritable conditions. Limitations to effective implementation of cascade genetic screening include: insufficient genetic risk assessment and knowledge by a majority of healthcare providers without genetics credentials; a shortage of genetic specialists, especially in rural areas; a low rate of reimbursement for comprehensive genetic counseling services; and an individual focus on prevention by clinical guidelines and insurance coverage. The family-centric approach of cascade genetic screening improves prevention and early diagnosis of heritable diseases on a population health level. Cascade genetic screening could be better supported and augmented through changes in health policy.

title: Precision Public Health for the Era of Precision Medicine.
abstract: The Precision Medicine Initiative1 promises a new healthcare era. A proposed 1 million—person cohort could create a deeper understanding of disease causation. Improvements in quality of sequencing, reduction in price, and advances in “omic” fields and biotechnology promise a new era, variably labeled personalized or precision medicine. Although genomics is one driver of precision health care, other factors may be as important (e.g., health information technology).

title: Pathogenic Germline Variants in 10,389 Adult Cancers
abstract: We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

title: Realizing the promise of cancer predisposition genes
abstract: Genes in which germline mutations confer highly or moderately increased risks of cancer are called cancer predisposition genes. More than 100 of these genes have been identified, providing important scientific insights in many areas, particularly the mechanisms of cancer causation. Moreover, clinical utilization of cancer predisposition genes has had a substantial impact on diagnosis, optimized management and prevention of cancer. The recent transformative advances in DNA sequencing hold the promise of many more cancer predisposition gene discoveries, and greater and broader clinical applications. However, there is also considerable potential for incorrect inferences and inappropriate clinical applications. Realizing the promise of cancer predisposition genes for science and medicine will thus require careful navigation.

title: Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality
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title: Predictive genetic testing of first degree relatives of mutation carriers is a cost-effective strategy in preventing hereditary non-polyposis colorectal cancer in Singapore
abstract: Colorectal cancer (CRC) is the most common cancer in Singapore. We sought to evaluate the long-term cost-effectiveness of targeted genetic testing and surveillance programs in individuals at high risk of hereditary non-polyposis colorectal cancer (HNPCC), as compared to an unselective clinical surveillance program alone in Singapore. A Markov model analysis from the healthcare service provider’s perspective was developed to follow over a lifetime a cohort of cancer-free 21-year-old individuals, who were first-degree relatives of HNPCC patients with a known mutation. Genetic testing strategy provided a lifetime saving of Singapore dollars (SGD) 13,588 per person and gained additional life years of 0.01, as compared to clinical surveillance alone, by sparing non-mutation carriers from unnecessary and invasive intensive clinical surveillance (assuming 100% compliance with recommended surveillance programs in both strategies). Sensitivity analyses showed that as long as the compliance rate in mutation carriers was not lower than that for individuals without genetic testing, pursuing a genetic testing strategy would either be a more favorable option with discounted incremental cost-effectiveness ratios ranging from SGD 6,961 to 17,289 per life year gained or a dominant status achieved (more life year gained and less costly). Genetic testing for individuals at high risk of HNPCC allows targeted clinical surveillance to be directed at mutation carriers, ensuring efficient use of healthcare resources and reduces CRC-related mortality. It can be regarded as a cost-effective strategy in Singapore, if an improved compliance with recommended surveillance protocol is achieved in proven mutation carriers.

title: Preventing future cancers by testing women with ovarian cancer for BRCA mutations.
abstract: Women with ovarian cancer have a 10% probability of carrying a BRCA mutation. If a mutation is identified, unaffected family members can undergo genetic testing and cancer risk-reducing strategies. We estimated the net health benefits and cost-effectiveness of different criteria for BRCA mutation testing in women with ovarian cancer, and the downstream benefits for their first-degree relatives (FDRs).



We developed a Markov Monte Carlo simulation model to compare four criteria for BRCA testing in women with ovarian cancer: no testing (reference); only if personal history of breast cancer, family history of breast/ovarian cancer, or Ashkenazi Jewish ancestry; only if invasive serous cancer; any invasive nonmucinous epithelial cancer. Net health benefit was life expectancy for FDRs and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of future breast and ovarian cancer cases in FDRs.



BRCA testing based on personal/family history and ancestry could prevent future cases in FDRs with an ICER of $32,018 per year of life (LY) gained compared with the reference strategy. BRCA testing based on serous or any nonmucinous epithelial ovarian cancer could prevent more cancer cases, but at ICERs of $128,465 and $148,363 per LY gained, respectively.



BRCA testing of women with ovarian cancer based on personal/family history of cancer or Ashkenazi Jewish ancestry is a cost-effective strategy to prevent future breast and ovarian cancers among FDRs. More inclusive testing strategies prevent additional cancer cases but at significant cost.

title: The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer
abstract: To estimate the cost-effectiveness of genetic testing strategies to identify Lynch syndrome among newly diagnosed patients with colorectal cancer and to offer targeted testing to relatives of patients with Lynch syndrome. We calculated incremental costs per life-year saved for universal testing relative to no testing and age-targeted testing for strategies that use preliminary genetic tests (immunohistochemistry or microsatellite instability) of tumors followed by sequencing of mismatch repair genes. We also calculated incremental cost-effectiveness ratios for pairs of testing strategies. Strategies to test for Lynch syndrome in newly diagnosed colorectal tumors using preliminary tests before gene sequencing have incremental cost-effectiveness ratios of ≤$45,000 per life-year saved compared with no testing and ≤$75,000 per life-year saved compared with testing restricted to patients younger than 50 years. The lowest cost testing strategies, using immunohistochemistry as a preliminary test, cost ≤$25,000 per life-year saved relative to no testing and ≤$40,000 per life-year saved relative to testing only patients younger than 50 years. Other testing strategies have incremental cost-effectiveness ratios ≥$700,000 per life-year saved relative to the lowest cost strategies. Increasing the number of relatives tested would improve cost-effectiveness. Laboratory-based strategies using preliminary tests seem cost-effective from the US health care system perspective. Universal testing detects nearly twice as many cases of Lynch syndrome as targeting younger patients and has an incremental cost-effectiveness ratio comparable with other preventive services. This finding provides support for a recent US recommendation to offer testing for Lynch syndrome to all newly diagnosed patients with colorectal cancer.

title: When is Genomic Testing Cost-Effective? Testing for Lynch Syndrome in Patients with Newly-Diagnosed Colorectal Cancer and Their Relatives
abstract: Varying estimates of the cost-effectiveness of genomic testing applications can reflect differences in study questions, settings, methods and assumptions. This review compares recently published cost-effectiveness analyses of testing strategies for Lynch Syndrome (LS) in tumors from patients newly diagnosed with colorectal cancer (CRC) for either all adult patients or patients up to age 70 along with cascade testing of relatives of probands. Seven studies published from 2010 through 2015 were identified and summarized. Five studies analyzed the universal offer of testing to adult patients with CRC and two others analyzed testing patients up to age 70; all except one reported incremental cost-effectiveness ratios (ICERs) < $ 100,000 per life-year or quality-adjusted life-year gained. Three studies found lower ICERs for selective testing strategies using family history-based predictive models compared with universal testing. However, those calculations were based on estimates of sensitivity of predictive models derived from research studies, and it is unclear how sensitive such models are in routine clinical practice. Key model parameters that are influential in ICER estimates included 1) the number of first-degree relatives tested per proband identified with LS and 2) the cost of gene sequencing. Others include the frequency of intensive colonoscopic surveillance, the cost of colonoscopy, and the inclusion of extracolonic surveillance and prevention options.

title: Delivery Of Cascade Screening For Hereditary Conditions: A Scoping Review Of The Literature.
abstract: Cascade screening is the process of contacting relatives of people who have been diagnosed with certain hereditary conditions. Its purpose is to identify, inform, and manage those who are also at risk. We conducted a scoping review to obtain a broad overview of cascade screening interventions, facilitators and barriers to their use, relevant policy considerations, and future research needs. We searched for relevant peer-reviewed literature in the period 1990-2017 and reviewed 122 studies. Finally, we described 45 statutes and regulations related to the use and release of genetic information across the fifty states. We sought standardized best practices for optimizing cascade screening across various geographic and policy contexts, but we found none. Studies in which trained providers contacted relatives directly, rather than through probands (index patients), showed greater cascade screening uptake; however, policies in some states might limit this approach. Major barriers to cascade screening delivery include suboptimal communication between the proband and family and geographic barriers to obtaining genetic services. Few US studies examined interventions for cascade screening or used rigorous study designs such as randomized controlled trials. Moving forward, there remains an urgent need to conduct rigorous intervention studies on cascade screening in diverse US populations, while accounting for state policy considerations.

title: Uptake of genetic testing by the children of Lynch syndrome variant carriers across three generations
abstract: Many Lynch syndrome (LS) carriers remain unidentified, thus missing early cancer detection and prevention opportunities. Tested probands should inform their relatives about cancer risk and options for genetic counselling and predictive gene testing, but many fail to undergo testing. To assess predictive testing uptake and demographic factors influencing this decision in LS families, a cross-sectional registry-based cohort study utilizing the Finnish Lynch syndrome registry was undertaken. Tested LS variant probands (1184) had 2068 children divided among three generations: 660 parents and 1324 children (first), 445 and 667 (second), and 79 and 77 (third). Of children aged >18 years, 801 (67.4%), 146 (43.2%), and 5 (23.8%), respectively, were genetically tested. Together, 539 first-generation LS variant carriers had 2068 children and grandchildren (3.84 per carrier). Of the 1548 (2.87 per carrier) eligible children, 952 (61.5%) were tested (1.77 per carrier). In multivariate models, age (OR 1.08 per year; 95% CI 1.06–1.10), family gene (OR 2.83; 1.75–4.57 for MLH1 and 2.59; 1.47–4.56 for MSH2 compared with MSH6), one or more tested siblings (OR 6.60; 4.82–9.03), no siblings (OR 4.63; 2.64–8.10), and parent under endoscopic surveillance (OR 5.22; 2.41–11.31) were independent predictors of having genetic testing. Examples of parental adherence to regular surveillance and genetically tested siblings strongly influenced children at 50% risk of LS to undergo predictive gene testing. High numbers of untested, adult at-risk individuals exist even among well-established cohorts of known LS families with good adherence to endoscopic surveillance.

title: Impact of subsidies on cancer genetic testing uptake in Singapore
abstract: Previous reports cite high costs of clinical cancer genetic testing as main barriers to patient's willingness to test. We report findings of a pilot study that evaluates how different subsidy schemes impact genetic testing uptake and total cost of cancer management.  We included all patients who attended the Cancer Genetics Service at the National Cancer Centre Singapore (January 2014–May 2016). Two subsidy schemes, the blanket scheme (100% subsidy to all eligible patients), and the varied scheme (patients received 50%–100% subsidy dependent on financial status) were compared. We estimated total spending on cancer management from government's perspective using a decision model. Results 445 patients were included. Contrasting against the blanket scheme, the varied scheme observed a higher attendance of patients (34 vs 8 patients per month), of which a higher proportion underwent genetic testing (5% vs 38%), while lowering subsidy spending per person (S$1098 vs S$1161). The varied scheme may potentially save cost by reducing unnecessary cancer surveillance when first-degree relatives uptake rate is above 36%.  Provision of subsidy leads to a considerable increase in genetic testing uptake rate. From the government's perspective, subsidising genetic testing may potentially reduce total costs on cancer management.

title: BRCA1/2 predictive testing: a study of uptake in two centres
abstract: Differences in reported uptake of genetic testing for mutations in BRCA1 and BRCA2 can largely be accounted for by different methodologies and by studying research vs nonresearch families. In our joint study of 75 nonresearch families from two UK centres in which at least 3 years had elapsed since the initial proband had been informed of the availability of testing, only 45 and 34% of eligible individuals from Manchester and London, respectively, had come forward for counselling. Final uptake rates using a non-proactive approach were 53 and 29% for women and 11–12% for men, but the figure among those attending clinic was 73 and 62%, respectively. Unlike previous studies, we did not find that uptake had stabilised after a year with 25% of those being tested more than 2 years after the family was informed, and several delaying a considerable time between genetics appointments. We believe that the particularly low uptake even of counselling in men may need to be addressed by improving family communication or providing information sheets for family members to disseminate.

title: Uptake of genetic testing by relatives of lynch syndrome probands: a systematic review.
abstract: Screening of persons with newly diagnosed colorectal cancer for Lynch syndrome can yield substantial benefits at acceptable costs, presuming sufficient uptake of genetic testing by first-degree relatives of Lynch syndrome probands. We performed a systematic review of the literature to determine the frequency of and factors associated with genetic testing of first-degree relatives of Lynch syndrome probands.



We searched 4 databases (CINAHL, PsycInfo, PUBMED, and SCOPUS) for articles published through May 2011 reporting uptake of genetic testing by relatives of Lynch syndrome probands. Two investigators independently screened articles to determine whether they met inclusion criteria; data were collected on study population, genetic counseling, and genetic testing. A narrative, qualitative systematic review was performed.



We identified 1258 potentially relevant articles; 533 underwent full-text review, and 8 were included in the final analysis. Of first-degree relatives of Lynch syndrome probands, 52% or less received genetic testing. For each proband, 3.6 or fewer relatives underwent genetic testing. Demographic factors (age <50 years, female sex, parenthood, level of education, employment, participation in medical studies), psychological factors (lack of depressive symptoms), and possibly family history (greater number of relatives with cancer) were associated with uptake of genetic testing.



Genetic testing appears to be underutilized by first-degree relatives of patients with Lynch syndrome. The clinical benefit and economic feasibility of screening persons with colorectal cancer for Lynch syndrome depend on optimizing family-wide uptake of genetic testing. Future research and clinical efforts should focus on ways to overcome barriers to genetic testing.

title: Familial communication and cascade testing among relatives of BRCA population screening participants
abstract: PurposePopulation BRCA1/BRCA2 screening identifies carriers irrespective of family history, yet this information is actionable for relatives. We examined familial communication rates and cascade testing in the screening setting and assessed sociodemographic and psychosocial predictors.MethodsParticipants in a BRCA1/BRCA2 screening study of healthy Ashkenazi Jews self-administered a family communication questionnaire. Intent to communicate was determined before genetic status was known, along with result communication (carriers and noncarriers) 6 months and 2 years after enrollment. Carriers underwent in-depth interviews and provided cascade testing information.ResultsIn total, 88% (524/595) of questionnaire responders and 97% (30/32) of carriers informed at least one relative. In multivariate analysis, family history (P = 0.005) and greater Satisfaction With Health Decision scores (P < 0.001) predicted communication of results. Among carriers’ adult first- and second-degree relatives, 71 (48%) had cascade testing, more commonly performed in first- (58%) than in second-degree relatives (26%, P = 0.0002), and in females (56%) vs. males (36%, P = 0.02). At least 11% remained uninformed.ConclusionFamilial communication rates and characteristics in a screening setting parallel those reported by Cancer Genetics clinics. Universal screening circumvents dependence on familial disclosure. However, our finding that satisfaction—a potentially modifiable factor—predicts communication, raises the hypothesis that improving the testing experience could facilitate familial communication.

title: Factors determining dissemination of results and uptake of genetic testing in families with known BRCA1/2 mutations.
abstract: Uptake of genetic testing remains low, even in families with known BRCA1 and BRCA2 (BRCA1/2) mutations, despite effective interventions to reduce risk. We report disclosure and uptake patterns by BRCA1/2-positive individuals to at-risk relatives, in the setting of no-cost genetic counseling and testing.



Relatives of BRCA1/2-positive individuals were offered cost-free and confidential genetic counseling and testing. If positive for a BRCA1/2 mutation, participants were eligible to complete a survey about their disclosure of mutation status and the subsequent uptake of genetic testing by at-risk family members.



One hundred and fifteen of 142 eligible individuals responded to the survey (81%). Eighty-eight (77%) of those surveyed disclosed results to all at-risk relatives. Disclosure to first-degree relatives (FDRs) was higher than to second-degree relatives (SDRs) and third-degree relatives (TDR) (95% vs. 78%; p < 0.01). Disclosure rates to male versus female relatives were similar, but reported completion of genetic testing was higher among female versus male FDRs (73% vs. 49%; p < 0.01) and SDRs (68% vs. 43%; p < 0.01), and among members of maternal versus paternal lineages (63% vs. 0%; p < 0.01). Men were more likely than women to express general difficulty discussing positive BCRA1/2 results with at-risk family members (90% vs. 70%; p = 0.03), while women reported more emotional distress associated with disclosure than men (48% vs. 13%; p < 0.01).



We report a very high rate of disclosure of genetic testing information to at-risk relatives. However, uptake of genetic testing among at-risk individuals was low despite cost-free testing services, particularly in men, SDRs, and members of paternal lineages. The complete lack of testing among paternally related at-risk individuals and the lower testing uptake among men signify a significant barrier to testing and a challenge for genetic counselors and physicians working with high-risk groups. Further research is necessary to ensure that family members understand their risk and the potential benefits of genetic counseling.

title: Genetic counseling for patients and families with hereditary breast and ovarian cancer in a developing Asian country: an observational descriptive study
abstract: Genetic counseling (GC) and genetic testing are vital risk management strategies in hereditary breast and ovarian cancer (HBOC) syndromes. Hitherto, cancer genetic testing amongst Asians has been described only in developed and high-income Asian countries. We studied the uptake and acceptance of GC and genetic testing services to Asian BRCA carriers in a middle-income country. A total of 363 patients were tested by full sequencing and large rearrangement analysis of both BRCA1 and BRCA2 genes in the Malaysian Breast Cancer (MyBrCa) Genetic Study. Of these, 49 index patients (13.5%) were found to carry deleterious mutations. GC pre- and post- result disclosures were provided and these groups of patients and their families were studied. GC and genetic testing were accepted by 82% of Malaysian patients at high risk for HBOC syndromes. However, risk assessment was limited by large, geographically dispersed, often polygamous or polyandrous families, and the lack of complete cancer registry. Cultural taboos about cancer diagnoses, social marginalization and lack of regulatory control of genetic discrimination were significant concerns. Only 78% of index patients informed their families of their risks and 11% of relatives came forward when offered free counseling and testing. Even when GC and genetic testing are provided at no cost, there remain significant societal and regulatory barriers to effective cancer genetic services in this underserved Asian population. Families believe there is a need for regulatory protection against genetic discrimination. Further studies are needed in the area of increasing awareness about the potential benefits of GC and genetic testing in Asians.

title: Discrepancy between initial high expression of interest in clinical cancer genetic testing and actual low uptake in an Asian population.
abstract: Little is known about the acceptance of clinical cancer genetic testing in Asians. We surveyed the attitudes and perceived motivators and barriers to genetic testing immediately after genetic counseling in at-risk patients for hereditary cancer in a cancer genetics clinic in Singapore, and compared the responses of actual test acceptors and decliners.



Three hundred seventeen patients participated, including 199 cancer-affected and 118 cancer-free probands or family members. Overall, 70% of patients expressed an initial willingness to be tested, and most did not perceive major barriers. However, only 69/199 (35%) of cancer-affected probands were actually tested. There was no significant difference in age, education, marital status, or initial expression of negative feelings toward genetic information between the test acceptors and decliners, although the decliners were more likely to have indicated a wish not to be tested (22% vs. 4%, p<0.001) and cited cost as a barrier (32% vs. 12%, p=0.002). The most common actual reasons against testing were cost (60%), not wanting to bear the emotional burden of genetic information (16%), and the perception that the medical management will not change (16%).



A significant discrepancy exists between an initial high interest in testing and actual low uptake. Health programs that address cost issues and education to correct misperceptions may improve genetic information utilization.

title: Communication of BRCA Results and Family Testing in 1,103 High-Risk Women
abstract: Genetic testing for hereditary cancer risk has implications for individuals and families. This study of women at risk of hereditary breast and ovarian cancer examines communication of BRCA results and subsequent genetic testing in the family.  We surveyed 1,103 female BRCA testers at two hospitals, querying for communication of results and testing in relatives.  Ninety-seven percent of participants communicated BRCA results with at least one relative. Communication was negatively associated with older age [odds ratio (OR), 0.66 per decade; 95% confidence interval, (95% CI), 0.4–0.9], Asian race (OR, 0.18; 95% CI, 0.06–0.5), and testing at the public hospital versus the cancer center (OR, 0.19; 95% CI, 0.07–0.5). Communication was positively associated with increased knowledge of hereditary breast and ovarian cancer screening and risk reduction recommendations (OR, 1.9; 95% CI, 1.1–3.4) and increased satisfaction with the decision to BRCA test (OR, 2.6; 95% CI, 1.6–4.0). Seventy-five percent of BRCA-positive participants reported that at least one relative pursued genetic testing. Family testing was negatively associated with Asian race (OR, 0.15; 95% CI, 0.02–0.8) and positively associated with increased socioeconomic status (OR, 1.4; 95% CI, 1.1–1.7) and increased satisfaction with decision (OR, 2.1; 95% CI, 1.1–4.1).  Despite high overall rates of communicating BRCA results, underserved and some minority women seem less likely to inform relatives of their BRCA status or have relatives test for a known family mutation. Satisfaction with the decision to BRCA test is positively associated with both outcomes.  This study identified several novel predictors of family communication and family genetic testing in a large population of high-risk women. This work can inform clinicians interested in improving family communication regarding cancer predisposition testing. Cancer Epidemiol Biomarkers Prev; 19(9); 2211–9.

title: Sharing genetic test results in Lynch syndrome: communication with close and distant relatives.
abstract: Clinical genetic testing can help direct cancer screening for members of Lynch syndrome families; however, there is limited information about family communication of genetic test results.



A total of 174 probands who had genetic testing for Lynch syndrome were enrolled through 4 US cancer genetics clinics. Subjects were asked whether they had disclosed their genetic test results to first-, second-, and third-degree relatives. Univariate and multivariate analyses were used to identify clinical and demographic factors associated with informing immediate and extended family of genetic test results.



One hundred seventy-one of 174 probands (98%; 95% confidence interval, 95%-100%) reported that they had disclosed their genetic test result to a first-degree relative. Communication of test results to other relatives occurred significantly less often, with only 109 of 162 (67%; 95% confidence interval, 59%-74%) subjects with second- or third-degree relatives sharing their results. Individuals with a pathogenic mutation were significantly more likely to inform distant relatives than were subjects with a negative or indeterminate test result (odds ratio, 2.49; 95% confidence interval, 1.14-5.40). Probands' age, sex, and cancer status did not influence communication of genetic test results. Lack of closeness and concerns that relatives would worry or not understand the implications of test results were the primary reasons for not sharing genetic test results.



Most individuals who undergo genetic testing for Lynch syndrome share their test results with first-degree family members; however, these results reach more distant relatives significantly less often. Interventions to improve communication of genetic test results to members of the extended family are necessary to provide optimal cancer prevention care to at-risk families.

title: Sharing BRCA1/2 test results with first-degree relatives: factors predicting who women tell.
abstract: Patient communication with relatives about cancer genetic test results is the primary means for alerting those who may benefit from identification of hereditary risk. This study identifies factors predicting patterns of disclosure of BRCA1/2 test results to first-degree relatives (FDRs) among women tested in a clinical protocol.



A total of 273 women completed a family communication measure 4 months after BRCA1/2 result disclosure. chi2 analyses and logistic regression models identified factors predicting sharing of the test result.



Most FDRs were informed of the participant's test result by 4 months; female relatives were more likely to be informed than males. Tested women conveyed inconclusive results (variant or negative without known familial mutation) less frequently to their sisters than conclusive (positive/true negative) results (P = .03). Twenty-three percent of participants did not inform their father. Informing brothers was more likely when BRCA1/2 was inherited through paternal lineage (P = .04), but 29% of brothers were not informed. Women older than age 40 were less likely to share their result with their parents (P = .03) than were women < or = 40. Children's ages influenced communication to offspring; most children were told.



Demographic, health-, and test-related factors predicted genetic test result communication to FDRs. Additional research investigating the full spectrum of discussion within families and motives for incomplete sharing of genetic test results with relatives may suggest strategies for providers and targeted educational interventions for patients to enhance family communication.

title: Quantifying family dissemination and identifying barriers to communication of risk information in Australian BRCA families
abstract: PurposeRecommendations for BRCA1 and BRCA2 mutation carriers to disseminate information to at-risk relatives pose significant challenges. This study aimed to quantify family dissemination, to explain the differences between fully informed families (all relatives informed verbally or in writing) and partially informed families (at least one relative uninformed), and to identify dissemination barriers.MethodsBRCA1 and BRCA2 mutation carriers identified from four Australian hospitals (n=671) were invited to participate in the study. Distress was measured at consent using the Kessler psychological distress scale (K10). A structured telephone interview was used to assess the informed status of relatives, geographical location of relatives, and dissemination barriers. Family dissemination was quantified, and fully versus partially informed family differences were examined. Dissemination barriers were thematically coded and counted. total of 165 families participated. Information had been disseminated to 81.1% of relatives. At least one relative had not been informed in 52.7% of families, 4.3% were first-degree relatives, 27.0% were second-degree relatives, and 62.0% were cousins. Partially informed families were significantly larger than fully informed families, had fewer relatives living in close proximity, and exhibited higher levels of distress. The most commonly recorded barrier to dissemination was loss of contact.ConclusionLarger, geographically diverse families have greater difficulty disseminating BRCA mutation risk information to all relatives. Understanding these challenges can inform future initiatives for communication, follow-up and support.

title: Non-uptake of predictive genetic testing for BRCA1/2 among relatives of known carriers: attributes, cancer worry, and barriers to testing in a multicenter clinical cohort.
abstract: BRCA1/2 test decliners/deferrers have received almost no attention in the literature and this is the first study of this population in the United Kingdom. The aim of this multicenter study is to examine the attributes of a group of individuals offered predictive genetic testing for breast/ovarian cancer predisposition who did not wish to proceed with testing at the time of entry into this study. This forms part of a larger study involving 9 U.K. centers investigating the psychosocial impact of predictive genetic testing for BRCA1/2. Cancer worry and reasons for declining or deferring BRCA1/2 predictive genetic testing were evaluated by questionnaire following genetic counseling. A total of 34 individuals declined the offer of predictive genetic testing. Compared to the national cohort of test acceptors, test decliners are significantly younger. Female test decliners have lower levels of cancer worry than female test acceptors. Barriers to testing include apprehension about the result, traveling to the genetics clinic, and taking time away from work/family. Women are more likely than men to worry about receiving less screening if found not to be a carrier. The findings do not indicate that healthy BRCA1/2 test decliners are a more vulnerable group in terms of cancer worry. However, barriers to testing need to be discussed in genetic counseling.

title: Establishing a Cancer Genetics Programme in Asia - the Singapore Experience
abstract: Cancer genetics is now an established oncology subspecialty with the primary prevention role of identifying high-risk individuals through genetic information for enrolment into screening and preventive programmes. Integrated into major Western centres since the late 1990s, such a programme has been established in Singapore since 2001. Our programme has evaluated 367 index patients comprising mainly breast and colorectal cancer cases. Cancer patients were receptive to genetic counselling, but cost posed a major barrier to genetic testing. However, when the cost barrier was removed through government subsidy plans, more than half of high-risk patients still declined testing. The major barriers were reluctance to involve family members, perception that the information would not change management, and fears of negative feelings. Confirmed mutation carriers were compliant to screening and receptive to prophylactic surgery. Uptake of predictive testing among cancer-free family members has been low, possibly arising from the stigma associated with cancer in our Asian culture. These potential barriers are being addressed through government subsidy plans, continuing education to increase awareness, and being culturally sensitive when dealing with the Asian family.

title: Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: Results of an Online Initiative
abstract: In cascade testing, genetic testing for an identified familial pathogenic variant extends to disease-free relatives to allow genetically targeted disease prevention. We evaluated the results of an online initiative in which carriers of 1 of 30 cancer-associated genes, or their first-degree relatives, could offer low-cost testing to at-risk first-degree relatives. In the first year, 1101 applicants invited 2280 first-degree relatives to undergo genetic testing. Of invited relatives, 47.5% (95% confidence interval [CI] = 45.5 to 49.6%) underwent genetic testing, and 12.0% (95% CI = 9.2 to 14.8%) who tested positive continued the cascade by inviting additional relatives to test. Of tested relatives, 4.9% (95% CI = 3.8 to 6.1%) had a pathogenic variant in a different gene from the known familial one, and 16.8% (95% CI = 14.7 to 18.8%) had a variant of uncertain significance. These results suggest that an online, low-cost program is an effective approach to implementing cascade testing, and that up to 5% of the general population may carry a pathogenic variant in 1 of 30 cancer-associated genes.

title: Patient and family involvement in decision making for management of cancer patients at a centre in Singapore
abstract: The practice of patient autonomy within the prevailing bioethical framework in the West appears increasingly at odds with the prominent influence of the family in medical decision making in the Asian culture. The actual extent of involvement of patient versus the family in the decision making process for cancer management in clinical practice is largely unknown in Asia.  To describe patient and family involvement in healthcare decision making in actual practice, and to determine whether those practices are consistent with Singapore law; and (2) to act as a pilot for a larger prospective study examining the preferences of cancer patients on the decision making process, and the reasons for excluding patients from that process.  A retrospective review of patients who died in an oncology ward in Singapore General Hospital from February to April 2011. Patient and family involvement in discussions on (1) disclosure of diagnosis, (2) initial treatment decisions and (3) initiation of a ‘maximum ward management’ order was evaluated by reviewing case notes completed by healthcare professionals.  Data were collected for 55 patients. Involvement of patients and families at first disclosure of diagnosis was noted in 61% and 64% of cases, respectively. In 12% of cases, the family requested withholding of the diagnosis from the patient. 86% of patients were involved in the initial treatment decisions, and their family was involved in 65% of cases. Only 9% of the 32 alert patients were consulted in end of life decisions. Factors associated with lower patient involvement were advanced age and inability to speak English.  While most cancer patients are involved in the healthcare decision making process during the early phase, familial involvement gains prominence as the disease progresses.

title: ONE SIZE FITS ALL? ON PATIENT AUTONOMY, MEDICAL DECISION-MAKING, AND THE IMPACT OF CULTURE.
abstract: While both medical law and medical ethics have developed in a way that has sought to prioritise patient autonomy, it is less clear whether it has done so in a way that enhances the self-determination of patients from non-western backgrounds. In this article, we consider the desire of some patients from non-western backgrounds for family involvement in decision-making and argue that this desire is not catered for effectively in either medical law or medical ethics. We examine an alternative approach based on relational autonomy that might serve both to allow such patients to exercise their self-determination while still allowing them to include family members in the decision-making process.

title: Genetic testing in asymptomatic minorsBackground considerations towards ESHG Recommendations
abstract: Although various guidelines and position papers have discussed, in the past, the ethical aspects of genetic testing in asymptomatic minors, the European Society of Human Genetics had not earlier endorsed any set of guidelines exclusively focused on this issue. This paper has served as a background document in preparation of the development of the policy recommendations of the Public and Professional Committee of the European Society of Human Genetics. This background paper first discusses some general considerations with regard to the provision of genetic tests to minors. It discusses the concept of best interests, participation of minors in health-care decisions, parents’ responsibilities to share genetic information, the role of clinical genetics and the health-care system in communication within the family. Second, it discusses, respectively, the presymptomatic and predictive genetic testing for adult-onset disorders, childhood-onset disorders and carrier testing.

title: Letting the family know: balancing ethics and effectiveness when notifying relatives about genetic testing for a familial disorder
abstract: To increase the awareness among at risk relatives of the availability of genetic testing for a familial disorder while respecting their autonomy and privacy.  This was a comparison of preintervention and postintervention cohorts of families carried out in a state wide clinical service providing genetic counselling and testing for people at risk of familial adult onset cancer. Unaffected relatives who were not clients of the service in 74 kindreds with familial mutations causing familial breast and ovarian cancer, hereditary non-polyposis colorectal cancer, or Cowden syndrome were included in the study. In the baseline cohort (41 kindreds), family members who were clients of the clinical service and had been shown to be carriers of mutations were asked to advise relatives that genetic testing was available. In the intervention cohort (33 kindreds), the clinical service obtained consent to advise at risk relatives by letter that genetic testing was available. The main outcome measures were: (a) proportion of unaffected first and second degree relatives of the proband in each family whose genetic status was clarified within 2 years of the mutation being identified in the family, and (b) concerns regarding privacy and autonomy voiced by relatives receiving these letters.  In the baseline cohort, the average proportion of relatives in each family whose genetic status was clarified was 23%. In the intervention cohort, the average proportion of relatives in each family whose genetic status was clarified was 40% (p = 0.001). None of the relatives in the intervention cohort complained of a breach of privacy or autonomy.  Clinical services can take an effective and proactive approach to notifying relatives who are not their clients of the availability of genetic testing without compromising principles of privacy and autonomy.

title: Direct contact in inviting high-risk members of hereditary colon cancer families to genetic counselling and DNA testing
abstract: Identification of hereditary predisposition to cancer has limited significance if not followed by efficient cancer prevention in the family. Probands are traditionally left to inform their relatives about the increased risk, but distant relatives may remain uninformed. An approach to contacting directly at-risk persons assumed to be unaware of their increased cancer risk was taken. With cancer prevention as the ultimate goal, the study was aimed at investigating attitudes towards and psychosocial consequences of this novel strategy.  In families with hereditary non-polyposis colorectal cancer (Lynch syndrome), 286 healthy adult relatives with a 50% risk of a predisposing mutation were contacted by letter. Of these, 112 participated in counselling and predictive testing. Baseline information and information obtained 1 month after the test for 73 respondents were compared with 299 corresponding subjects, approached via the proband (family-mediated approach in our previous study) in these families.  After the contact letter, 51% consented to the study. Of these, 92% approved of the direct contact and 33% had tried to seek information. In 34% of the mutation carriers, neoplasia was identified in the first post-test colonoscopy. Although post-test fear of cancer increased among the mutation carriers and decreased among noncarriers, almost all participants were satisfied with their decision to participate, independently of their test results, parallel to the family-mediated approach.  In this large-scale study, relatives in cancer families were actively contacted to inform them of the condition and genetic counselling. Their attitudes were encouraging, and the psychosocial consequences were similar to the family-mediated approach. Our results suggest the appropriateness of direct contact as an alternative method of contact in cases of life-threatening treatable disease.

title: A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome
abstract: BackgroundIndividuals who carry deleterious BRCA mutations face significantly elevated risks of breast, ovarian, and other cancers. These individuals are also responsible for informing relatives of their increased risk for carrying the family BRCA mutation. Few interventions have been developed to facilitate this family communication process.MethodsWe developed the Sharing Risk Information Tool (ShaRIT), a personalized educational intervention, to support BRCA carriers as they discuss BRCA positive results and their implications with relatives. We conducted a pilot study of 19 BRCA carriers identified through the University of California San Francisco Cancer Risk Program. Our study had two aims: 1) to assess the feasibility and acceptability of ShaRIT, and 2) describe characteristics associated with increased family communication and BRCA testing. Participants in our study were divided into two groups: those who had not received ShaRIT as part of their genetic counseling protocol (control group, n = 10) and those who received ShaRIT (n = 9).ResultsAll 9 women who received ShaRIT reported that it was a useful resource. Characteristics associated with increased sharing and testing included: female gender, degree of relationship, and frequency of communication. Increased pedigree knowledge showed a trend toward higher rates of sharing.ConclusionsBoth participants and genetic counselors considered ShaRIT a well-received, comprehensive tool for disseminating individual risk information and clinical care guidelines to Hereditary Breast and Ovarian Cancer Syndrome families. Because of this, ShaRIT has been incorporated as standard of care at our institution. In the future we hope to evaluate the effects of ShaRIT on family communication and family testing in larger populations of BRCA positive families.

title: Sustainable Health Care Financing: The Singapore Experience
abstract: The Singapore health system has been lauded for achieving impressive population health outcomes utilizing only a modest 4–5 per cent of GDP, with the government's share only one third of this. Measured health spending is consistent with a larger government commitment to fiscal prudence and discipline in balancing budgets. In fact, the Singapore constitution permits a government to only spend revenue raised during its term of office. Drawing down of national reserves can only be done during exceptional circumstances and requires specific approval from the president. However, the sustainability of Singapore's health system is under pressure from changing demographics, disease trends and growing demands from citizens for greater equity and expanded health care services. In the face of these challenges, the Singaporean government has responded by introducing three major costly policy reforms: the Pioneer Generation Package, to help elderly people pay for medical treatment; MediShield Life, to expand insurance coverage; and the Community Health Assistance Scheme (CHAS), to provide government subsidies for primary care for those that qualify. Despite the expansion of funding and services, the government remains committed to the longstanding principles of fiscal prudence and not drawing from past reserves.