Cost-effectiveness Of Genetic Testing Research Articles

Imaging-based stratification of adult gliomas prognosticates survival and correlates with the 2021 WHO classification.

Because of the lack of global accessibility, delay, and cost-effectiveness of genetic testing, there is a clinical need for an imaging-based stratification of gliomas that can prognosticate survival and correlate with the 2021-WHO classification. In this retrospective study, adult primary glioma patients with pre-surgery/pre-treatment MRI brain images having T2, FLAIR, T1, T1 post-contrast, DWI sequences, and survival information were included in TCIA training-dataset (n = 275) and independent validation-dataset (n = 200). A flowchart for imaging-based stratification of adult gliomas(IBGS) was created in consensus by three authors to encompass all adult glioma types. Diagnostic features used were T2-FLAIR mismatch sign, central necrosis with peripheral enhancement, diffusion restriction, and continuous cortex sign. Roman numerals (I, II, and III) denote IBGS types. Two independent teams of three and two radiologists, blinded to genetic, histology, and survival information, manually read MRI into three types based on the flowchart. Overall survival-analysis was done using age-adjusted Cox-regression analysis, which provided both hazard-ratio (HR) and area-under-curve (AUC) for each stratification system(IBGS and 2021-WHO). The sensitivity and specificity of each IBSG type were analyzed with cross-table to identify the corresponding 2021-WHO genotype. Imaging-based stratification was statistically significant in predicting survival in both datasets with good inter-observer agreement (age-adjusted Cox-regression, AUC > 0.5, k > 0.6, p < 0.001). IBGS type-I, type-II, and type-III gliomas had good specificity in identifying IDHmut 1p19q-codel oligodendroglioma (training - 97%, validation - 85%); IDHmut 1p19q non-codel astrocytoma (training - 80%, validation - 85.9%); and IDHwt glioblastoma (training - 76.5%, validation- 87.3%) respectively (p-value < 0.01). Imaging-based stratification of adult diffuse gliomas predicted patient survival and correlated well with 2021-WHO glioma classification.

Cost-effectiveness of DNA testing for Lynch syndrome for colorectal cancer patients in Switzerland

Abstract Purpose To estimate the cost-effectiveness of genetic testing for Lynch syndrome among newly diagnosed patients with colorectal cancer and targeted testing for their relatives in Switzerland. Methods We integrated decision tree and Markov model to calculate incremental costs per quality adjusted life-year saved for universal genetic testing for Lynch syndrome relative to using preliminary tumor tests (immunohistochemistry or microsatellite instability) followed by DNA sequencing test for patients with colorectal cancer. Results The incremental cost-effectiveness ratio (ICER) of the proposed strategy using universal genetic testing for Lynch syndrome with systematic CASCADE testing of their relatives is CHF 65,058 per QALY saved, which is cost-effective in Swiss settings where cost-effectiveness threshold is CHF 100,000 per QALY saved. The gained utility is 361,358 QALYs saved. Sensitivity analysis demonstrated cost-effectiveness of the proposed strategies in most of the scenarios. Conclusions The overall effectiveness of the universal genetic testing is greatly dependent on willingness of patients and relatives to be tested and compliance with the increased surveillance. Therefore, close cooperation across different stakeholders such as family doctors, oncologists, genetic clinicians, and laboratories is crucial to encourage and educate patients about the importance of the LS screening. Key messages Universal genetic testing for Lynch syndrome for all patients with colorectal caner is cost-effective in Swiss settings. Close cooperation across all stakeholders such as family doctors, oncologists, genetic clinicians, and laboratories is crucial to encourage and educate patients about the importance of the LS testing.

Time to Think Differently About Sarcomere-Negative Hypertrophic Cardiomyopathy.

Time to Think Differently About Sarcomere-Negative Hypertrophic Cardiomyopathy.

Association of NOS3 Genetic Polymorphism With the Predisposition to Diabetes and Pre-Diabetes, Retrospective Study

Background: Endothelial nitric oxide synthetase (eNOS) encoded by NOS3 gene has an important role in modulating vascular endothelial function. Many studies reported a possible role of NOS3 in the pathogenesis of diabetes mellitus (DM). This study investigated the association of NOS3 (G>T) rs1799983 genetic polymorphism with DM, pre-diabetes (pre-DM), and insulin resistance (IR). Methods: A random sample of 220 subjects (DM & pre-DM) compared with 220 healthy subjects. Sample obtained from Palestinian adults who consented to genetic and biochemical testing. All subjects genotyped for NOS3 (G > T) rs1799983 SNP using ARMS PCR. Fasting blood sugar (FBS) and triglyceride (TGA) levels were obtained for all subjects. Triglyceride glucose index (TyG) was used as a surrogate marker for IR. Regression analysis adjusted for age and body mass index (BMI) was performed to investigate the association between DM & Pre-DM status, FBS, and TyG with NOS3 genetic polymorphism. Results: NOS3 minor allele frequency positively correlated with FBS levels after controlling for age and BMI (P-value 0.006). DM & pre-DM were more frequent in homozygous NOS3 subjects with an odds ratio of 2.04 (P = 0.05). NOS3 minor allele frequency positively correlated with TyG but not statistically significant association (P = 0.061). Discussion: Many studies reported a potential role of NOS3 genetic polymorphism in DM and IR pathogenesis. In this study, NOS3 minor allele frequency positivity correlated with FBS levels. Homozygous NOS3 was associated with a 2-fold increase in the prevalence of DM & pre-DM. NOS3 genetic polymorphism didn’t show a statistically significant correlation with TyG (P = 0.061). With the increasing availability of genetic testing, NOS3 may serve as an early screening tool to identify subjects with a high risk for elevated FBS. Further studies are required to understand the exact role of NOS3 genetic polymorphism in the pathogenesis of DM, and to evaluate the clinical efficacy and cost-effectiveness of genetic testing. Conclusion: NOS3 genetic polymorphism has a statistically significant relationship with the FBS level. Further studies are required to confirm the association between NOS3 and DM.

Cost Effectiveness of Genotype-Guided Antiplatelet Therapy in Asian Ischemic Stroke Patients: Ticagrelor as an Alternative to Clopidogrel in Patients with CYP2C19 Loss of Function Mutations

Patients with ischemic stroke are often treated with clopidogrel monotherapy as part of secondary stroke prevention. The prevalence of loss of function (LOF) mutations in the CYP2C19 gene is higher in Asians than in Western populations. Patients with loss of function (LOF) mutations are at risk for poorer secondary outcomes when prescribed clopidogrel. We aimed to determine the cost effectiveness of genotype-guided antiplatelet therapy in an Asian population with the aim of prescribing ticagrelor as an alternative to patients with LOF mutations. Markov models were developed to look at the cost effectiveness of genetic testing of CYP2C19, with patients who screened positive for LOF alleles being switched to ticagrelor compared to universal clopidogrel treatment. Effect ratios were obtained from the literature and incidence rates and costs were obtained from the national data published by the Singapore Ministry of Health. Lifetime costs and quality-adjusted life-years (QALYs) were calculated. The primary endpoints were the incremental cost-effectiveness ratios (ICERs). The prevalence of the LOF mutations was 61% in the population, with 65% of ethnic Chinese, 60% of ethnic Indian, and 53% of ethnic Malay patients having LOF mutations. Based on this prevalence, the overall ICER of genetic testing was S$33,839/QALY with ICERS of S$30,755/QALY, S$33,177/QALY, and S$41,470/QALY for Chinese, Indians, and Malays, respectively. This study suggests that it is cost effective to screen for LOF mutations in the CYP2C19 gene in ischemic stroke populations, with ticagrelor as a substitute for clopidogrel in those with LOF mutations.

1661-P: NHG-KTPH Monogenic Diabetes Registry: Understanding Monogenic Diabetes in a Multiethnic Asian Population in Singapore

Introduction: Monogenic diabetes (also known as maturity-onset diabetes of the young or MODY) is a rare genetic disorder with an undetermined prevalence in Singapore. The NHG-KTPH Monogenic Diabetes Registry was set up in mid-2017 to capture longitudinal data of individuals genetically diagnosed with monogenic diabetes to study their prevalence and disease trajectories. Methods: Patients with clinical phenotype suggestive of monogenic diabetes i.e., diabetes onset =&amp;lt;45 years old, BMI &amp;lt;32.5 kg/m2 and GAD autoantibody-negative were recruited and subjected to genetic testing comprising of next-generation 16-MODY gene panel sequencing, mt.3242A&amp;gt;G TaqMan genotyping and multiplex ligation-dependent probe amplification (MLPA) for 4 common MODY genes. Genetic variants annotated as likely pathogenic/pathogenic according to ACMG guidelines were validated using Sanger sequencing. Individuals with such variant(s) were included in the Registry. EQ-5D-5L instrument was also administered for quality of life assessment. Results: Among 171 patients who were subjected to MODY genetic testing, 26 (15%) were found to harbor likely pathogenic/pathogenic variants. 93% of these variants were found in common MODY genes (HNF1A, HNF4A, GCK, HNF1B, MT-TL1) that had important clinical implications. Biomarkers such as C-peptide, hs-CRP and HDL were significantly different in those with likely pathogenic/pathogenic variants than those without. Discussion: Monogenic diabetes is present in 15% of our study participants with young-onset diabetes, which is greater than the reported 5% in UK. Clinical demographics and biomarkers can be further evaluated to improve the pick-up rate of monogenic diabetes among young-onset diabetes, with specific calibration applied to different subtypes of monogenic diabetes. This will improve cost-effectiveness of genetic testing and facilitate implementation of precision medicine for individuals with monogenic diabetes. Disclosure S. Ang: None. C. Tan: None. Y. Kon: None. L. Xia: None. S. Lim: None.

A scalable, aggregated genotypic-phenotypic database for human disease variation.

Next generation sequencing multi-gene panels have greatly improved the diagnostic yield and cost effectiveness of genetic testing and are rapidly being integrated into the clinic for hereditary cancer risk. With this technology comes a dramatic increase in the volume, type and complexity of data. This invaluable data though is too often buried or inaccessible to researchers, especially to those without strong analytical or programming skills. To effectively share comprehensive, integrated genotypic–phenotypic data, we built Color Data, a publicly available, cloud-based database that supports broad access and data literacy. The database is composed of 50 000 individuals who were sequenced for 30 genes associated with hereditary cancer risk and provides useful information on allele frequency and variant classification, as well as associated phenotypic information such as demographics and personal and family history. Our user-friendly interface allows researchers to easily execute their own queries with filtering, and the results of queries can be shared and/or downloaded. The rapid and broad dissemination of these research results will help increase the value of, and reduce the waste in, scientific resources and data. Furthermore, the database is able to quickly scale and support integration of additional genes and human hereditary conditions. We hope that this database will help researchers and scientists explore genotype–phenotype correlations in hereditary cancer, identify novel variants for functional analysis and enable data-driven drug discovery and development.

Abstract P4-12-02: Cost-effectiveness of genetic testing with a hereditary cancer panel in women at risk of hereditary breast cancer

Abstract Background: The role of the BRCA1/2 genes in breast cancer risk has been well characterized. However, pathogenic variants in additional genes also confer hereditary breast cancer risk and if detected can lead to interventions that can facilitate increased life expectancy. For example, the National Comprehensive Cancer Network (NCCN) guidelines (Version 2.2017) recommend MRI screening for women who carry a pathogenic variant in CHEK2 and MRI screening or risk-reducing mastectomy for women who carry a pathogenic variant in PALB2. Testing women at risk of hereditary breast cancer with a 7-gene panel was recently reported to be more cost-effective than testing only BRCA1/2 genes (Li et al. Value Health, 2017). Objectives: To evaluate the cost-effectiveness of a multigene panel testing strategy including 11 genes with risk reduction recommendations by the NCCN guidelines compared with testing only BRCA1/2 genes. Methods: Using a Markov model modified from the recent Li et al. publication, the 11-gene model was used to estimate life expectancies and total healthcare costs from a payers' perspective. The model included costs for genetic testing, genetic consultation, and cancer treatment as well as risk reduction strategies recommended by the guidelines: prophylactic surgery, MRI surveillance, and mammography. Probabilistic sensitivity analyses were carried out to determine the robustness of the modeling. Results: In the base case, the incremental cost-effectiveness ratio (ICER) for the 11-gene multigene testing strategy compared with BRCA1/2 testing was $22,377 per life-year gained ($47,240 per quality-adjusted life-year gained) for a 40-year-old cohort and $36,690 per life-year gained ($63,384 per quality-adjusted life-year gained) for a 50-year-old cohort. The sensitivity analysis indicated that the multigene testing strategy had a 97% chance of costing less than $100,000 per quality-adjusted life-year gained for the 40-year-old cohort. Conclusion: In patients at risk of hereditary breast cancer, testing using a multigene panel followed by risk reducing interventions is cost-effective compared with testing only BRCA1/2 genes. Citation Format: Li Y, Arellano AR, Bare LA, Devlin JJ. Cost-effectiveness of genetic testing with a hereditary cancer panel in women at risk of hereditary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-12-02.

Cost effectiveness of genetic testing in CRC uncertain

Cost effectiveness of genetic testing in CRC uncertain

Cost-Effectiveness of Genetic Testing for Allopurinol Sensitivity in Gout Patients

The urate-lowering therapy allopurinol is associated with rare but potentially fatal cutaneous reactions — Stevens-Johnson syndrome (SJS) and toxic

Genomics of platelet disorders.

Genetic diagnosis in families with inherited platelet disorders (IPD) is not performed widely because of the genetic heterogeneity of this group of disorders and because in most cases, it is not possible to select single candidate genes for analysis using clinical and laboratory phenotypes. Next-generation sequencing (NGS) technology has revolutionized the scale and cost-effectiveness of genetic testing, and has emerged as a valuable tool for IPD. This review examines the potential utility of NGS as a diagnostic tool to streamline detection of causal variants in known IPD genes and as a vehicle for new gene discovery.

Atypical hemolytic uremic syndrome: a clinical conundrum.

Patients negative for Shiga toxin-producing E. coli (STEC) are categorized as having atypical hemolytic uremic syndrome (HUS) and are associated with an increased risk for complement mutations and poorer prognosis compared with typical HUS. However, STEC identification is limited by the natural history of HUS. The current study is aimed at identifying HUS patients with poor outcomes based on the presence or absence of diarrhea (D) or Shiga toxin (S). A single-center retrospective review (2003-2012) of 42 HUS patients (follow-up 31.3 ± 38.7months) was carried out. HUS was managed clinically with supportive treatments such as dialysis, plasma therapy, and eculizumab. There was no significant difference in the D+S+ (31%), D+S- (50%) and D-S- (19%) groups in the outcome variables of chronic kidney disease stages I-II (100% vs 81% vs 67%) and proteinuria at follow-up (20% vs 12.5% vs 33.3%), hospitalization duration (16.0 ± 8.7 vs 18.1 ± 9.5 vs 23.7 ± 12.9days); dialysis requirement (50% vs 81% vs 66.7%), and dialysis duration (10.2 ± 1.9 vs 33.3 ± 72.8 vs 10.3 ± 8.1days). There was no significant difference in study outcomes in STEC+ (59%) versus STEC- (41%) groups. Genetic testing was performed in 12% of HUS patients based on age, recurrent HUS, familial HUS, persistently low C3, or prolonged dialysis, and 80% of the patients tested were positive for genetic mutations. Our study does not show poorer outcomes in STEC- HUS. Indications and the cost-effectiveness of genetic testing, eculizumab, and plasmapheresis in STEC- HUS need to be evaluated further.

The Cost Effectiveness of Genetic Testing for CYP2C19 Variants to Guide Thienopyridine Treatment in Patients with Acute Coronary Syndromes

A recent clinical trial has demonstrated that patients with acute coronary syndromes (ACS) and the reduced function allele CYP2C19*2 (*2 allele), who are treated with thienopyridines, have an increased risk of adverse cardiac events with clopidogrel, but not with prasugrel. The frequency of the *2 allele varies by ethnicity and the Maoris, Asians and Pacific Islanders of New Zealand have a relatively high incidence. Our objective was to evaluate, from a New Zealand health system perspective, the cost effectiveness of treating all ACS patients with generic clopidogrel compared with prasugrel, and also compared with the genetically guided strategy that *2 allele carriers receive prasugrel and non-carriers receive clopidogrel. A decision-tree model consisting of five health states (myocardial infarction, stroke, bleeding, stent thrombosis and cardiovascular death) was developed. Clinical outcome data (two TRITON-TIMI 38 genetic sub-studies) comparing clopidogrel and prasugrel for both *2 allele carriers and non-carriers were combined with the prevalence of the heterozygosity for the *2 allele in New Zealand Europeans (15%), Maoris (24%), Asians (29%) and Pacific Islanders (45%) to determine the predicted adverse event rate for the New Zealand population. National hospital diagnosis-related group (DRG) discharge codes were used to determine alternative adverse event rates, along with the costs of hospitalizations during the 15 months after patients presented with an ACS. The primary outcome measure was the incremental cost per QALY (calculated using literature-reported weights). Monte Carlo simulations and alternative scenario analysis based on both clinical trial and national hospital incidence were used. Additional analysis considered the overall TRITON-TIMI 38 rates. Costs (in New Zealand dollars [$NZ], year 2009 values) and benefits were discounted at 3% per annum. Actual hospital-based adverse event rates were higher than those reported in the TRITON-TIMI 38 randomized controlled trial and the genetic sub-studies, especially for myocardial infarction and cardiovascular death, and for Maoris and Pacific Islanders. For both sources of adverse event rates, treating the population with prasugrel was associated with worse outcomes (QALYs) than clopidogrel. However, prasugrel became cost effective ($NZ31 751/QALY) when the overall TRITON-TIMI 38 rates were used. A genetic test to guide the selected use of prasugrel was cost effective ($NZ8702/QALY versus $NZ24 617/QALY) for hospital and clinical trial incidence, respectively. Based on the hospital rates, the genetically guided strategy was especially cost effective for Maoris ($NZ7312/QALY) and Pacific Islanders ($NZ7041/QALY). These results were robust to the sensitivity analysis, except the genetically guided strategy under the 15-month clinical trial event rate scenario ($NZ168 748/QALY) did not remain cost effective under a $NZ50 000 threshold. Use of a genetic test to guide thienopyridine treatment in patients with ACS is a potentially cost-effective treatment strategy, especially for Maoris and Pacific Islanders. This treatment strategy also has the potential to reduce ethnic health disparities that exist in New Zealand. However, the results comparing clopidogrel and prasugrel are sensitive to whether the genetic sub-studies or the overall TRITON-TIMI 38 rates are used. While the national hospital event rates may be more appropriate for the New Zealand population, many assumptions are required when they are used to adjust the genetic sub-studies rates.

Abstract ES3-1: Evaluation of Breast Cancer Predisposition in Different Clinical Venues

Abstract DNA sequence-based cancer susceptibility testing of the BRCA1/2 genes is now one of the most commonly ordered genetic tests in the United States. Increasingly sophisticated computer models help to inform the clinician as to the probability of identify a cancer-associated mutation based on both the nature of the tumor, e.g. estrogen receptor status, the age of onset of cancer, presence of ovarian cancer and the family history of the patient. However, even in clearly high-risk families there are additional levels of complexity which impact the cost of the testing, test choice and the usefulness of the results. Whenever possible it is preferable to initiate testing with an individual with cancer first, in order to clarify whether a BRCA1/2 mutation is responsible for the cancer susceptibility. Results of comprehensive sequence analysis can include either negative, deleterious mutation or variant of uncertain significance (VUS). Currently, the potential cancer risk associated with a VUS result is very broad which leads to confusion among providers and patients. Recommendations for further classifying these VUS results into risk stratified categories to aid clinical decision making have been proposed and efforts to implement these recommendations are being initiated by international groups. A key reason to pursue genetic testing is to identify which healthy relatives are at increased of cancer. Thus, to maximize the cost effectiveness of genetic testing, research on how testing is being performed on these downstream relatives is needed. In particular, the most efficient and least expensive testing requires that physicians caring for the relatives have available the detailed test results of the cancer patient. If the cancer patient carries a VUS, then testing of the healthy relative is typically not indicated. If the cancer patient carries a deleterious mutation, then testing of the relative should be for that specific mutation known as single site testing (or familial mutation testing). Our group queried physicians across five different medical specialties (family medicine, internal medicine, obstetrics/gynecology, general surgery and hematology/oncology) for test recommendations of at-risk relatives. The majority of physicians recommended full BRCA1/2 sequencing of a healthy at-risk relative whether provided information that the relative with cancer carried a deleterious mutation or VUS. These findings were not impacted by the physician's own experience with BRCA1/2 testing and potentially result in tenfold higher testing costs compared with national recommendations. Thus, utilization of genetic professionals and improved education of diverse physician specialties about family-centered genetic test decision making may improve efficacy of risk prediction and substantially reduce costs associated with genetic testing for cancer susceptibility. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES3-1.

Cost-effectiveness of genetic testing for BRCA1 and BRCA2 mutations.

Abstract Abstract #6100 Purpose&amp;#x2028; Women who carry a BRCA1 or BRCA2 genetic mutation are at significantly increased risk of breast and ovarian cancer. Current guidelines recommend genetic testing of women who have a greater than 10% likelihood of carrying a mutation. We sought to evaluate the cost-effectiveness of this suggested guideline by simulating genetic testing in cohorts of women at various risk for the BRCA1 and BRCA2 genetic mutations.&amp;#x2028; Methods&amp;#x2028; A Markov model was developed to compare the effectiveness and cost-effectiveness of genetic testing in cohorts of 30-year old women without a prior breast or ovarian cancer diagnosis at varying likelihoods of carrying a genetic mutation. Women who test positive for a mutation were assumed to select surgical prevention (mastectomy, oophorectomy, or both mastectomy and oophorectomy) at previously observed rates in carrier populations. Costs were estimated using Medicare reimbursement rates and secondary sources. Transition rates and other model variables were estimated from the literature. Effectiveness was measured in life-years gained and quality-adjusted life-years (QALYs) gained.&amp;#x2028; Results&amp;#x2028; In a high-risk cohort of women aged 30 of whom 10% are expected to carry a BRCA mutation, genetic testing has an incremental cost-effectiveness ratio (ICER) of less than $50,000 per life-year gained and of less than $50,000 per QALY gained in most scenarios. The proportion of women carrying a genetic mutation did not significantly affect this result. However, among women who are not eligible for intensive surveillance (mammography, transvaginal ultrasound, annual CA-125 blood test) at age 30, the incremental cost per QALY gained increases to greater than $50,000. Very low rates of prophylactic surgery in mutation carriers can cause genetic testing to become prohibitively expensive. Genetic testing is also prohibitively expensive if testing identifies a large number of individuals with variant of unknown significance (VUS) or uninformative negative results, especially if those individuals have moderate or high rates of prophylactic intervention.&amp;#x2028; Conclusions&amp;#x2028; Current guidelines for genetic testing are cost effective under most scenarios considered; however, these results are dependent on a number of variables. Surprisingly, these results are less dependent on the proportion of mutation carriers in the testing cohort than the proportion of women who are found to have VUS or uninformative negative results and the rate of prophylactic intervention in that population, as the value of these interventions is lower in this group. Cost-savings generated by decreased surveillance in the population that tests negative greatly influences the cost effectiveness of genetic testing, a result that will be strengthened as MRI becomes more widespread in the high-risk population. These results suggest that genetic testing is cost-effective in any population that is at significant risk to warrant intensive surveillance. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6100.

Towards more effective and equitable genetic testing for BRCA1 and BRCA2 mutation carriers

Cochrane1 proposed that, because resources are always limited, they should be used to provide equitably those forms of health care that have been shown in properly designed evaluations to be...

Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics

Objectives:Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing...

A Prospective, Multicenter, Population-Based Study of BRAF Mutational Analysis for Lynch Syndrome Screening

Mismatch repair (MMR) deficiencies are the hallmark of tumors arising in Lynch syndrome, however, in approximately 15% of sporadic colorectal cancers (CRC) these deficiencies most often are associated with somatic methylation of the MMR gene MLH1. Recently, an oncogenic mutation in the BRAF gene has been involved in sporadic CRC showing MMR deficiencies as a result of MLH1 promoter methylation. The aim of this study was to evaluate the contribution of BRAF V600E mutation analysis in the identification of MSH2/MLH1 gene mutation carriers in newly diagnosed CRC patients. BRAF V600E mutation was analyzed in CRC patients with MMR deficiencies (microsatellite instability and/or lack of MLH1/MSH2 protein expression) in the EPICOLON population-based study. The effectiveness and efficiency of different strategies were evaluated with respect to the presence of MSH2/MLH1 germline mutations. MMR deficiencies were detected in 119 of the 1222 CRC patients with tumors showing either microsatellite instability (n = 111) or loss of protein expression (n = 81). BRAF mutation was detected in 22 (18.5%) of the patients. None of the patients with unambiguous germline mutation had BRAF mutation. Regardless of the strategy used to identify MSH2/MLH1 gene carriers, the introduction of BRAF analysis in these patients slightly improves their effectiveness. The introduction of BRAF mutation analysis as a step before germline genetic testing in patients with MMR deficiencies achieved a significant reduction in costs per mutation detected. Detection of BRAF V600E mutation could simplify and improve the cost effectiveness of genetic testing for hereditary nonpolyposis colorectal cancer, especially in patients whose family history is incomplete or unknown.

Economic Evaluation of the Familial Cancer Programme in Western Australia: Predictive Genetic Testing for Familial Adenomatous Polyposis and Hereditary Non-Polyposis Colorectal Carcinoma

Aim: To evaluate costs and outcomes of genetic testing for familial colorectal cancer through services provided by Genetic Services of Western Australia (GSWA). Methods: Costs and outcomes of predictive DNA-based testing for inherited colorectal cancers (CRC) were assessed, specifically for familial adenomatous polyposis (FAP) and hereditary non-polyposis CRC (HNPCC) using a decision-analysis model. Costs were assigned according to standards of care in Western Australia (WA). Cancer risks and the efficacy of surveillance on long-term outcomes were derived from the published literature. Results: The cost-effectiveness of genetic testing was compared in first-degree relatives of known mutation carriers who have a 50% risk of carrying the mutated gene (intervention group) to individuals with the same risk but who do not undergo a genetic test (control subjects). Compared with control subjects undergoing the same high-level surveillance and surgery, the FAP and HNPCC intervention groups provided total savings of $ 13,390 and 14,783–15,460 per person (males-females), respectively. HPNCC mutation carriers also gained 1 CRC-free year. Compared to control subjects having only population surveillance, individuals in the FAP intervention group delayed the onset of CRC by 40 years for a net cost of $ 9,042. Individuals in the HNPCC intervention group delayed the onset of CRC by 8 years at a net cost of $ 12,141 for males and $ 12,596 for females. Conclusions: Genetic testing for familial CRC in WA allows targeted surveillance for mutation carriers, which ensures the efficient use of resources and reduces cancer-related morbidity, if clinical recommendations for intervention are adopted.

Genetics and Preventive Medicine: A Time for Inquiry

ANYONE WHO HAS BROWSED THE HUMAN GENOME SEQUENCE CAN READILY appreciate its immense power and potential as well as its staggering complexity, and imperfection. Nevertheless, following its release, British Prime Minister Tony Blair declared, “Today we are witnessing a revolution in medical science whose impact can far surpass the discovery of antibiotics.” And just 5 days prior, fears about the creation of a “genetic ghetto” swirled around London when one of Britain’s largest private life insurers to revealed that it had illegally used data from experimental genetic tests to evalute some insurance applications. Could genetic research rival the clinical utility of antibiotics or spawn a genetic underclass? We do not yet know. Only gradually, through painstaking research, will the true social and medical impact of genetic science be clarified. This issue of MSJAMA explores how researchers, policy makers, and clinicians are defining a role for genetics in preventive medicine. One essential component will be determining the risk conferred by particular genotypes. Complicating this process is the fact that many diseases may have multiple genetic etiologies or may arise from complex interactions between several genetic variants and environmental factors. Karen Steinberg, Marta Gwinn, and Muin Khoury discuss the role of the Centers for Disease Control in dissecting the genetic etiologies of common diseases. Wendy Rubinstein and Reynold LopezSoler explore the heterogeneous genetic causes of sudden cardiac death. However, even the most comprehensive genetic databases cannot be useful without the means to integrate that information into clinical practice. Sue Goldie and April Levine discuss analytic methods used to evaluate the clinical utility and cost effectiveness of genetic testing. John Phillips presents important clinical tools that can facilitate the application of genetic information to patient care. In examining the human genome project Freeman Dyson noted, “Technology only gives us tools. Human desires and institutions decide how we use them.” The use of poorly studied genetic tests to inflate insurance premiums, or fears that genetic research will result in genetic discrimination, constitute harmful reactions to incomplete data. Moreover, given the potential social and economic importance of genetic research, premature reactions to it will not be easily averted in the near future. In realizing the benefits of genetic testing in disease prevention, physicians and policy makers must establish mechanisms to evaluate and respond to the implications of new genetic information as soon as it becomes available. They can thereby protect the public, not only from disease, but also from alarmists and profiteers.