Amie Blanco

Strategies to Identify the Lynch Syndrome Among Patients With Colorectal Cancer: A Cost-Effectiveness Analysis

BACKGROUND Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine. OBJECTIVE To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives. DESIGN Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers. DATA SOURCES Published literature. TARGET POPULATION All persons with newly diagnosed colorectal cancer and their relatives. TIME HORIZON Lifetime. PERSPECTIVE Third-party payer. INTERVENTION Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery. OUTCOME MEASURES Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of

Lynch Syndrome Patients’ Views of and Preferences for Return of Results Following Whole Exome Sequencing

36,200 per life-year gained. RESULTS OF SENSITIVITY ANALYSIS The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of

Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome.

50,000 per life-year gained. Immunohistochemistry followed by BRAF mutation testing was preferred in 59% of iterations in probabilistic sensitivity analysis at a threshold of

Psychological functioning in persons considering genetic counseling and testing for Li-Fraumeni syndrome

100,000 per life-year gained. Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost

Performance of Lynch Syndrome Predictive Models in a Multi-Center US Referral Population

44,000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost

Evaluation of a decision aid for families considering p53 genetic counseling and testing.

88,700 per incremental life-year gained compared with screening only up to age 70 years. LIMITATION Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered. CONCLUSION Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome. PRIMARY FUNDING SOURCE National Institutes of Health.

Impact of genetic testing on endometrial cancer risk-reducing practices in women at risk for Lynch syndrome.

Whole exome sequencing (WES) uses next generation sequencing technology to provide information on nearly all functional, protein-coding regions in an individual’s genome. Due to the vast amount of information and incidental findings that can be generated from this technology, patient preferences must be investigated to help clinicians consent and return results to patients. Patients (n = 19) who were previously clinically diagnosed with Lynch syndrome, but received uninformative negative Lynch syndrome genetic results through traditional molecular testing methods participated in semi-structured interviews after WES testing but before return of results to explore their views of WES and preferences for return of results. Analyses of interview results found that nearly all participants believed that the benefits of receiving all possible results generated from WES outweighed the undesirable effects. The majority of participants conveyed that relative to coping with a cancer diagnosis, information generated from WES would be manageable. Importantly, participants’ experience with Lynch syndrome influenced their notions of genetic determinism, tolerance for uncertain results, and family communication plans. Participants would prefer to receive WES results in person from a genetic counselor or medical geneticist so that an expert could help explain the meaning and implications of the potentially large quantity and range of complicated results. These results underscore the need to study various populations with regard to the clinical use of WES in order to effectively and empathetically communicate the possible implications of this new technology and return results.

Preferences for outcomes associated with decisions to undergo or forgo genetic testing for Lynch syndrome

Although there is consensus on the cost-effectiveness of a universal approach of screening all colorectal cancer patients for Lynch syndrome (LS) using mismatch-repair (MMR) protein immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing, the question of universal versus selective screening of endometrial cancer patients remains to be resolved. We have prospectively implemented a selective screening algorithm for newly diagnosed endometrial cancer patients, triggered by patient age 50 years or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, and/or presence of MMR-associated tumor morphology. Four-protein MMR IHC and MSI testing were performed if any of the criteria were met. This algorithm excluded screening of older patients without a cancer pedigree and whose tumors lacked MMR morphology. The aim of this study was to retrospectively determine whether these exclusion criteria missed any tumors with abnormal MMR. Among 273 consecutive patients with newly diagnosed endometrial cancers, 181 (66%) lacked criteria for screening. Retrospective MMR IHC confirmed intact MMR in 177 (97.8%) of these 181 unscreened patients, loss of MSH6 in 1 patient (0.5%), and loss of MSH1/PMS2 due to MLH1 promoter hypermethylation in 3 patients (1.7%). In comparison, 41% of patients fulfilling 1 or more criteria for screening had abnormal MMR IHC/MSI, mostly consisting of loss of MLH1/PMS2. MMR morphology contributed to detection of 92% of the abnormal MMR cases while cancer pedigree contributed to detection of the remainder. All of the abnormalities due to MSH2 and PMS2 were detected by the screening algorithm, but 1 of the 4 MSH6 cases was not. The latter finding is consistent with the literature that MSH6 endometrial cancers exhibit a phenotype different than those of the other MMR genes. We conclude that a genotype-specific approach to screening endometrial cancer for LS could consist of universal testing by MSH6 IHC and selective testing by MLH1, PMS2, and MSH2 IHC on the basis of age, cancer pedigree, and MMR morphology. Cost-effectiveness of this hybrid selective strategy deserves further study, particularly in comparison with a universal strategy. Further work to identify phenotypic features of endometrial cancers with methylated MLH1 that would allow them to be excluded from LS screening would also contribute to cost-effectiveness.

Lynch Syndrome Limbo: Patient Understanding of Variants of Uncertain Significance

Objective: Li–Fraumeni syndrome (LFS) confers an increased risk of multiple types of cancer in both children and adults. Clinical genetic testing for deleterious germline p53 gene mutations can identify most LFS‐affected families. We evaluated factors associated with cancer‐specific distress and perceived self‐efficacy in coping with a positive genetic test result among persons at risk of having deleterious p53 mutations.

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017

OBJECTIVES:Lynch syndrome is the most common cause of inherited colorectal cancer (CRC) and is due to germline mutations in mismatch repair (MMR) genes. Early Lynch syndrome diagnosis and appropriate CRC surveillance improves mortality. Traditional qualitative clinical criteria including Amsterdam and Bethesda guidelines may miss mutation carriers. Recently, quantitative predictive models including MMRPredict, PREMM(1,2,6), and MMRPro were developed to facilitate diagnosis. However, these models remain to be externally validated in the United States. Therefore, we evaluated the test characteristics of Lynch syndrome predictive models in a tertiary referral group at two US academic centers.METHODS:We retrospectively collected data on 230 consecutive individuals who underwent genetic testing for MMR gene mutations at the University of Chicago and University of California at San Franciscos Cancer Risk Clinics. Each individuals risk of mutation was examined using MMRPredict, PREMM(1,2,6), and MMRPro. Amsterdam and Bethesda criteria were also determined. Testing characteristics were calculated for each of the models.RESULTS:We included 230 individuals in the combined cohort. In all, 113 (49%) probands were MMR mutation carriers. Areas under the receiver operator characteristic curves were 0.76, 0.78, and 0.82 for MMRPredict, PREMM(1,2,6), and MMRPro, respectively. While similar in overall performance, our study highlights unique test characteristics of these three quantitative models including comparisons of sensitivity and specificity. Moreover, we identify characteristics of mutation carriers who were missed by each model.CONCLUSIONS:Overall, all three Lynch syndrome predictive models performed comparably in our multi-center US referral population. These results suggest that Lynch syndrome predictive models can be used to screen for MMR mutation carriers and can provide improved test characteristics compared with traditional clinical criteria. Identification of MMR mutation carriers is paramount as appropriate screening can prevent CRC mortality in this high-risk group.