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

Purpose Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample. Methods Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at −80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants. Results In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes. Conclusion Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients.

Purpose Racial/ethnic disparities in cancer survival in the United States are well documented, but the underlying causes are not well understood. We quantified the contribution of tumor, treatment, hospital, sociodemographic, and neighborhood factors to racial/ethnic survival disparities in California. Materials and Methods California Cancer Registry data were used to estimate population-based cancer-specific survival for patients diagnosed with breast, prostate, colorectal, or lung cancer between 2000 and 2013 for each racial/ethnic group (non-Hispanic black, Hispanic, Asian American and Pacific Islander, and separately each for Chinese, Japanese, and Filipino) compared with non-Hispanic whites. The percentage contribution of factors to overall racial/ethnic survival disparities was estimated from a sequence of multivariable Cox proportional hazards models. Results In baseline models, black patients had the lowest survival for all cancer sites, and Asian American and Pacific Islander patients had the highest, compared with whites. Mediation analyses suggested that stage at diagnosis had the greatest influence on overall racial/ethnic survival disparities accounting for 24% of disparities in breast cancer, 24% in prostate cancer, and 16% to 30% in colorectal cancer. Neighborhood socioeconomic status was an important factor in all cancers, but only for black and Hispanic patients. The influence of marital status on racial/ethnic disparities was stronger in men than in women. Adjustment for all covariables explained approximately half of the overall survival disparities in breast, prostate, and colorectal cancer, but it explained only 15% to 40% of disparities in lung cancer. Conclusion Overall reductions in racial/ethnic survival disparities were driven largely by reductions for black compared with white patients. Stage at diagnosis had the largest effect on racial/ethnic survival disparities, but earlier detection would not entirely eliminate them. The influences of neighborhood socioeconomic status and marital status suggest that social determinants, support mechanisms, and access to health care are important contributing factors.

The incidence of colorectal cancer (CRC) is increasing worldwide. CRC has high mortality when detected at advanced stages, yet it is also highly preventable. Given the difficulties in implementing major lifestyle changes or widespread primary prevention strategies to decrease CRC risk, screening is the most powerful public health tool to reduce mortality. Screening methods are effective but have limitations. Furthermore, many screen-eligible persons remain unscreened. We discuss established and emerging screening methods, and potential strategies to address current limitations in CRC screening. A quantum step in CRC prevention might come with the development of new screening strategies, but great gains can be made by deploying the available CRC screening modalities in ways that optimize outcomes while making judicious use of resources.