Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA.
Ann Intern Med. 2011 Jul 19;155(2):69-79. doi: 10.7326/0003-4819-155-2-201107190-00002.
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.
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.
Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers.
Published literature.
All persons with newly diagnosed colorectal cancer and their relatives.
Lifetime.
Third-party payer.
Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery.
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.
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.
Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered.
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.
National Institutes of Health.
人们提倡对所有新诊断出结直肠癌的患者进行检测，以确定是否存在林奇综合征（一种常染色体显性遗传的癌症易感综合征，是个性化医疗的范例）家族。
评估识别林奇综合征的策略的有效性和成本效益，同时关注性别、筛查时的年龄以及先证者和亲属的差异影响。
纳入结直肠、子宫内膜和卵巢癌风险的马尔可夫模型。
已发表的文献。
所有新诊断出结直肠癌的患者及其亲属。
终生。
第三方付款人。
基于临床标准、预测算法、肿瘤检测或预先进行种系突变检测，然后进行针对性筛查和降低风险的手术。
生命年、癌症病例和死亡、成本以及增量成本效益比。
所有策略的获益主要归因于携带与林奇综合征相关的突变的亲属，尤其是女性，她们通过接受子宫切除术和输卵管卵巢切除术并遵循结直肠癌筛查建议，预期寿命可延长约 4 年。在当前的种系检测、筛查和预防性手术率下，这些策略将结直肠癌相关死亡降低了 7%至 42%，并将子宫内膜癌和卵巢癌相关死亡降低了 1%至 6%。在肿瘤检测策略中，免疫组织化学检测后再进行 BRAF 突变检测是首选，增量成本效益比为每获得 1 个生命年增加 36200 美元。
每位先证者检测的亲属数量是影响有效性和成本效益的关键决定因素，大多数策略需要检测 3 到 4 名亲属，才能达到每获得 1 个生命年增加 5 万美元的阈值。在每获得 1 个生命年增加 10 万美元的阈值下，概率敏感性分析中有 59%的迭代情况首选免疫组织化学检测后再进行 BRAF 突变检测。与仅在 60 岁之前进行筛查相比，仅对年龄在 70 岁以下的患者进行免疫组织化学检测后再进行 BRAF 突变检测的筛查，每增加 1 个生命年的成本为 44000 美元；与仅在 70 岁之前进行筛查相比，不设年龄上限的筛查每增加 1 个生命年的成本为 88700 美元。
未考虑其他类型的癌症、不确定的家族谱系和具有未知意义的遗传变异。
广泛开展结直肠肿瘤检测以识别林奇综合征家族可能会以可接受的成本带来显著获益，尤其是对携带与林奇综合征相关的突变且开始定期筛查并接受降低风险手术的女性而言。这种检测的成本效益取决于林奇综合征高危亲属的参与率。
美国国立卫生研究院。
