Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study
Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study
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DOI：
10.1016/s1470-2045(16)30249-2
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发表时间：
2016-09-01
期刊：
影响因子：
51.1
通讯作者：
Malkin, David
中科院分区：
文献类型：
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作者：
Villani, Anita;Shore, Ari;Malkin, David
背景：生殖系TP53致病变异体的携带者有相当大的终生癌症风险。2011年，我们进行了一项前瞻性观察性研究，对象是那些选择接受全面的李-弗劳梅尼综合征患者监测方案或不接受监测方案的家庭成员。我们试图更新我们对监测方案的评估和修改，因此在这项研究中，我们报告了对这些患者和其他接受监测的患者的更长时间的随访，并更新了最初提出的监测方案。方法2004年1月1日，在加拿大和美国的三个三级护理中心引入了一项临床监测方案，使用体检和频繁的生化和影像检查(包括全身MRI、脑MRI、乳腺MRI、乳房X光摄影、腹部和盆腔超声以及结肠镜检查)，以检测TP53变异型携带者。在确认TP53突变后，参与者要么选择接受监测，要么选择不接受监测。患者可以在任何时候在不同的组之间交换。主要的结果衡量标准是通过监测调查发现无症状肿瘤。次要结果是根据症状诊断的肿瘤(非监测组)与监测诊断的肿瘤确定的5年总存活率。2004年1月1日至2015年7月1日，我们在39个无关家系中发现了89个TP53致病变异体携带者，其中40人(45%)同意监测，49人(55%)拒绝监测。19名(21%)患者从非监测组转到监测组，总共有59名(66%)患者接受了中位数32个月的监测(IQR12-87)。在接受监测的59名患者中，19名(32%)发现了40个无症状肿瘤。在监测评估(假阴性)之间又诊断出两种癌症，两种活检的病变在病理复查中是非肿瘤性实体(假阳性)。在最初拒绝监测的49人中，43名患者(88%)诊断出61例有症状的肿瘤。没有接受监测的43名患癌症的人中有21人(49%)存活，而接受监测的19名患癌症的人中有16人(84%)活着(p=0。未监测者的中位随访期为46个月(IQR 22-72)，监测者的随访期中位数为38个月(12-86)。5年总存活率为88。8%(95%可信区间78。7-100)，监测组59人。6%(47.2比75。2)在非监测组(p=0。我们的研究结果表明，对携带致病性TP53变异的个体进行早期肿瘤检测的全面监测方案的长期遵守是可行的，通过监测早期发现肿瘤与改善长期存活率相关。应该考虑将这种方法应用到这些患者的临床治疗中。
Background Carriers of a germline TP53 pathogenic variant have a substantial lifetime risk of developing cancer. In 2011, we did a prospective observational study of members of families who chose to either undergo a comprehensive surveillance protocol for individuals with Li-Fraumeni syndrome or not. We sought to update our assessment of and modify the surveillance protocol, so in this study we report both longer follow-up of these patients and additional patients who underwent surveillance, as well as update the originally presented surveillance protocol.Methods A clinical surveillance protocol using physical examination and frequent biochemical and imaging studies (consisting of whole-body MRI, brain MRI, breast MRI, mammography, abdominal and pelvic ultrasound, and colonoscopy) was introduced at three tertiary care centres in Canada and the USA on Jan 1, 2004, for carriers of TP53 pathogenic variants. After confirmation of TP53 mutation, participants either chose to undergo surveillance or chose not to undergo surveillance. Patients could cross over between groups at any time. The primary outcome measure was detection of asymptomatic tumours by surveillance investigations. The secondary outcome measure was 5 year overall survival established from a tumour diagnosed symptomatically (in the non-surveillance group) versus one diagnosed by surveillance. We completed survival analyses using an as-treated approach.Findings Between Jan 1, 2004, and July 1, 2015, we identified 89 carriers of TP53 pathogenic variants in 39 unrelated families, of whom 40 (45%) agreed to surveillance and 49 (55%) declined surveillance. 19 (21%) patients crossed over from the non-surveillance to the surveillance group, giving a total of 59 (66%) individuals undergoing surveillance for a median of 32 months (IQR 12-87). 40 asymptomatic tumours have been detected in 19 (32%) of 59 patients who underwent surveillance. Two additional cancers were diagnosed between surveillance assessments (false negatives) and two biopsied lesions were non-neoplastic entities on pathological review (false positives). Among the 49 individuals who initially declined surveillance, 61 symptomatic tumours were diagnosed in 43 (88%) patients. 21 (49%) of the 43 individuals not on surveillance who developed cancer were alive compared with 16 (84%) of the 19 individuals undergoing surveillance who developed cancer (p= 0 . 012) after a median follow-up of 46 months (IQR 22-72) for those not on surveillance and 38 months (12-86) for those on surveillance. 5 year overall survival was 88 . 8% (95% CI 78 . 7-100) in the surveillance group and 59 . 6% (47 . 2-75 . 2) in the non-surveillance group (p= 0 . 0132).Interpretation Our findings show that long-term compliance with a comprehensive surveillance protocol for early tumour detection in individuals with pathogenic TP53 variants is feasible and that early tumour detection through surveillance is associated with improved long-term survival. Incorporation of this approach into clinical management of these patients should be considered.