PO.PR01.03 · 预防研究

Li-Fraumeni综合征纵向癌症筛查的效能

Performance of longitudinal cancer screening in Li-Fraumeni syndrome

编号 6342 展板 28 时间 4/21 02:00–05:00 区域 Section 36 主讲 Payal Khincha, MBBS;MHS

分会场 Genomics, Proteomics, Biomarkers, and Risk Stratification

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作者与单位 Authors & Affiliations

Payal P. Khincha¹, Sophia Ty², Siddharth Roy³, Jessica N. Hatton¹, Ashkan Malayeri⁴, Megan N. Frone¹, Margarita Aryavand¹, Phuong Mai⁵, Paul Albert³, Sharon A. Savage⁶

¹Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD,²Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX,³Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD,⁴Department of Radiology and Imagi, Fairfax radiology Centers, Fairfax, VA,⁵Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA,⁶NCI Div. of Cancer Epidemiology & Genetics, Rockville, MD

摘要 Abstract

中文摘要

Li-Fraumeni综合征（LFS）是一种由种系[可能]致病性（P/LP）TP53变异引起的癌症易感综合征，其自婴儿期起即赋予升高的多器官癌症风险和较高的多原发癌终生风险。异质性的癌症谱要求进行多模式的终生癌症筛查以促进早期检测。本研究纳入了145名（62%为女性）携带种系P/LP TP53变异的个体，他们参加了国家癌症研究所经IRB批准的LFS纵向研究（NCT01443468），并在NIH临床中心接受了癌症筛查，包括每年一次的全身MRI（WBMRI）、脑部MRI、乳腺MRI（>20岁女性）、乳腺X线摄影（>40岁女性）、血液检查、每三年一次的结肠镜检查（>25岁）以及每4个月一次的腹部超声（3-16岁）。首次筛查就诊时的中位年龄为34岁（范围3-68岁）。总共完成了772次年度筛查就诊（每位参与者中位5次，范围1-10次），进行了3956项筛查检测，依从率为92.8%。筛查检测导致了545次随访检测。WBMRI在29.1%的扫描中导致至少一次随访检测（n=225/772）。侵入性活检占所有随访的8.3%（n=45/545），其中48.9%（n=22/45）导致了癌症诊断。WBMRI导致了所有活检中的62%（n=28/45），其中42.8%（n=12/28）导致了癌症诊断。在研究期间诊断出的72例癌症/癌前病变中，75%（n=54）为筛查检出（32/54，即59%来自WBMRI）。18例（25%）间期癌在末次筛查检测后中位8个月（范围3-13个月）被诊断出。无症状癌的患病率在首次就诊时为7%，在后续就诊中在4%至11%之间变动。该筛查方案的灵敏度为71.7%，特异度为89%，假阳性率（FP）为11%，阴性预测值（NPV）为99.1%。使用带广义估计方程的逻辑回归分析了每项筛查检测对可筛查检出癌症的诊断特性。WBMRI的灵敏度为94%，特异度为94.8%（胸部癌症为91.6%，上肢为97.6%），FP为27%，NPV为99.9%。脑部MRI的灵敏度为85.7%，特异度为98%，FP为2%，NPV为99.9%。乳腺MRI的灵敏度为88.9%，特异度为83.6%，FP为16.3%，NPV为98.9%。种系TP53变异和年龄均未显著影响特异度。某解剖区域既往的癌症诊断会降低WBMRI在该区域的特异度（OR=0.12，95% CI 0.06-0.25，<0.001）。某解剖区域既往的假阳性发现会增加该区域出现额外假阳性发现的概率（p<0.001）。这项迄今为止规模最大的LFS纵向癌症筛查研究表明，多模式筛查表现良好，大多数报告的癌症为筛查检出。假阳性率较高，但低于此前的报道。尽管仍需对替代筛查策略和癌症预防进行进一步研究，但筛查对于LFS患者的早期癌症检测在临床上至关重要。

查看英文原文 English abstract

Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome caused by germline [likely] pathogenic (P/LP) TP53 variants, confers elevated multi-organ cancer risks from infancy and high lifetime risk of multiple primary cancers. The heterogeneous cancer spectrum necessitates multi-modal lifelong cancer screening to facilitate early detection. The study included 145 individuals (62% female) with a germline P/LP TP53 variant who enrolled in the National Cancer Institute's IRB-approved longitudinal LFS study (NCT01443468) and received cancer screening at the NIH Clinical Center including annual whole-body MRI (WBMRI), brain MRI, breast MRI (females>20 years), mammography (females>40 years), bloodwork, triennial colonoscopy (>25 years), and abdominal ultrasound every 4 months (age 3-16 years). Median age was 34 years (range 3-68) at the first screening visit. In all, 772 annual screening visits were completed (median 5 visits per participant, range 1-10) and 3956 screening tests performed at a compliance of 92.8%. Screening tests led to 545 follow-up tests. WBMRI led to at least one follow-up test in 29.1% scans (n=225/772). Invasive biopsies comprised 8.3% (n=45/545) of all follow-ups, 48.9% (n=22/45) of which resulted in a cancer diagnosis. WBMRI led to 62% (n=28/45) of all biopsies, of which 42.8% (n=12/28) resulted in a cancer diagnosis. Of the 72 cancers/pre-cancers diagnosed during the study, 75% (n=54) were screen-detected (32/54, 59% from WBMRI). The 18 (25%) interval cancers were diagnosed at a median of 8 months (range 3-13) after last screening test. Prevalence of asymptomatic cancer was 7% at first visit, varying between 4% and 11% at subsequent visits. The screening protocol had a sensitivity of 71.7%, specificity 89%, false positive rate (FP) 11%, negative predictive value (NPV) 99.1%. Diagnostic properties of each screening test for screen-detectable cancers were analyzed using logistic regression with generalized estimating equations. WBMRI sensitivity was 94%, specificity 94.8% (between 91.6% for thoracic cancers and 97.6% for upper extremity), FP 27%, NPV 99.9%. Brain MRI had sensitivity of 85.7%, specificity 98%, FP 2%, NPV 99.9%. Breast MRI had sensitivity of 88.9%, specificity 83.6%, FP 16.3%, NPV 98.9%. Neither germline TP53 variant nor age significantly affected specificity. A previous cancer diagnosis in an anatomical region reduced specificity of WBMRI (OR=0.12, 95% CI 0.06-0.25, <0.001). A previous false positive finding in an anatomic region increased the probability of additional false positive findings in that region (p<0.001). This largest longitudinal LFS cancer screening study to date shows that multi-modal screening performs well with most reported cancers being screen-detected. FP rate is high but lower than previously reported. While further research on alternative screening strategies and cancer prevention is needed, screening is clinically crucial to early cancer detection in LFS.

利益披露 Disclosure

P. P. Khincha, None.. S. Ty, None.. S. Roy, None.. J. N. Hatton, None.. A. Malayeri, None.. M. N. Frone, None.. M. Aryavand, None.. P. Mai, None.. P. Albert, None.

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