LBPO.PR01 · 预防研究 · Late-Breaking
Li-Fraumeni 综合征中纵向癌症筛查的效能
Performance of longitudinal cancer screening in Li-Fraumeni syndrome
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
Li-Fraumeni 综合征（LFS）是一种由生殖系[可能]致病性（P/LP）TP53 变异引起的癌症易感综合征，自婴儿期起即赋予多器官癌症风险升高以及终生罹患多原发癌症的高风险。异质性的癌症谱要求进行多模态终生癌症筛查以促进早期检出。本研究纳入 145 例携带生殖系 P/LP TP53 变异的个体（62% 为女性），他们入组了美国国家癌症研究所经 IRB 批准的纵向 LFS 研究（NCT01443468），并在 NIH 临床中心接受癌症筛查，包括每年一次全身 MRI（WBMRI）、脑 MRI、乳腺 MRI（>20 岁女性）、乳腺钼靶（>40 岁女性）、血液检查、每三年一次结肠镜检查（>25 岁）以及每 4 个月一次腹部超声（3-16 岁）。首次筛查就诊时的中位年龄为 34 岁（范围 3-68）。共完成 772 次年度筛查就诊（每名参与者中位 5 次，范围 1-10），并实施了 3956 项筛查检测，依从率为 92.8%。筛查检测导致了 545 项后续检测。WBMRI 在 29.1% 的扫描中（n=225/772）导致了至少一项后续检测。侵入性活检占所有后续检测的 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。在研究期间诊断的 72 例癌症/癌前病变中，75%（n=54）为筛查检出（32/54，59% 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）被诊断。无症状癌症的患病率在首次就诊时为 7%，在后续就诊时在 4% 至 11% 之间变化。该筛查方案的敏感性为 71.7%，特异性为 89%，假阳性率（FP）为 11%，阴性预测值（NPV）为 99.1%。采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 敏感性为 94%，特异性为 94.8%（胸部癌症为 91.6% 至上肢为 97.6%），FP 为 27%，NPV 为 99.9%。脑 MRI 敏感性为 85.7%，特异性为 98%，FP 为 2%，NPV 为 99.9%。乳腺 MRI 敏感性为 88.9%，特异性为 83.6%，FP 为 16.3%，NPV 为 98.9%。生殖系 TP53 变异和年龄均未显著影响特异性。某一解剖区域既往的癌症诊断降低了 WBMRI 的特异性（OR=0.12，95% CI 0.06-0.25，<0.001）。某一解剖区域既往的假阳性发现增加了该区域出现额外假阳性发现的概率（p<0.001）。这项迄今为止最大规模的纵向 LFS 癌症筛查研究表明，多模态筛查表现良好，所报告的大多数癌症为筛查检出。FP 率虽高，但低于既往报道。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 LFS 患者的癌症早期检出具有关键的临床意义。
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..
S. A. Savage, None.