Abstract LB211: Performance of longitudinal cancer screening in Li-Fraumeni syndrome

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. Citation Format: Payal Prem Chand Khincha, Sophia Ty, Siddharth Roy, Jessica N. Hatton, Ashkan Malayeri, Megan N. Frone, Margarita Aryavand, Phuong Mai, Paul Albert, Sharon A. Savage. Performance of longitudinal cancer screening in Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB211.