Abstract 7403: Colorectal neoplasia rates in Li Fraumeni syndrome
Authors: Sophia R. Spiegel, Caitlin Orr, Mikia J. Croom, Nicolas U. Edgar, Sophie R. Cahill, Anh N. Le, Madeline Good, Jo Anson, Soren Feola, Casey Mehrhoff, Anne Naumer, Jennie Vagher, Luke D. Maese, Judy E. Garber, Asaf Maoz, Bryson W. Katona, Suzanne P. MacFarland, Kara N. Maxwell
Journal: Cancer Research (2025)

Abstract Background and Aims: Li Fraumeni Syndrome (LFS) is an inherited cancer predisposition syndrome with up to 90% lifetime cancer risk and is caused by TP53 pathogenic germline variants (PGVs). Current NCCN guidelines for LFS recommend colonoscopy for colorectal cancer (CRC) screening every 2-5 years, beginning at age 25 or 5 years before earliest known familial CRC, based on recent literature suggesting ∼5-7% of LFS patients develop CRC. However, no data exists on findings of screening colonoscopy in LFS patients to support use of earlier and more frequent screening. In this study, we determined colon neoplasia detection rates of colonoscopy in LFS patients. Methods: We analyzed CRC diagnoses from our entire LFS cohort (n=220 adults) and fully documented screening colonoscopies (n=123) from January 2019 - August 2024 in a cohort of adult LFS patients (n=90). TP53 PGVs were classified based on variant type and functional effect into dominant negative (DN) loss of function (LOF) missense, truncating LOF variants, or hypomorphic variants. Analysis is ongoing of validation cohorts at Huntsman Cancer Institute and Dana Farber Cancer Institute and of pediatric data at these institutions. Results: Of 220 adult LFS patients, 15 (6.8%) had a diagnosis of CRC at a median (IQR) age of 39(32-46). Compared to LFS patients without CRC, patients with CRC were more likely to be male (73% vs 26%, p=0.0004), but not more likely to have a DNLOF/LOF vs hypomorphic PGV (30% vs 39%, p=0.78). Of 90 adult LFS patients with fully documented colonoscopies, the average age at time of data abstraction was 42.6 ± 12.5 y/o, 72% were female, and 73% of patients had a prior malignancy. 31% of PGVs were DNLOF missense, 24% were LOF truncating variants, 38% were hypomorphic, and 7% were unknown. Overall detection rates for any neoplastic finding, adenoma (ADR), serrated lesion (SDR), advanced precancerous polyp, and CRC were 34%, 24%, 9%, 4%, and 0.8% respectively. Detection rates for any neoplastic finding, adenoma, advanced adenoma, serrated lesion, advanced serrated lesion, and CRC were similar between patients aged 25-44 (34%, 32%, 8%, 13%, 0 and 3% respectively) and 45-75 (36%, 28%, 6%, 6%, 0 and 2%), with no significant difference by gender. No significant difference in precancerous polyp (p=0.8438) and colon neoplasia (p=1) detection rates was found in patients with hypomorphic TP53 PGVs compared to DNLOF/LOF PGVs. Conclusion: Our data show that LFS patients have a lower ADR (24%) but similar SDR (9%) to the endoscopic benchmarks in standard risk adults (35% and 6%, respectively); however, LFS patients undergo earlier and more frequent screening, suggesting that LFS patients have comparable polyp burdens at an earlier age. These data support the NCCN guidelines for earlier and more frequent colonoscopy in LFS patients. Citation Format: Sophia R. Spiegel, Caitlin Orr, Mikia J. Croom, Nicolas U. Edgar, Sophie R. Cahill, Anh N. Le, Madeline Good, Jo Anson, Soren Feola, Casey Mehrhoff, Anne Naumer, Jennie Vagher, Luke D. Maese, Judy E. Garber, Asaf Maoz, Bryson W. Katona, Suzanne P. MacFarland, Kara N. Maxwell. Colorectal neoplasia rates in Li Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7403.