Madeline Good

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer (BC) is the most common cancer in LFS females. Here, we perform a multimodal analysis, comparing LFS-BC with sporadic premenopausal breast cancer which shows that nearly all LFS-BC undergo biallelic loss of TP53 , with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibit a high burden of short amplified aneuploid segments. Pro-apoptotic p53 target genes BAX and TP53I3 fail to be up-regulated in LFS-BC unlike in sporadic BC compared to normal breast tissue. LFS-BC has lower CD8 + T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC is marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

INTRODUCTION: Individuals with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome caused by TP53 pathogenic germline variants (PGV), have an increased risk of colorectal cancer (CRC). However, limited data exist on colonoscopy metrics, including total neoplasia detection rates, in patients with LFS. METHODS: We conducted a retrospective cohort study of colorectal neoplasia incidence and characteristics in 663 individuals with LFS. We determined total neoplasia detection rate, adenoma detection rate (ADR), advanced ADR, serrated lesion detection rate (SDR), and CRC detection rate, stratified by age, sex, and PGV subtype, in 311 surveillance colonoscopies from 206 adults performed January 2019 to August 2024. RESULTS: CRC was reported in 4.5% of 663 adults and 0.8% of 124 pediatric patients with LFS. Among 206 adults undergoing colonoscopy, total neoplasia detection rate, ADR, SDR, advanced precancerous polyp detection rate, and CRC detection rate were 37%, 27%, 9.3%, 4.5%, and 0.64%, respectively. Detection rates were similar between loss of function and hypomorphic PGVs. Adults aged 45–75 had higher total neoplasia detection rate, ADR, advanced ADR, SDR, and CRC detection rate than those aged 25–45. Male sex was associated with increased total neoplasia detection rate (53.7% vs 30.7%, P = 0.0004), ADR (41.2% vs 22.1%, P = 0.0013), and advanced ADR (7.5% vs 1.3%, P = 0.0105). DISCUSSION: Patients with LFS have comparable ADR and higher SDR with average-risk adults despite earlier, more frequent surveillance, irrespective of TP53 PGV subtype. Our data support current recommendations for earlier and more frequent colonoscopy surveillance than average-risk guidelines, across LFS phenotypes.

Supplementary Table 1 shows non-malignant findings identified on WBMRI screening in our patient cohort with corresponding patient IDs to cancer diagnoses identified on WBMRI screening.

Supplementary Table 2 outlines prior studies of initial WBMRI screening in LFS cohorts both in pediatric and adult patient populations including length of the study, number of patients with findings, and number of cancers detected.

Supplementary Table 1 shows non-malignant findings identified on WBMRI screening in our patient cohort with corresponding patient IDs to cancer diagnoses identified on WBMRI screening.

Supplementary Table 1 shows non-malignant findings identified on WBMRI screening in our patient cohort with corresponding patient IDs to cancer diagnoses identified on WBMRI screening.

Supplementary Table 2 outlines prior studies of initial WBMRI screening in LFS cohorts both in pediatric and adult patient populations including length of the study, number of patients with findings, and number of cancers detected.

Supplementary Table 2 outlines prior studies of initial WBMRI screening in LFS cohorts both in pediatric and adult patient populations including length of the study, number of patients with findings, and number of cancers detected.

Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome with up to 90% lifetime cancer risk. Cancer screening, including annual whole-body MRI (WB-MRI), is recommended due to known survival advantage, with cancer detection rate of 7% on initial screening. Intervention and cancer detection rates on subsequent screenings are unknown. Clinical data for pediatric and adult patients with LFS (n = 182) were reviewed, including instances of WB-MRI screening and interventions based on screening results. For each WB-MRI screening, interventions including biopsy and secondary imaging, as well as rate of cancer diagnosis, were analyzed comparing initial versus subsequent WB-MRI. Of the total cohort (n = 182), we identified 68 adult patients and 50 pediatric patients who had undergone at least two WB-MRI screenings, with a mean of 3.8 ± 1.9 (adults) and 4.0 ± 2.1 (pediatric) screenings. Findings on initial screening led to an imaging or invasive intervention in 38% of adults and 20% of children. On follow up, overall intervention rates were lower for adults (19%, P = 0.0026) and stable for children (19%, P = NS). Thirteen cancers were detected overall (7% of adult and 14% of pediatric scans), on both initial (pediatric: 4%, adult: 3%) and subsequent (pediatric: 10%, adult: 6%) screenings. Rates of intervention after WB-MRI screening decreased significantly in adults between first and subsequent exams and remained stable in pediatric patients. Cancer detection rates were similar on screening (3%–4% initial, 6%–10% subsequent) for both children and adults. These findings provide important data for counseling patients with LFS about screening outcomes.Prevention Relevance:The cancer detection rate, burden of recommended interventions, and rate of false-positive findings found on subsequent WB-MRI screenings in patients with LFS are not well understood. Our findings suggest that annual WB-MRI screening has clinical utility and likely does not result in an unnecessary invasive intervention burden for patients.

Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome with up to 90% lifetime cancer risk. Cancer screening, including annual whole-body MRI (WB-MRI), is recommended due to known survival advantage, with cancer detection rate of 7% on initial screening. Intervention and cancer detection rates on subsequent screenings are unknown. Clinical data for pediatric and adult patients with LFS (n = 182) were reviewed, including instances of WB-MRI screening and interventions based on screening results. For each WB-MRI screening, interventions including biopsy and secondary imaging, as well as rate of cancer diagnosis, were analyzed comparing initial versus subsequent WB-MRI. Of the total cohort (n = 182), we identified 68 adult patients and 50 pediatric patients who had undergone at least two WB-MRI screenings, with a mean of 3.8 ± 1.9 (adults) and 4.0 ± 2.1 (pediatric) screenings. Findings on initial screening led to an imaging or invasive intervention in 38% of adults and 20% of children. On follow up, overall intervention rates were lower for adults (19%, P = 0.0026) and stable for children (19%, P = NS). Thirteen cancers were detected overall (7% of adult and 14% of pediatric scans), on both initial (pediatric: 4%, adult: 3%) and subsequent (pediatric: 10%, adult: 6%) screenings. Rates of intervention after WB-MRI screening decreased significantly in adults between first and subsequent exams and remained stable in pediatric patients. Cancer detection rates were similar on screening (3%–4% initial, 6%–10% subsequent) for both children and adults. These findings provide important data for counseling patients with LFS about screening outcomes.Prevention Relevance:The cancer detection rate, burden of recommended interventions, and rate of false-positive findings found on subsequent WB-MRI screenings in patients with LFS are not well understood. Our findings suggest that annual WB-MRI screening has clinical utility and likely does not result in an unnecessary invasive intervention burden for patients.