Mutational landscapes of brain metastases across various histological subtypes of lung cancer.

The TP53 gene encodes the tumor suppressor protein 53, which is critical for maintaining genomic stability and preventing tumorigenesis. Mutations in TP53, particularly missense mutations, have a substantial impact on cancer progression because they give gain-of-function features that enhance proliferation, metastasis, and treatment resistance. This review examines the mechanisms underlying p53 mutations, including their interactions with critical regulatory circuits, and assesses novel medication and prodrug options targeting TP53 mutations in various malignancies. Small-molecule correctors, statins, Hsp90 inhibitors, and new drugs like Eprenetapopt and COTI-2 are among the therapeutic options proposed. The mechanisms of action and potential efficacy in treating leukemia, lung, breast, and ovarian malignancies are investigated. Emerging techniques for restoring wild-type p53 functionality or degrading mutant p53 demonstrate the therapeutic potential of these approaches. Challenges such as medication resistance, side effects, and the chemical complexity of p53 pathways are also addressed, emphasizing the importance of ongoing research. This review contributes to our understanding of TP53-targeted cancer medicines, offering hope for more innovative treatments with improved outcomes.

Small cell lung cancer (SCLC), accounting for ~15% of lung cancers, is an aggressive and lethal tumor type. It is characterized by rapid proliferation, early metastasis, and poor prognosis. Current therapies, including platinum-based chemotherapy and recently introduced immune checkpoint inhibitors, provide modest survival benefits due to frequent relapse and therapeutic resistance. At the molecular level, SCLC is marked by near-universal loss of the tumor suppressors genes TP53 and RB1, and exhibits marked heterogeneity driven by several key master transcription factors. These factors define distinct molecular subtypes with unique gene expression programs and therapeutic vulnerabilities, enabling cell plasticity and subtype switching in response to treatment pressures. A thorough understanding of these subtype-specific dependencies and the epigenetic mechanisms regulating transcription is critical for developing effective and durable therapies. This review focuses on these aspects and evaluates the potential of epigenetic-targeted strategies in the treatment of SCLC.

Adrenal lesions often occur in patients with multiple endocrine neoplasia type 1 (MEN1), mostly adrenal cortical adenomas (ACAs), although the frequency of adrenal cortical carcinomas (ACCs) is higher than in the general population. The coexistence of benign and malignant masses has seldom been documented, leaving open the question of ACC progression from benign forms. We report a comprehensive genetic characterization of three adrenal cortical tumor samples obtained from a familial MEN1 patient, operated for the rapid progression of an initially stable nonfunctional adrenal incidentaloma. Histologically, the tumor consisted of a small ACA contiguous to a large ACC, which subsequently relapsed. Exome sequencing of ACC, ACA and recurrence evidenced a MEN1 loss of heterozygosity (LOH) in ACC but not in ACA, where, however, a second hit driven by alternative mechanisms could not be excluded. The majority of the ACA variants were found to co-occurred in ACC (n = 36/42) and were benign, except for two of unknown significance in KANK1 and REN genes, described as associated with renal cancer. Among variants shared between ACC and its recurrence (n = 69), 11 were Tier III, while 2 affecting TP53 and NF1 genes were pathogenic. Bioinformatic clonal evolution analysis identified one clone - characterized by TP53 and NF1 mutations - absent in ACA but present in ACC and recurrence, as well as 2 clones shared between ACA and ACC but lost in the recurrence. In conclusion, comparative Whole Exome Sequencing (WES) analysis of three adrenal tumors in a MEN1 patient suggests a possible relationship between malignant and benign lesions occurring in MEN1 patients, without, however, demonstrating any causal adenoma-to-carcinoma progression driven by MEN1 LOH. Overall, these data further suggest an increased risk of MEN1 patients to develop adrenocortical malignancy.

The aim of this study is to evaluate the association between genes related to cellular senescence and ferroptosis and their relevance to hepatocellular carcinoma (HCC). Genes associated with senescence and ferroptosis in HCC were retrieved from public databases. A protein-protein interaction (PPI) network was constructed to identify for hub genes, and validate their expression. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis, while prognostic significance was determined through Kaplan-Meier analysis. A prognostic nomogram model was developed based on selected hub genes and Tumor Node Metastasis (TNM) staging. A total of 52 senescence-ferroptosis-related genes were identified in HCC. ROC analysis indicated moderate to high diagnostic efficacy for TP53 (AUC = 0.723, CI: 0.669-0.776), JUN (AUC = 0.733, CI: 0.659-0.806), RELA (AUC = 0.854, CI: 0.808-0.901), and CDKN2A (AUC = 0.953, CI: 0.932-0.974). Kaplan-Meier analysis revealed that TP53, HIF1A, and CDKN2A were significantly associated with overall survival (OS) in patients with HCC. A nomogram model incorporating these three genes and TNM staging achieved a concordance index (C-index) of 0.699. Calibration curves indicated concordance between the predicted and observed survival probabilities at 1-, 2-, and 3-year intervals. The senescence-ferroptosis-related genes TP53, HIF1A, and CDKN2A demonstrated potential as diagnostic and prognostic biomarkers in HCC. The developed nomogram may support individualized prognostic assessment and inform early diagnostic and therapeutic strategies in patients with HCC.

Abnormal RNA splicing is an underrecognized driver of pathogenicity in germline TP53 - the cause of Li-Fraumeni syndrome (LFS). We re-evaluated exonic single-nucleotide variants (SNVs) that yield missense or synonymous changes for spliceogenic effects by integrating SpliceAI prediction, in-vitro minigene assays, and analysis of tumor RNA-seq from TCGA, and assessed genotype-phenotype correlations using clinical data from multiple databases and national registries. We identified 58 spliceogenic exonic SNVs (SE-SNVs) across the TP53 gene (40 missense, 18 synonymous). Experimental validation confirmed aberrant splicing for 15 out of 17 tested variants, most often through cryptic splice-site activation that introduced frameshifts and premature termination. Clinically, carriers of SE-SNVs previously considered as mild or of low-pathogenicity by protein-based assays showed earlier onset and LFS-signature cancers, indicating that splicing disruption can override amino-acid effects. The recurrent c.375 G > A (p.(Thr125 = )) showed heterogeneous effect: with both childhood/adolescent and adult onset, consistent with partial, variable retention of canonical splicing. These data reveal a substantial burden of spliceogenic pathogenicity in TP53 and strong support integrating splicing prediction, functional validation, and transcript-level evidence into variant interpretation and risk stratification in LFS.

This study investigates outcomes of The Cancer Genome Atlas (TCGA)-surrogate molecular types of endometrial cancer in South Indian patients, including polymerase epsilon (POLE)-mutated, mismatch repair-deficient (MMRd), p53 aberrant, and no specific molecular profile (NSMP) types. The retrospective cohort, followed-up prospectively consisted of 151 patients from two institutions in Kerala, India: Government Medical College, Kozhikode, and MVR Cancer Center. The study spanned from January 1, 2016, to October 31, 2024. Sanger sequencing of the POLE gene (exons 9 and 13), TP53 (exons 5-8), CTNNB1, and PTEN genes, along with immunohistochemistry for mismatch repair (MMR) proteins, p53, estrogen receptor, and progesterone receptor, was performed to determine molecular types and associated variables. The study identified four subtypes: 39 POLE mutated (25.8%), 44 MMRd (29.1%), 29 p53 aberrant (19.2%), and 39 NSMP (25.8%). The 5-year recurrence-free survival (RFS) rates are POLE mutated (69%), MMRd (87%), p53abn (89%), and NSMP (64%) (P = 0.012). The study identified a "non-pathogenic" POLE-mutated subtype showing poor outcomes for overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) (hazard ratios [HRs] for OS 5.45, P = 0.010; HR for DSS 4.83, P = 0.020; HR for RFS 4.12, P = 0.017) in multivariable analysis. Follow-up averaged 5.1 years. Estrogen receptor-positive low-grade endometrioid POLE-mutated tumors demonstrated excellent survival, while high-grade tumors negatively affected the POLE-mutated group. MMRd subtype, despite presenting in advanced stages with high-risk uterine factors, had excellent prognosis. The p53 aberrant group, predominantly with endometrioid histology and low-grade tumors, also showed good prognosis with standard treatment protocols. NSMP subtype revealed unfavorable outcome. Neither CTNNB1 mutation or ER PR status was noted to be a determinant of the poor outcome.Multiple-classifier tumors (>1 TCGA-surrogate type) were identified, with POLEmut-p53 being the largest group, showing characteristics similar to POLEmut. The study's findings diverge from prognostic implications of TCGA-surrogate molecular types, suggesting genetic diversity and ethnicity as potential outcome determinants in South Indian endometrial cancer patients.

Introduction. B-cell prolymphocytic leukemia (B-PLL) is an extremely rare condition, accounting for less than 1% of all lymphoid leukemias. The identification of more than 55% of lymphocytes in the blood or bone marrow with prolymphocytic morphology is the hallmark feature of B-PLL. Conventional cytogenetic and molecular testing can detect MYC and TP53 abnormalities and mutations, identifying 3 distinct B-PLL groups with different clinical outcomes. Methods. Optical genome mapping (OGM) is a new genome-wide technology that can detect structural genomic variations (SVs) including translocations, inversions, deletions, duplications etc., copy number variations (CNVs) and whole-chromosome aneuploidies with high resolution. In the present study, cryopreserved mononuclear cells obtained from 3 patients with B-PLL were processed to obtain Ultra-high molecular weight (UHMW) DNA samples useful to perform OGM analyses by Bionano Saphyr instrumentation.Results. OGM detected an extremely complex genome with extensive copy number alterations and chromosomal rearrangements in all patients (Figure 1). OGM analyses found in case#1 the deletion of TNFRSF10A/B/C/D (alias DR4, DR5, BcR1 and DcR2) cluster and IKBKB gene in 8p loss, deletion of FAS and PTEN in loss of chromosome 10 and deletion of TP53 gene in 17p loss, implying that both intrinsic and extrinsic apoptotic pathways may be affected in this patient. Of interest, in case #1, the 1.25Mb loss at 13q22.2q22.3 comprised FBXL3 and MYCBP2 genes involved in MYC regulation. In case#2, deletion of BCL2L11 (alias BIM) in 2q loss, deletion of TP53 in chromosome 17p loss, together with amplification of BCL2 gene in 18q gain and MDM2 in chromosome 12 gain were observed, implying multifactorial alterations that can affect the intrinsic apoptotic pathway in case#2. Additionally, OGM detected gains of CDK2, CDK4 on chromosome 12, and gain of BCL6 and KLHL6 genes on chromosome 3, implicated in cell cycle regulation and germinal center formation. Interestingly, in case#2 chromosomes 12,17, and 21 were involved in multiple chained translocations, a typical pattern of complex genomic rearrangements that fall under the category of chromoanagenesis (Figure 1). In case#3, 11p15p11 CNV gain comprised WT1 and CD44 gene, whereas TP53 and BCOR were present in CNV losses identified by OGM analyses. Conclusions. OGM revealed that, in addition to the frequent TP53 dysfunction (deletions and mutations) and MYC alterations, multiple concomitant genomic changes affect other genes and pathways involved in apoptosis and cell-cycle regulation. These findings highlight the intricate genomic landscape of B-PLL, indicating that further pathogenetic mechanisms may contribute to disease, and underscores the ability of OGM to comprehensively capture this genomic complexity, including catastrophic rearrangements and multiple structural variations.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) is a disorder caused by autosomal-dominant mutations in the TP63 gene. AEC is characterised by the presence of severe and painful skin erosions that can take years to heal. Current treatment options for these devastating lesions are limited, highlighting the need for new therapeutic strategies. We previously generated keratinocytes from patient-derived induced pluripotent stem cells (iPSC-K) and identified defects in several cell adhesion complexes, including desmosomes, hemidesmosomes and focal adhesions. In the present study, we developed a complementary invitro model using NTERT keratinocytes transduced with lentiviral constructs expressing AEC-related TP63 mutations (N-AEC). This model allows for the large-scale production of disease-relevant material, overcoming the limitations of iPSC-derived keratinocytes, which have the characteristics of primary keratinocytes, including limited cell doublings and lifespan. We demonstrate that N-AEC keratinocytes exhibit key defects observed in AEC iPSC-K and AEC patient skin, including downregulation of cell adhesion proteins. In addition, 3D epidermal equivalents generated from these cells replicate pathological features seen in AEC patient skin, such as intra-epidermal cysts, reduced desmosomal protein expression and altered expression of differentiation markers. Our N-AEC model provides a valuable tool for investigating the mechanisms underlying skin fragility in AEC and other genetic skin disorders and advances the potential for novel therapeutic development.

Characterizing Biological Behavior Beyond Morphologic Features: Next-Generation Sequencing Analysis of Large vs Small Pancreatic Cystic Lesions in a Large Multicenter Cohort of Patients.

Altered expression and mutations in cell cycle genes CCND1, CDK4, CDKN2B and TP53 are associated with Pakistani breast cancer patients.

While TP53 mutations in myeloproliferative neoplasms (MPN) are associated with an increased risk of leukemic transformation, not all patients carrying a TP53 mutation progress. To better risk-stratify MPN patients with TP53 mutations, we analyzed data from 1540 patients treated at four specialized cancer centers. Among them, 1429 had wildtype TP53 and 111 had mutations in the TP53 gene. At first MPN diagnosis, 32% had polycythemia vera, 39% had essential thrombocythemia, and 25% had primary myelofibrosis. Among all MPN patients with TP53 mutations, presence of fibrosis in the bone marrow (hazard ratio (HR): 3.84, 95% CI: 1.98-7.43), multi-hit TP53 mutation status (HR: 2.74, 95% confidence interval (CI): 1.52-4.97), and higher PHANTM score (HR: 1.87, 95% CI: 1.02-3.42) were associated with worse OS in a multivariable analysis. Based on these variables, we developed a risk model to identify TP53-mutated MPN patients who are at high risk for inferior OS. Median OS from time of TP53 detection was 0.5 years in high-risk patients, compared to 2.3 years for patients with intermediate risk and 6.3 years for patients with low risk. This scoring system may help refine risk stratification for chronic phase MPN patients harboring TP53 aberrations.

TP53 is a tumor-suppressor gene involved in regulating apoptosis, DNA repair, and genomic stability. Mutations in TP53 are implicated in approximately half of all detected cancers, including breast, lung, colorectal, and ovarian cancers, making it a significant target for therapeutic interventions. Many pharmaceutical drugs aim to restore TP53 function, and there is a need for predictive tools to assess how compounds may affect TP53 expression. In this study, we propose a new ensemble machine-learning model to predict the direction of TP53 relative gene expression in response to pharmaceutical compounds. Our model utilizes molecular fingerprints, descriptors, and scaffold-based features extracted from SMILES representations of compounds concatenated into a single feature vector. Trained using our newly generated benchmark dataset based on the Connectivity Map (CMap) database and addressing class imbalance with the Synthetic Minority Over-sampling Technique (SMOTE), our model achieves 62.9%, 93.9%, 40.3%, and 0.39 in terms of accuracy, sensitivity, specificity, and Matthews Correlation Coefficient (MCC), respectively. As the first-of-its-kind TP53 gene regulation prediction, our study serves as a convincing proof-of-concept that paves the way for future investigation. GenReP as a stand-alone predictor, its source code, and our newly generated benchmark dataset are publicly available.

Gingivobuccal Squamous Cell Carcinoma: A Different Genomic Entity.

Background/Objectives: The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancers, with alterations predominantly affecting its DNA-binding domain (DBD). However, the mutational landscape and functional consequences of TP53 variants remain poorly characterized in African populations. This study aimed to characterize mutations in exons 5-6 of TP53 in oral cavity cancer (OCC), prostate cancer (PC), and breast cancer (BC) in a Senegalese population, and to assess their structural effects, functional consequences, and impact on protein-protein interactions with BCL-2. Methods: Seventy-eight archived tumor DNA samples from Senegalese patients with OCC, PC, and BC were analyzed. Variants were annotated using COSMIC and dbSNP databases. Functional impact was evaluated with PolyPhen-2. Structural stability changes (ΔΔG) were predicted using FoldX, conformational dynamics (ΔΔSvib) were assessed with ENCoM, and effects on the p53-BCL-2 interaction were analyzed using DDMut-PPI. Statistical analyses were also performed. Results: BC exhibited the highest TP53 mutation frequency, whereas OCC showed greater mutational diversity. Exon-level analysis revealed a significant enrichment of exon 6 mutations in BC. Structural analyses indicated that exon 5 mutations across all cancers and mutations in OCC were predominantly destabilizing and associated with loss-of-function effects. In contrast, recurrent exon 6 mutations in PC and BC, particularly V217L and V218M, were predicted to stabilize the p53 structure. Conformational dynamics differences between exons were significant only in PC. All analyzed mutations were predicted to stabilize the p53-BCL-2 interaction. Conclusions: This integrative in silico study identified cancer and exon-specific TP53 mutation patterns in a Senegalese population, highlighting exon 6 as a context-dependent hotspot with potential oncogenic implication in PC and BC. Despite its computational nature, the study provides valuable insights that merit further investigation.

Abstract Cancer remains the second leading cause of death worldwide, with 5-10% of cases attributed to hereditary syndromes. Among these, Li-Fraumeni Syndrome (LFS) is closely associated with pathogenic germline variants in the TP53 gene, a critical tumor suppressor responsible for maintaining genomic stability and regulating cell cycle and apoptosis. In Brazil, the TP53-R337H variant is highly prevalent due to a well-documented founder effect, particularly in the central and southern regions. Recent studies have revealed the co-segregation of the truncating variant XAF1-E134* with TP53-R337H, forming a functional haplotype associated with increased tumor aggressiveness and earlier onset (Jung et al., 2020; Fortes et al., 2021).This study aimed to evaluate the frequency and clinical impact of this haplotype in a cohort of Brazilian individuals with suspected hereditary cancer syndromes, recruited through the Brazilian Unified Health System (SUS). A total of 527 participants (probands and relatives) were referred to the Human Genetics Center at the Federal University of Goiás (UFG), based on NCCN 2025 criteria for Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and LFS. After informed consent, venous blood samples were collected for DNA extraction. Next-generation sequencing (NGS) was used to analyze the coding region of TP53, and genotyping assays were performed to detect the R337H and XAF1-E134*variants in both probands and their family members.Among the 527 participants, 198 (37.56%) were probands and 329 (62.44%) were family members. Of the probands, 7.58% (15/198) carried pathogenic TP53 variants, with 93.33% (14/15) being R337H. Thirteen probands were tested for XAF1-E134*, and 76.92% (10/13) tested positive. Of these, 90% (9/10) had a confirmed cancer diagnosis, with a mean age at diagnosis of 40.7 years. Furthermore, 30% (3/10) presented with multiple primary tumors, including prostate, osteosarcoma, sarcoma, and adenocarcinoma. Metastasis was observed in 10% (1/10). Among family members, 14.29% (47/329) carried TP53 variants. Of the 35 relatives tested for XAF1-E134*, 91.43% (32/35) were positive.These results provide strong evidence for co-inheritance of TP53-R337H and XAF1-E134*, forming a high-risk haplotype associated with more aggressive cancer phenotypes. Notably, in families where probands were negative for TP53-R337H, relatives were also negative for both variants, supporting the hypothesis of joint transmission. The clinical manifestations observed among carriers reinforce the functional synergy between these two variants and their potential contribution to early-onset and multifocal malignancies.This study highlights the relevance of including XAF1-E134* in genetic screening panels, particularly in Brazilian regions affected by the R337H founder mutation. Incorporating haplotype-based analysis into clinical genetics can improve risk stratification, facilitate early diagnosis, and guide personalized prevention and surveillance strategies in high-risk families. Further studies are essential to clarify the molecular mechanisms underlying this haplotype and to define its role in cancer pathogenesis and clinical management. Citation Format: K. M. Veiga, P. F. Silva, W. D. Oliveira;, D. C. Maia, R. M. Rahal, E. P. Silveira-Lacerda. Co-segregation of XAF1-E134and TP53-R337H in a brazilian cohort: clinical impact of a high-risk haplotype [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-02-11.

Abstract Background: Li-Fraumeni syndrome (LFS), caused by monoallelic germline pathogenic variant (PV) in TP53 gene, causes an elevated risk of developing certain cancers, mainly early onset breast cancer, sarcoma and brain tumors. While LFS patients are believed to be at an increased risk for radiation-induced sarcomas, only a few retrospective studies have been published studying the impact of radiationtherapy in the treatment of breast cancer among these patients. This study reviews the data concerning LFS patients treated at the Institut Curie with adjuvant radiation therapy for localized breast cancer. Methods: A retrospective study was conducted on female breast cancer patients with confirmed TP53 PV treated at the Institut Curie. Data concerning patients’ characteristics, treatments received, radiotherapy if received, rates of recurrences, rates of radiation induced sarcomas (RIS) and patient outcomes were collected. Results: From 1989 to 2024, we identified 47 female LFS breast cancer patients who met our inclusion criteria. Median age at diagnosis was 31 years (range 18-72). Of them, 76.6% had a family history of cancer suggestive of LFS. 31.9% had tumoral HER2 amplification. 51.1% received a mastectomy and 31.9% received a lumpectomy. 23 patients (48.9%) received radiotherapy as a part of their treatment strategy. The median follow up was 111 months (range 7-413). Among patients who received radiotherapy, 3 (13%) had a known diagnosis of LFS prior to treatment. No case of radiation-induced sarcomas was observed during the follow-up period. In the radiotherapy group, 5 patients (21.7%) later developed a malignancy within the irradiated field. At 10 years post-diagnosis, overall survival did not differ significantly between patients who received radiotherapy and those who did not (58.2% [95%CI: 36.8-91.9] vs. 80.1% [95%CI: 64.2-100]). Similarly, there was no significant difference in loco regional recurrence-free survival (95.2% [95%CI: 86.6-100] vs. 74.0% [95%CI: 54.8-99.9]) or in survival free from subsequent non-breast cancers (59.6% [95%CI: 36.5-97.2] vs. 67.2% [95%CI: 49.8-90.7]). Univariate analysis did not find any correlation between hormonal status, grade, surgical technique, stage, use or non-use of radiotherapy and overall survival, cancer-specific survival, loco regional recurrence-free survival, metastasis-free survival. Conclusion: The incidence of radiation-induced sarcomas and local recurrences in LFS breast cancer patients was lower than anticipated. Further studies with larger cohorts and extended follow-up are required to validate these findings. Citation Format: A. A. Shrebati, P. Loap, E. Mouret-Fourme, K. Cao, M. Belotti, D. Stoppa-Lyonnet, Y. Kirova. Radiation therapy for breast cancer in patients with Li-Fraumeni syndrome (LFS): a single institution cohort study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-03-06.

Abstract Background: Li-Fraumeni Syndrome (LFS), caused by pathogenic/likely pathogenic (P/LP) variants in TP53, is a cancer predisposition syndrome that increases the risk for numerous cancer types in both children and adults. Many studies have shown that cancer rates can vary between races and ethnicities. For example, the 2024 Cancer Statistics published by the American Cancer Society reported the incidence for breast cancer to be highest for White individuals and lowest for Hispanic/Latino individuals. One LFS study showed East Asian individuals were more frequently diagnosed with gastric cancer compared to North Americans and Europeans. Other studies identified P/LP TP53 variants associated with specific populations, such as the South and Southeast Brazil founder variant, p.Arg337His. However, there lacks extensive research on the variable expressivity of cancers within the LFS population, based on genotype, race, and/or ethnicity. This study aims to describe the specific TP53 germline variants, cancer rates, and cancer types among individuals of different racial and ethnic groups diagnosed with LFS. Methods: A retrospective chart review of individuals with germline P/LP TP53 variants at the University of Texas MD Anderson Cancer Center was completed. Data collected includes race, ethnicity, number of cancer diagnoses, cancer types, and location of the TP53 variant (exon and codon). Individuals with a suspected somatic TP53 variant were excluded from this study. Racial groupings included Asian, Black or African American, White, and Other/Unspecified. Ethnicity was categorized as Hispanic, Non-Hispanic, and Other/Unspecified. There were also six cancer type categories: adrenocortical carcinoma, brain cancer, breast cancer, osteosarcoma, soft tissue sarcoma, and non-core LFS cancers. Descriptive and statistical analyses, including chi-squared or Fisher’s exact tests and pairwise comparisons, were performed using R software (v4.4.1). Results: Two hundred and fifty individuals with a confirmed P/LP TP53 variant were included in the analysis. Breast cancer was the most common cancer type diagnosed for all ethnic and racial groups, except Asian individuals, who most frequently had non-core LFS cancer diagnoses. There was a significant difference in the rate of breast cancer across racial groups (p = 0.037), with Black or African American individuals with LFS having the highest rate of breast cancer at 76.5%. Additionally, individuals who identified as Black or African American were 1.87 times more likely to develop breast cancer in comparison to those who identified as White. For cancer rates, most individuals in each racial and ethnic group were diagnosed with one primary cancer. Statistical analysis did not identify a significant difference in cancer rates across groups defined by race or ethnicity. Regarding the location of variants within the TP53 gene, there was a significant difference in the rate of variants in exon four (p = 0.021) and exon six (p = 0.016) across racial groups, with variants in exon four being more common in Asian individuals (33.3%) and variants in exon six being more common in Black or African American individuals (35.3%). Conclusion: This study highlights similarities in the rates and types of cancers seen across racial and ethnic groups within a cohort of individuals with LFS. However, this study also identified potential differences in the rates of breast cancer and variant location across racial populations within the cohort. The results of this study provide information that can lead to more personalized counseling for patients and train risk models to accurately predict cancer risk for individuals with LFS of differing races and ethnicities. Citation Format: H. Esplen, B. Arun, C. DiNardo, H. Abdel-Salam, K. Richardson, C. Peterson, J. Corredor. Evaluating Cancer Rates, Cancer Types, and Variant Hotspots Across Races and Ethnicities in Individuals with Li-Fraumeni Syndrome [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-13.

Abstract Background: The population prevalence of pathogenic variants (PVs) in breast cancer susceptibility genes (BCSG’s) remains largely unknown, in part due to restrictions in genetic testing guidelines. We report early BCSG prevalence estimates from the Women Informed to Screen Depending on Measures of Risk (WISDOM) Trial, where women in the personalized screening arm were offered unrestricted genetic testing, and evaluate the relationship of test positivity to family history and other patient characteristics. Methods: The WISDOM Trial enrolled women without breast cancer between 2016-2023 aged 40-74 in a pragmatic randomized screening trial comparing annual screening mammography to personalized risk-based screening. Participants in the personalized arm were offered germline testing for nine breast cancer susceptibility genes (BRCA1, BRCA2, ATM, CHEK2, PALB2, CDH1, PTEN, STK11, TP53). We report the prevalence of PVs in the trial and the distribution of self-reported demographic and family history data in the sub-population with PVs. Results: Among 23,098 participants who enrolled in the trial and completed genetic testing, 714 (3.1%) carried a PV. After excluding those previously aware of their PV, the detection rate was 2.6%. PVs were most common in CHEK2 (1.47%) and less common in higher-penetrance BRCA1 (0.14%), BRCA2 (0.36%), and PALB2 (0.19%) variants. PVs in the CDH1, PTEN, STK11, and TP53 genes were rare (<0.1%). Notably, 30% of women with PVs did not report a first- or second-degree female relative with breast or ovarian cancer, a male relative with breast cancer, or Jewish ancestry. Conclusion and Relevance: Unrestricted access to genetic testing in a real-world setting identified a substantial number of women with clinically actionable results, many of whom would not have qualified for genetic testing under guideline-concordant criteria. These findings support expanding genetic testing to all women as part of personalized breast cancer risk assessment. Citation Format: K. B. Fergus, K. Ross, M. Scheuner, B. S. Tong, A. Blanco, A. Fiscalini, D. DeRosa, E. Silver, D. Goodman-Gruen, H. Anton-Culver, A. Borowsky, J. Esserman, A. Kaster, A. LaCroix, R. Lancaster, A. Naeim, H. Park, B. Parker, V. Arasu, N. Wenger, H. Harvey, D. Heditsian, S. Brain, V. Lee, D. Moorehead, A. Petruse, L. Sabacan, R. Hiatt, Y. Shieh, E. Ziv, O. I. Olopade, J. Tice, M. Eklund, L. Van 'T Veer, L. J. Esserman, L. Madlensky. Germline pathogenic variants in the personalized screening arm of the WISDOM Study: Findings from 23,098 women with no personal history of breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF5-04.

Abstract Background: Triple-negative breast cancer (TNBC) is a high-risk subtype characterized by aggressive clinical behavior with limited targeted therapies. The addition of pembrolizumab to neoadjuvant chemotherapy (NACT) has improved pathologic complete response (pCR) rates in early-stage TNBC. However, racial disparities in outcomes remain, and limited data exist on how these disparities may impact pathologic response to chemoimmunotherapy. Our prior retrospective analysis revealed statistically significant differences in pCR among Black or African-American (AA) women following NACT. This study evaluates genomic differences among TNBC patients treated with a pembrolizumab-based NACT regimen at a regional health system, aiming to identify genetic markers that may predict treatment response and provide insight into observed racial disparities. Methods: Patient records from Ochsner Health, a regional healthcare network, were reviewed to identify individuals with early-stage TNBC treated with pembrolizumab-based NACT from 2020-2024. Exclusion criteria included unknown receptor status and age <18 years. Eligible patients were required to have archived formalin-fixed paraffin-embedded (FFPE) biopsy samples available at the main campus. Consented participants underwent tumor DNA sequencing performed by Tempus using their archived diagnostic tissue. Results: Archived FFPE tumor samples were obtained from 50 TNBC patients treated with NACT and pembrolizumab. Of these, 43 samples passed Tempus quality control measures, and 40 were included in the final analysis (excluding 1 patient who identified as “Other” race and 2 without definitive surgery or pCR data). Among the 40 analyzed patients, 25 identified as AA and 15 as White. The average number of mutations detected per patient was 16.5 with an average of 18 mutations/patient in AA patients and 13 mutations/patient in White patients (Table). 95% (38/40) of patients harbored mutations in the TP53 gene—substantially higher than reported in broader breast cancer cohorts. A correlation was observed between variant allele frequency (VAF) of TP53 mutations and pCR status (p=0.047). Conclusion: With small numbers, the prevalence of the most frequently mutated genes was not statistically significant. Mutations in KMT2C/D were statistically significant. These methyltransferase mutations may serve as biomarkers for immunotherapy response in TNBC given the high pCR rates seen in these, regardless of race. Response to immunotherapy among patients with these mutations is consistent with findings in other cancer types. Patients with a higher VAF of TP53 had worse pCR rates, regardless of race, suggesting that mutation burden may influence treatment response. As more data is collected, it may reveal insight into racially distinct genomic signatures that could serve as predictors of response to NACT with immunotherapy. Citation Format: M. Sheen, E. Biggs, C. Taylor, M. Lakey, R. DeArmitt, R. Emnance, M. Bratton. Molecular characteristics of TNBC and pathologic response to chemoimmunotherapy: a focus on racial disparities [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-11-22.