Description of six cases of melanoma in 512 patients with germline pathogenic variants in the TP53 gene.

Spectrum, molecular features, and clinical outcomes of hematologic malignancies and clonal hematopoiesis in li fraumeni syndrome

10530 Background: Germline pathogenic variants (PV) in the tumor suppressor gene TP53 are associated with a high risk of developing diverse malignancies, often at young age, and predispose to Li-Fraumeni syndrome (LFS). Surveillance programs for presymptomatic PV carriers have shown survival benefit in a non-randomized trial. Here we describe the surveillance findings and clinical outcomes of adults with TP53 PV undergoing a standardized screening protocol. Methods: We identified adults with germline PV in TP53 who underwent surveillance at the University Hospitals Leuven, Belgium, between 04/2013 and 08/2020. Patients with prior cancer were allowed, while patients with an active malignancy requiring treatment at diagnosis of the TP53 PV were excluded. Surveillance was performed per modified Toronto protocol, including annual whole body diffusion-weighted MRI (WB-DWI/MRI), brain MRI, abdominal ultrasound (US), endoscopic surveillance, laboratory tests, dermatological examination and breast MRI/US in females. The primary aim was to evaluate the number and type of malignancies and premalignant lesions diagnosed during screening and to assess the proportion of malignancies detected by surveillance. Secondary outcomes were the cancer detection rate during the first year of screening, the proportion of carriers with false-positive findings, and overall survival. Results: We included 42 adults from 20 apparently unrelated families. Median age was 38y (range, 17-70y) and 23 had a history of prior cancer. After a median follow-up of 41.5mo, we diagnosed 18 cancers in 12/42 participants (29%). Overall survival was 95% in all participants, including 2 carriers who opted to discontinue surveillance. Surveillance detected 10/18 cancers (56%), the majority of whom through WB-DWI/MRI (6/10; 60%). No malignancies were identified with brain MRI. In 5/42 individuals (12%), surveillance detected a malignancy during the first year of screening. Only 2/10 cancers discovered with surveillance (1 soft tissue and 1 bone sarcoma) belong to the LFS core tumors. Cancers not detected with surveillance (8/18) were 6 non-melanoma skin cancers and 2 interval cancers (sarcoma post radiation, secondary acute leukemia). Additionally, we detected 27 premalignant lesions in 11/42 patients (26%), of whom 78% were diagnosed by colonoscopy. False-positive findings occurred in 7/42 patients (17%) and were mostly seen with WB-DWI/MRI. Conclusions: Adults with germline PV in TP53 that undergo surveillance have high cancer detection rates. The majority of malignancies were asymptomatic at diagnosis and detected with WB-DWI/MRI. Despite the high cancer incidence, few LFS core cancers were diagnosed and survival was encouraging. Increased genetic testing changes the clinical picture of germline TP53 carrier populations, justifying the transition from LFS to a wider concept of heritable TP53-related cancer syndrome.

Pathogenic variants in TP53 have been classically thought to cause Li-Fraumeni syndrome (LFS), a cancer predisposition with high risks for various childhood- and adult-onset malignancies. However, increased genetic testing has lately revealed, that pathogenic variant carriers exhibit a broader range of phenotypes and that penetrance may be dependent both on variant type and modifiers. Using next generation sequencing and short tandem repeat analysis, we identified germline pathogenic variants in TP53 and RAD51C located in cis on chromosome 17 in a 43-year-old male, who has developed a rare sebaceous gland carcinoma (SGC) but so far no tumors of the LFS spectrum. This course mirrors a Trp53-Rad51c-double-mutant cis mouse-model, which similarly develops SGC, while the characteristic Trp53-associated tumor spectrum occurs with significantly lower frequency. Therefore, we propose that co-occurent pathogenic variants in RAD51C and TP53 may predispose to SGC, reminiscent of Muir-Torre syndrome. Further, this report supports the diversity of clinical presentations associated with germline TP53 alterations, and thus, the proposed expansion of LFS to heritable TP53-related cancer syndrome.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome with exceptionally high lifetime cancer risks, caused primarily by germline pathogenic variants in TP53. Sarcomas, pre-menopausal breast cancer, brain tumors and adrenocortical carcinomas are the ‘core’ LFS cancers among a multitude of other cancers that can occur. Individuals with LFS are also at risk of developing multiple primary cancers over their lifetime. Clinical criteria have been established to denote LFS and ‘Li-Fraumeni like’ (LFL) families to facilitate genetic testing for TP53. De novo pathogenic germline variants in TP53 are estimated to cause between 7-25% of LFS. Gonadal mosaicism is an alternate explanation for presumed de novo variants and is yet to be described in LFS. We present a proband who developed WHO grade II astrocytoma at age 18 years, who had a deceased brother with osteosarcoma diagnosed at age 13 years, and a healthy older sibling. The only other cancer history was leukemia at age 62 years in the paternal grandmother, who also had polycythemia vera. The family meets Eele’s criteria for LFL. The proband’s germline genetic testing revealed a heterozygous TP53 c.743G>A p.R248Q pathogenic variant. Subsequent clinical genetic testing of the parents failed to reveal the variant, and the proband was presumed to have a de novo variant. Given the characteristic LFS-associated cancers in the brothers, we investigated further and identified the same TP53 pathogenic variant in the brother’s osteosarcoma tissue and pathology-confirmed benign liver tissue. TP53 sequencing of the brother’s tumor did not show loss of heterozygosity. Parental relationships to the proband and brother were confirmed through STR-based identifiler profiling. Ultra-deep sequencing (>50,000x) of DNA derived from the parents’ blood, saliva and father’s benign colon polyp did not identify the variant, thus ruling out somatic mosaicism in the parents. We were unable to test gonadal tissues from the parents. In the setting of two siblings with the same pathogenic variant in TP53 which is absent in both parents, this family presents a case of assumed gonadal mosaicism resulting from a post-zygotic event. The possibility of gonadal mosaicism presents complexity in genetic counselling of families with inherited disorders, and a conundrum in syndromes such as TP53-associated LFS where the presumed de novo rate is high and cancer risks are significantly elevated. The presented family suggests that further investigation of individuals with presumed de novo variation, especially in the setting of suspicious family cancer history, is required to accurately identify family members at-risk. Citation Format: Payal P. Khincha, Kristine Jones, Kedest Teshome, Belynda Hicks, Phuong L. Mai, Sharon A. Savage. Gonadal mosaicism in a family with TP53-associated Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4159.

Li-Fraumeni syndrome (LFS) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors at an early age. Approximately 70% of families with classic LFS have pathogenic variants in the tumor suppressor gene TP53 that disrupt protein function or stability. While more than 70% of pathogenic variants in TP53 are missense variants, the vast majority occur very infrequently, and thus their clinical significance is uncertain or conflicting. Here, we report an extremely rare TP53 missense variant, c.799C > T (p.Arg267Trp), identified in a 2-year-old Saudi proband diagnosed with choroid plexus carcinoma (CPC) and six of his first- and second-degree relatives. CPC is frequently found in families with LFS, and this is the first detailed report of a family with this variant. Intriguingly, the proband’s father is homozygous for TP53 c.799C > T and phenotypically normal at 39 years of age. While loss of TP53 heterozygosity is often observed in tumors from individuals with LFS, homozygous germline TP53 pathogenic variants are rare. Based on our analysis of this single family, we hypothesize that TP53 c.799C > T has low or variable penetrance for LFS, with predisposition to the development of CPC. The observations from this family have furthered our understanding of the phenotypic variability that may be caused by one variant of TP53, even in the same family, and suggest that other factors (genetic and/or environmental) may play a role in mechanism of disease manifestation in LFS.

Li-Fraumeni syndrome is a rare hereditary cancer predisposition syndrome associated with germline pathogenic variants in TP53 gene. The phenotype may vary from classical to variant forms, known as Li-Fraumeni-like phenotypes. We searched for pathogenic variants in TP53 in a 14 year-old female diagnosed with fibrolamellar hepatocellular carcinoma, a rare subtype of hepatocellular carcinoma. The proband is a heterozygote carrier of the TP53 c.467G>A (p.Arg156His) in exon 5, and her mother is an asymptomatic carrier. Analysis of tumor DNA disclosed an additional somatic mutation in TP53, c.461G>A; p.Gly154Asp. The TP53 germline and somatic pathogenic variants may have acted as possible driver mutations, resulting in genomic instability and tumor development. The fibrolamellar subtype of hepatocellular carcinoma may be part of the broad spectrum of tumors associated with Li-Fraumeni phenotype.

Disclosure: M.C. Fragoso: None. M. Sousa: None. M. Lacerda: None. M. Buchpiguel: None. M. Almeida: None. A. Latronico: None. B. Mendonça: None. D. Di Matteo: None. W. Lins: None. M. Jatene: None.Introduction: Li-Fraumeni Syndrome (LFS) is an autosomal dominant disorder caused by pathogenic variants (PV) in TP53, encoding a transcription factor critical for tumor suppression. Around 20% of LFS families carry one of six hotspot PVs (p.R175H, p.G245S, p.R248Q, p.R248W, p.R273H, p.R282W). TP53 variants influence disease penetrance, cancer predisposition, and secondary malignancy risk. Common tumors include adrenocortical carcinoma, soft tissue sarcomas, and bone tumors. The clinical and genetic aspects of this syndrome predispose individuals to develop multiple types of cancer at an early age. Given the severity and associated risks, a panel of experts recommends that all individuals with a confirmed clinical or molecular diagnosis undergo strict surveillance. Early screening using the Toronto Protocol is essential for detecting and intervening in malignancies at initial stages. To illustrate the clinical impact of PV in TP53 and surveillance importance, we report a pediatric case. Case Report: A 5-year-old boy with a significant family history of cancer in close relatives before the age of 45 was diagnosed with LFS. Genetic analysis revealed c.818G>A (p.Arg273H), a heterozygous variant in exon 8. The child had no gestational or perinatal complications. To date, no signs or symptoms of hormonal hyperfunction have been observed. Systematic screening for syndrome-associated malignancies was initiated using imaging studies, including annual Magnetic Resonance Imaging (MRI) of the chest, abdomen, pelvis, and brain. In February 2023, a chest MRI revealed a 2.5 cm nodule on the right side. PET-FDG imaging identified a nodular lesion with increased uptake, with a metabolic size of 6.7 × 4.6 × 4.2 cm, to the right of the midline (SUVmax: 6,8). A thymus biopsy via radiointervention confirmed a type B1 thymoma, leading to an initial decision for surveillance. In July, a follow-up MRI showed a heterogeneous solid mass with cystic areas and no contrast enhancement, measuring 5.5 × 4.5 × 3.7 cm in the anterior mediastinum, paracardiac on the right. This mass showed a significant increase in size within just five months and was not detected in a previous examination in 2021, surgical excision was performed. Histopathological analysis confirmed thymic carcinoma. Conclusion: LFS plays a crucial role in the pathogenesis of pediatric cancers, with PV in TP53 being associated with an increased predisposition to aggressive tumors with a poorer prognosis. Although the relationship between thymic tumors and pathogenic TP53 changes is rare, particularly in pediatric populations, surgical resection is a fundamental therapeutic approach for controlling neoplasms linked to the syndrome. This case highlights the importance of genetic and imaging screening in timely detection and management of malignancies in LFS patients.Presentation: Sunday, July 13, 2025

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder characterized by an extreme lifetime risk of multiple and early-onset tumors, driven by inherited pathogenic variants in the TP53 gene. While somatic mutations in TP53 are among the most frequent genetic alterations in cancer, germline mutations remain rare. Although LFS has long been recognized as a prototypical cancer predisposition syndrome, recent advances have significantly reshaped its diagnostic criteria and deepened our understanding of its associated cancer risks. The review illustrates the evolving diagnostic landscape of LFS and the updated indication criteria for germline TP53 testing, which have broadened the definition of the syndrome into the more inclusive entity of heritable TP53-related cancer predisposition syndrome (hTP53rc). The adoption of NGS has streamlined molecular diagnostics in hereditary cancer syndromes. Germline analysis of TP53 has become standard practice in hereditary cancer predisposition testing, even if a proband does not exhibit a LFS phenotype. However, the accurate identification of germline pathogenic TP53 variants remains challenging, particularly due to confounding factors, such as mosaicism or clonal hematopoiesis of indeterminate potential. Confirmatory testing using an independent tissue sample, along with estimation of allelic fraction is necessary to distinguish true germline variants. Another major hurdle is the assessment of the pathogenicity of rare germline TP53 variants, which requires a thorough genotype-phenotype correlation analyses. Recently, gene-specific American College of Medical Genetics and Genomics / Association for Molecular Pathology criteria have been introduced to support the classification of germline TP53 variants. Importantly, only carriers of a clearly established germline pathogenic variant should be considered for inclusion in an intensive clinical surveillance and prevention program. The present work underscores a paradigm shift in the understanding of one of the most significant cancer predisposition syndromes and aims to stimulate further discussion on the organization of care for high-risk carriers of pathogenic TP53 variants in the Czech Republic.

Pathogenic germline variants in TP53 predispose carriers to the multi-cancer Li-Fraumeni syndrome (LFS). Widespread multigene panel testing is identifying TP53 pathogenic variants in breast cancer patients outside the strict clinical criteria recommended for LFS testing. We aimed to assess frequency and clinical implications of TP53 pathogenic variants in breast cancer cohorts ascertained outside LFS. Classification of TP53 germline variants reported in 59 breast cancer studies, and publicly available population control sets was reviewed and identified evidence for misclassification of variants. TP53 pathogenic variant frequency was determined for: breast cancer studies grouped by ascertainment characteristics; breast cancer cohorts undergoing panel testing; and population controls. Early age of breast cancer onset, regardless of family history or BRCA1/BRCA2 previous testing, had the highest pick-up rate for TP53 carriers. Patients at risk of hereditary breast cancer unselected for features of LFS carried TP53 pathogenic variants at a frequency comparable to that of other non-BRCA1/2 breast cancer predisposing genes, and ∼threefold more than reported in population controls. These results have implications for the implementation of TP53 testing in broader clinical settings, and suggest urgent need to investigate cancer risks associated with TP53 pathogenic variants in individuals outside the LFS spectrum.

Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (version r2.0.2, n=138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 database. Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555-5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400-865 individuals, mainly due to the inclusion of the controvertible p.N235S, p.V31I, and p.R290H variants. This study shows a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants even with the most conservative estimates. However, these estimates may not necessarily reflect the prevalence of the classical LFS phenotype, which is based upon family history of cancer. Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance, and LFS-associated phenotype.

Introduction: Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome, primarily caused by germline pathogenic variants (PV) in the tumor suppressor gene TP53. Women with these PVs have an 85% lifetime risk of developing breast cancer (BC) and early onset BC, with a 50% risk by age 30. NCCN guidelines recommend risk-reducing mastectomy (RRM) to manage BC risk in women with LFS. However, rate of uptake of RRM, either bilateral (B-RRM) or contralateral (C-RRM), in LFS is unknown. Methods: 205 women (≥15 years of age) with a confirmed TP53 PV enrolled in NCI's LFS study (NCT01443468) and reported lifetime BCs and mastectomies through Oct. 2019. Validated pathology reports were obtained in 86% of BCs and 74% of mastectomies. Women in the screening arm of the study were evaluated annually (clinic cohort). Remaining women completed questionnaires and provided data only (field cohort). Results: The rate of any RRM was 40%, n=82 (Table 1). Median age at C-RRM and B-RRM was 33 (range [r]=17-65) and 37 (r= 24-52) years. Most women completed C-RRM within 1 year of BC diagnosis (77.8%, r=0-23 years) and genetic testing (69.2%, r=0-15 years), respectively. Women who chose B-RRM (mean age=43.7, SD=16.4) were older than those with no RRM (mean age=36.3, SD=8.7), t =-2.35 (31.63), p=0.025. 41.2% of women completed B-RRM within 1 year of genetic testing. Rates of C-RRM (χ2=6.54 (1), p=.011) and B-RRM (χ2=5.97 (1), p=.015) were higher in the clinic compared to the field cohort. Rates of mastectomy among female TP53 mutation carriersFull sample (N=205)Unilateral Breast Cancer (N=105)No History of Breast Cancer (N=80)Clinic Cohort (N=81)Field Cohort (N=124)No Mastectomy38.0% (n=78)10.5% (n=11)83.8% (n=67)25.9% (n=21)46.0% (n=57)Treatment Mastectomy only22.0% (n=45)24.8% (n=26)N/A18.5% (n=15)24.2% (n=30)C-RRM31.7% (n=65)61.9% (n=65)N/A43.2% (n=35)24.2% (n=30)B-RRM8.3% (n=17)*2.9% (n=3)*16.3% (n=13)12.3% (n=10)5.6% (n=7)*3 women completed bilateral mastectomy with prophylactic intent several years after BC diagnosis. One woman completed bilateral mastectomy with prophylactic intent and bilateral BC was identified at the time of surgery. Conclusion: Rates of C-RRM are high in women with LFS, consistent with risk reducing guidelines. Rates of B-RRM in women with TP53 PVs remain low in comparison with BRCA1/2 mutation carriers (~30-44%). Lack of LFS-specific RRM research and lack of guidelines tailored to their unique needs may contribute to low uptake. Consistent with this hypothesis, rate of RRM was higher in the clinic cohort, suggesting that counseling from LFS specialists may increase uptake. More research is needed to design and disseminate RRM guidelines accounting for unique needs of LFS women. Citation Format: Atara Siegel, Renee C. Bremer, Payal Khincha, William Klein, Sharon A. Savage, Jennifer T. Loud. Rates of risk reducing mastectomy in women with Li-Fraumeni Syndrome [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5801.

Li–Fraumeni syndrome (LFS) is an inherited autosomal dominant disease characterized by a predisposition to many cancers. Germline pathogenic variants in TP53 are primarily responsible for LFS. By performing a targeted sequencing panel in a proband with liver carcinoma having a deceased son affected by osteosarcoma, we found the novel heterozygous frameshift variant c.645del (p.Ser215Argfs*32) in the TP53 gene. This variant co-segregated with typical LFS cancers in the family pedigree, consistent with the pathogenicity of this novel and previously undescribed TP53 variant.

Background: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant inherited cancer syndrome; clinical diagnosis of it is mainly based on familial and personal history of cancer. Currently, most clinicians are lack of knowledge and experience of this rare disease, resulting in a difficulty to identify it. Consider that this is a rare tumor-type syndrome and 60-80% of the patients have germline variants of TP53, herein, we analyzed germline pathogenic/likely pathogenic (P/LP) TP53 variants in a Chinese tumor cohort with unknown familial history, and successfully established an analysis process to better screen for LFS patients. Methods: We retrospectively analyzed the germline TP53 mutations of a total of 19,226 Chinese tumor patients with unknown familial history. The screening process of LFS patients was as follows: 1) Germline P/LP TP53 variants must satisfy P/LP in any of the three databases: UMD_TP53, ClinVar or HGMD. It also must be defined as “non-functional” mutations in IARC database which includes all TP53 germline mutations of clinically determined LFS patients; 2) Follow up the familial and personal histories of patients with germline P/LP TP53 variants. Results: After screening, 26 germline P/LP TP53 variants were obtained, which involved 54 patients, mainly in brain cancer (34 pts) and lung cancer (9 pts). The median age of these 34 brain cancer patients was younger than that of 5,845 brain cancer patients in the cohort (28 vs. 44 year-old). Yet no such phenomenon was observed in lung cancer. It is necessary for young brain cancer patients to detect germline TP53 mutations. We then analyzed the relationship between germline P/LP TP53 variants and LFS in the 54 patients. According to the Chompret criterion of LFS, two patients who respectively had adrenocortical carcinoma (R175H of TP53) and choroid plexus carcinoma (G245S) were both LFS patients regardless of whether they had a familial history. We finally obtained follow-up information of 17 patients. Among them, four brain cancer patients (R248Q/R158H/C238Y/M237I), one lung cancer patient (R175H) and one leiomyosarcoma patient (R213Q) had family members who had cancers before 46-year-old. Another brain cancer patient (G245S; 1/17) had more than one cancer before 46-years-old. Hence, these seven patients (7/17; 41.18%) were also defined as LFS patients by the Chompret criterion. In total, 9 patients had LFS. It shows a high positive detection rate in our cohort by our analysis process. Conclusions: We have established an analysis process based on germline P/LP TP53 variants, which can efficiently screen for LFS patients in clinic. Citation Format: Changyu Lu, Yu Fang, Fachen Zhou, Yuntong Liu, Hongchuan Niu, Kai Li, Tonghui Ma, Xiaoyan Zhang. Enrichment and screening of LFS patients by analyzing TP53 germline mutations of a Chinese cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 810.

Background:Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome associated with early age of onset and high lifetime risk of multiple malignancies. Pathogenic germline variants (PV) in TP53 cause ~70% of LFS. Our prior work using the Colored Eco-Genetic Relationship Map found that non-bloodline relationships (i.e., spouses or friends) provide significant support to individuals with LFS. The Bull's Eye (BE) is a simplified tool to capture the types and degree of support obtained from family members (FMs) and social networks. We report on pilot BE data from a large family with LFS. Methods: Guided by investigators, patients in NCI's longitudinal LFS cohort (ClinicalTrials.gov Identifier: NCT01443468) independently completed a BE during annual screening visits. This tool is comprised of four concentric circles, with the innermost signifying the patient and outer circles indicating increasingly limited support. Individuals identified on the BE were coded 0-8 to indicate proximity to the patient. Independent sample T-tests and a linear regression were used in analyses. Results: Fifteen FMs from 1 family participated, including 10 TP53 PV carriers, 4 spouses of carriers, and 1 untested FM. The 7 males and 8 females ranged from 14-56 years of age (Median = 29). No significant association was detected between gender and number of FMs reported. Women cited significantly more non-family members (NFMs) than did men (Mean [M] = 7.6 ± 4.1 and M = 3.1 ± 2.4, respectively; p = 0.02.). There was no significant association between participant PV status and number of FMs reported. Spouses cited significantly more NFMs than did TP53 PV carriers (M = 8.8 ± 2.5 and M = 4.0 ± 3.9, respectively; p = 0.04). We assessed the relationship between gender, PV status and number of NFMs identified. The overall model explained a significant amount of variance in number of NFMs reported (r2 = 0.46; p = 0.02), driven by female gender and spouses of PV carriers. Gender independently contributed significantly to the model (B = 3.88, p = 0.04) while PV status did not (B = 0.03, p = 0.13). Conclusion: The BE is a practical and efficient tool to evaluate support in this LFS kindred. Women in this family had larger social networks than men, particularly through NFM relationships. In contrast, men primarily received support from close kin (i.e., siblings). Notably, spouses reported larger NFM networks than did TP53 PV carriers, seeking emotional support from friends, coworkers, and church groups. It is possible that PV carriers may be more comfortable sharing their LFS-related life experiences with FMs. Additional research with larger samples will clarify relative impacts of gender and PV status. Future analyses will evaluate other NCI LFS families to determine if: 1) patterns hold, 2) differences exist based on cancer history, 3) generational differences exist, and 4) bi-directional responses differ between FMs. Citation Format: Radhika Srivastava, Renee Bremer, Jessica Bayer, Allison Werner-Lin, Megan Frone, Sharon Savage, Payal P. Khincha, Jennifer Loud. The Bull's Eye: A research tool to characterize family, friends and social networks within a Li-Fraumeni Syndrome family [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2036.

Background: The lifetime risk of cancer in individuals with Li Fraumeni syndrome (LFS) is more than 70% for men and more than 90% for women. Breast cancer (BC) is the most common type of cancer in premenopause women with pathogenic allelic TP53 variants (PVs). However, little is known about the BC response to systemic therapy and the prognosis in these patients. We aim to analyze the phenotype and the outcomes of patients with LFS and BC. Methods: We evaluated a cohort of patients with PVs or likely PVs of TP53 with BC diagnosis treated from December 1999 to June 2020 from a single tertiary cancer center. Our primary objective is to evaluate the outcomes of these patients. Secondary objective is to describe the BC phenotype, characterizing the clinical and the pathological features.Results: Among 56 patients with PVs or likely PVs of TP53, 25 were diagnosed with BC. Median age at BC diagnosis was 39.2 years (range 23.4-57.4 years). The majority (N= 18, 72%) harbored a germline PV TP53 p.R337H in heterozygosity status. The most common histology type was an invasive carcinoma of no special subtype, 73% were hormone receptor-positive, and 32% were HER2-positive. Three (12%) patients were metastatic at diagnosis. Seven (28%) of the patients with localized disease at diagnosis received neoadjuvant chemotherapy, and other 7 (28%) received adjuvant chemotherapy. Among patients treated with neoadjuvant chemotherapy, 5 (71%) had a tumor response, while 2 (29%) presented with disease progression. No pathologic complete response was achieved. After a median follow-up of 52.6 months, no deaths secondary to breast cancer occurred. Only 1 patient died due to another neoplasm (jaw osteosarcoma), and 3 (12%) patients developed radiotherapy-induced malignancies in the irradiated field. Conclusions: BC in patients with LFS is mainly the invasive carcinoma of no special subtype, enriched in hormone receptor and HER2 positivity. Although response to neoadjuvant chemotherapy is high, no pathologic complete response occurred in this cohort. Favorable outcomes were observed, with a high BC specific survival. Secondary malignancies remain a major concern. Larger cohorts should test whether new genes act as modifiers of p53 function and breast cancer susceptibility. Citation Format: Vanessa Petry. Phenotype and prognosis of patients with breast cancer and pathogenic TP53 variants [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-34.