Li-Fraumeni Research Articles

What's the Cost: Financial Toxicity and Screening Fatigue in Li-Fraumeni Syndrome.

Patients with Li-Fraumeni syndrome are recommended to follow a comprehensive surveillance protocol, but the demanding nature may limit adherence. We sought to identify barriers to adherence, and to determine whether screening fatigue and financial hardship are contributors. A 39-item online survey was developed and distributed to patients presenting to a LFS clinic between 2017 and 2022. Of the 39 patients eligible, 20 responded to the survey (51%). Of respondents, 75% reported they do not skip surveillance tests, though this was not consistent when asked about specific tests, with only 65% and 40% up to date with colonoscopy and esophagogastroduodenoscopy, respectively. 100% of those diagnosed within the last 5 years said they never skip tests, whereas only 50% of those diagnosed over 5 years ago reported the same (p=0.01). Barriers to adherence were reported by 85% and most commonly included finances (40%), time (25%), and difficulty scheduling (25%). Only 21% felt no financial stress. 63% worried at least somewhat about their future financial situation because of LFS. Even with insurance, 65% felt their share of healthcare costs was too high. Adherence to rigorous cancer surveillance is imperfect and decreases over time among patients with LFS. While number of tests was not a commonly cited barrier, time and difficulty scheduling were common and may contribute to screening fatigue. The degree of financial stress in the affluent population studied should raise even greater concern about financial strain in the LFS population in general.

NIMG-31. CASE REPORT: DIAGNOSIS OF AN INFILTRATIVE GLIOMA IN A LI-FRAUMENI SYNDROME PATIENT OBSCURED BY LESION RESPONSIVENESS TO NSCLC TREATMENT

Abstract Li-Fraumeni syndrome is a rare, autosomal dominant disorder linked to germline mutations of the TP53 suppressor gene. Patients with this syndrome are predisposed to various malignancies and a variety of brain tumors to include choroid plexus carcinoma, medulloblastoma, and glioma. We present a 46-year-old woman with a history of Li-Fraumeni syndrome which manifested with multiple systemic malignancies including breast cancer, ovarian teratoma, and leiomyosarcoma. The patient had been undergoing MRI brain surveillance since 2018, which was initially notable for a right cerebellar midline focus of enhancement associated with slowly evolving right middle cerebellar peduncle FLAIR signal, with no detectable neurologic symptoms. She underwent systemic therapy for non-small cell lung cancer (NSCLC) with pemetrexed/cisplatin. Her next MRI brain in August 2023 showed resolution of the cerebellar enhancement with small residual FLAIR signal. In April 2024, the patient presented with new neurologic symptoms to include ataxia, dizziness, difficulty swallowing, and memory loss. Repeat MRI brain revealed new infiltrative FLAIR signal throughout the right temporal lobe extending from the posterior fossa, contiguous with the previously seen cerebellar findings and consistent with infiltrative glioma. Due to fragmented records and care in multiple systems, her updated MRI initially created a diagnostic challenge with a radiographic interpretation of likely encephalitis. This is a unique case documenting a middle-aged female with Li-Fraumeni syndrome, followed for multiple cancers, presenting with new neurologic symptoms and progressive infiltrative FLAIR changes spanning from the cerebellum into the right temporal lobe. These findings highlight the natural history of a TP53 deficient tumor that ostensibly responded to a cisplatin-based regimen given for a different indication, thereby delaying time to symptom onset and need for biopsy. Surveillance of low grade lesions in patients with underlying tumor predisposition syndromes must be interpreted in context of systemic disease burden and concurrent treatments for other neoplasms.

EPCO-56. INHERITED PREDISPOSITION TO ADULT GLIOMAS: OVERVIEW OF THE CURRENT CLINICAL PRACTICE AND FUTURE RECOMMENDATIONS

Abstract Gliomas are the most common adult primary malignant brain tumor and occur in ages 45-65 years old. While most gliomas are sporadic in nature, a small portion is related to cancer predisposition syndromes (CPS), such as Li Fraumeni or Lynch syndromes. Given that 5–10% of patients will have a family history of glioma, there is currently an effort in identifying germline variants associated with gliomas. Additionally, with the advent of somatic tumor testing, it is possible to pick up suspected germline mutations in genes that cause CPS. Our experience includes a 32-year-old patient diagnosed with astrocytoma IDH mutant, Grade 2 who was found to have a BRAC1 mutation on somatic brain tumor testing. 10 years later, the patient was found with metastatic ovarian cancer and a germline BRAC1 mutation. Early identification of CPS can lead to early detection or prevention of malignancies in affected patients and relatives. However, gliomas are rarely the primary or presenting tumor of CPS, and guidance of CPS screening for these individuals is still lacking. Due to the increasing interest and importance of CPS testing in patients with glioma we have developed a collaborative protocol between our neuro-oncologists and genetic counselors aso that patients have access to germline testing. We propose that all patients with glioma at age of 50 or under, patients with strong family history of cancer including gliomas, and patients with suspected germline mutations based on tumoral somatic mutational profile should be referred to the genetic counselors. Our preliminary findings include 8 patients who completed germline genetic testing. Of these, one patient tested positive for a BRCA1 pathogenic variant. We are planning to continue to collect this data to better inform clinical practice.

Case report: Efficacy of later-line fam-trastuzumab deruxtecan in a patient with triple-positive breast cancer with brain metastases

Fam-trastuzumab deruxtecan (T-DXd) has demonstrated substantial antitumor activity and durable responses in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report here the treatment outcomes of T-DXd in a patient with HER2+ breast cancer with brain metastases that repeatedly recurred and progressed after two lines of salvage therapy. In 2016, a 23-year-old G0P0 female with risk factors including menarche at age 9 years, Li-Fraumeni syndrome, and a strong family history of cancer was diagnosed with bilateral, triple-positive breast cancer. She received chemotherapy, HER2-targeted therapies, total mastectomy, and locoregional radiotherapy, but a brain metastasis in the left parieto-occipital lobe was detected in 2020. After receiving capecitabine, lapatinib, gonadotropin-releasing hormone (GnRH) agonist, and tamoxifen, multiple new lesions appeared in the brain after 14 months. The patient then received capecitabine, neratinib, GnRH agonist, and letrozole; however, her brain metastases still progressed after 7 months. In 2022, she started T-DXd treatment. Good response to treatment was observed 4 months later, including a continuous decrease in the cancer antigen 15-3 level, a reduction in the size of the major brain tumor, and the absence of new lesions. Now aged 30, the patient is continuing to receive T-DXd treatment to prevent recurrence. We conclude that T-DXd was effective for the treatment of brain metastases in this young patient with triple-positive metastatic breast cancer who had multiple risk factors and had received several anti-HER2 therapies prior to T-DXd.

Clustering of TP53 variants into functional classes correlates with cancer risk and identifies different phenotypes of Li-Fraumeni syndrome

Clustering of TP53 variants into functional classes correlates with cancer risk and identifies different phenotypes of Li-Fraumeni syndrome

Communicatively constructing resilience: Exploring family resilience in the experience of hereditary cancer

AbstractObjectiveThe goal was to explore how families communicate to cope with hereditary cancer conditions and identify factors that may enhance resilience and recommended decision‐making.BackgroundFamilies with Hereditary Breast and Ovarian Cancer syndrome (HBOC), Lynch syndrome (LS), and Li‐Fraumeni syndrome (LFS) have an increased lifetime risk of developing cancer. We use the communication theory of resilience (CTR) to examine how families engage in resilience and make health decisions about hereditary cancer risks over time.MethodWe conducted 42 dyadic interviews with families with HBOC, LS, and LFS. Themes emerged through qualitative analysis for each of the resilience processes outlined by CTR (crafting normalcy, communication networks, identity anchors, alternative logics, and foregrounding productive action while legitimizing negative feelings), illustrating how family members manage stressors associated with hereditary cancer over time.ResultsParticipants described enacting each of the five CTR processes to manage the acute and chronic stressors associated with hereditary cancer. We described themes that emerged within each of the five resilience processes.ConclusionFindings demonstrate the ways in which families managing hereditary cancer risks enact resilience processes and how these processes may have a complex relationship to coping and medical decision‐making.ImplicationsFindings demonstrate areas for intervention to support familial resilience.

Chronic obesity does not alter cancer survival in Tp53 R270H/+ mice.

Obesity is a complex chronic disease characterized by excessive adiposity and associations with numerous co-morbidities, including cancer. Despite extensive research, we have limited understanding of the mechanisms coupling obesity to cancer risk, and, of the contexts in which obesity does or does not exacerbate disease. Here, we show that chronic high-fat diet (HFD)-induced obesity has no significant effect on the Tp53 R270H/+ mouse, a model of human Li-Fraumeni multi-cancer syndrome. Surprisingly, despite inducing rapid and highly penetrant obesity and long-term differences in metabolic and adiposity, greater than one year of HFD had no significant effect on survival or tumor burden. These findings were replicated in two separate cohorts and thus provide important negative data for the field. Given strong publication bias against negative data in the literature, this large cohort study represents a clear case where chronic diet-induced obesity does not accelerate or aggravate cancer outcomes. The data thus carry high impact for researchers, funders, and policymakers alike.

Li-Fraumeni Syndrome in Breast Cancer: Development of Theranostic Probes on Variation of P53

Li-Fraumeni Syndrome (LFS) is a hereditary condition characterized by a high predisposition to various cancers due to mutations in the p53 protein. Effectively targeting and treating this syndrome requires early detection and personalized treatment according to one’s specific nucleotide sequence. With the use of various forms of theranostics, LFS can be treated, increasing life expectancy; however, there is no absolute cure that could immediately end this syndrome. This paper delves into three different theranostic approaches: Gendicine (rAd-p53), Phesgo, and gold nanoshell poly(D, L-lactic-co-glycolic acid) nanoparticles (PLGA NPs). While each approach has limitations, PLGA nanoparticles exhibit advantages that outweigh their drawbacks, making it an attractive solution. This proposal will describe improvements to PLGA nanoparticles, which are a promising area of research for the development of new LFS treatments.

The molecular genetics of adrenal cushing.

Adrenal Cushing represents 20% of cases of endogenous hypercorticism. Unilateral cortisol-producing adenoma (CPA), a benign tumor, and adrenocortical carcinoma (ACC), a malignant tumor, are more frequent than bilateral adrenal nodular diseases (primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary pigmented nodular adrenal disease (PPNAD)).In cortisol-producing adrenal tumors, the signaling pathways mainly altered are the protein kinase A and Wnt/β-catenin pathways. Studying components of these pathways and exploring syndromic and familial cases of these tumors has historically enabled identification of many of the predisposing genes. More recently, pangenomic sequencing revealed alterations in sporadic tumors.In ACC, mainly due to TP53 alterations causing Li-Fraumeni syndrome, germline predisposition is frequent in children, while it is rare in adults. Pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2, which cause Lynch syndrome or alterations of IGF2 and CDKN1C (11p15 locus) in Beckwith-Wiedemann syndrome, can also cause ACC. Rarely, ACC is described in other hereditary tumor syndromes due to germline pathogenic variants in MEN1 or APC and, in very rare cases, NF1, SDH, PRKAR1A, or BRCA2. Concerning ACC somatic alterations, TP53 and genetic or epigenetic alterations at the 11p15 locus are also frequently described, as well as CTNNB1 and ZNRF3 pathogenic variants.CPAs mainly harbor somatic pathogenic variants in PRKACA and CTNNB1 and, less frequently, PRKAR1A, PRKACB, or GNAS1 pathogenic variants. Isolated PBMAH is due to ARMC5 inactivating pathogenic variants in 20 to 25% of cases and to KDM1A pathogenic variants in food-dependent Cushing. Syndromic PBMAH may be due to germline pathogenic variants in MEN1, APC, or FH, causing type 1 multiple endocrine neoplasia, familial adenomatous polyposis, or hereditary leiomyomatosis-kidney cancer syndrome, respectively. PRKAR1A germline pathogenic variants are the main alteration causing PPNAD (isolated or part of Carney complex).

Li-Fraumeni-associated osteosarcomas: The French experience.

Describe clinical characteristics and outcome of Li-Fraumeni syndrome (LFS)-associated osteosarcomas. TP53 germline pathogenic/likely pathogenic variant carriers diagnosed with osteosarcoma in France between 1980 and 2019 were identified via the French Li-Fraumeni database at Rouen University Hospital. Sixty-five osteosarcomas in 52 patients with available clinical and histological data were included. The main clinical characteristics were compared with data from National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) for patients of the same age group. Median age at first osteosarcoma diagnosis was 13.7years (range: 5.9-36.7). Compared to unselected osteosarcomas, LFS-associated osteosarcomas occurred more frequently in patients less than 10years of age (23% vs. 9%), and when compared with osteosarcomas in patients less than 25years were characterized by an excess of axial (16% vs. 10%) and jaw sites (15% vs. 3%) and histology with predominant chondroblastic component and periosteal subtypes (17% vs. 1%). Metastases incidence (25%) was as expected in osteosarcomas. After the first osteosarcoma treatment, the rate of good histologic response (62%) and the 5-year progression-free survival (55%, 95% confidence interval [CI]: 42.6-71.1) were as expected in unselected series of osteosarcomas, whereas the 5-year event-free survival was 36.5% [95% CI: 25.3-52.7] due to the high incidence of second malignancies reaching a 10-year cumulative risk of 43.4% [95% CI: 28.5-57.5]. In osteosarcoma, young age at diagnosis, axial and jaw sites, histology with periosteal or chondroblastic subtype, and synchronous multifocal tumors should prompt suspicion of a germline TP53 mutation. Standard treatments are effective, but multiple malignancies impair prognosis. Early recognition of these patients is crucial for tailored therapy and follow-up.

8657 Thymic Neoplasia In A Pediatric Patient With LI-Fraumeni Syndrome: A Case Report

Abstract Disclosure: M.A. Souza: None. W.M. Lins: None. D. di Matteo: None. J.L. Marcayata: None. A. Kuhn: None. H. Charcar: None. F. Ledesma: None. M.Q. Almeida: None. F. Jatene: None. B.B. Mendonca: None. M.C. Fragoso: None. Introduction: Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant hereditary cancer predisposition syndrome primarily caused by pathogenic variants in the TP53 tumor suppressor gene. The individuals affected are typically young, with a cancer risk of approximately 90% in lifetime. Parents choosing to test their young children face the dilemma of when to disclose their own or the child's status and when to initiate cancer screening if LFS is detected. This process presents psychosocial challenges for both parents and affected children. Both providers and patients question whether the surveillance benefits outweigh the psychological burden of knowing LFS status and screening-related concerns, creating ambivalence toward genetic testing decisions.Case Report: We describe a 6-year-old male with Li-Fraumeni syndrome carrier of the germline pathogenic variant TP53 c.818G>A (p.R273H) in heterozygous (exon 8).In the family history, there are three relatives with advanced tumor cases, with the grandmother already deceased, the mother undergoing chemotherapy treatment, and the cousin being cancer-free for 10 years.The patient in question had no gestational complications. No consanguinity between parents. No signs or symptoms of hormonal hyperfunction. As proposed in the literature, Li-Fraumeni Syndrome patients should undergo frequent screening for early tumor detection, the patient began screening according to the Toronto protocol in 2018, at the age of 1 year and 7 months, through cranial and thoracic MRI, abdominal ultrasound, and annual hormonal assays. In the thoracic MRI conducted in February 2023, an enlarged and heterogeneously signaling thymus was identified, with a nodular formation (absent in previous exams), measuring about 2.5 cm. Facing suspicion of a thymoma, thymic carcinoma, or lymphoma, a biopsy guided by tomography in March 2023 was done. Histological examination was compatible with primary thymic neoplasia. During follow-up, a significant growth of the mass to 9 cm was observed. The patient underwent surgical treatment in August 2023 with resection of the mediastinal mass, and the anatomopathological examination revealed undifferentiated thymic carcinoma, followed in conjunction with the pediatric oncology team. The dilemma is about the adjuvant radiotherapy since the possibility to acquire a new tumor radio-induced such as sarcoma. We proposed to follow with MRI imaging each 3 months and if minimal signal of recurrence he will underwent radiotherapy. Conclusion: In addition to the intrinsic rarity of Li-Fraumeni Syndrome, this case draws attention to the possibility of a thymic tumor, an extremely rare neoplasm in syndrome carriers. In the literature, only scattered case reports show this association. Furthermore, this case reinforces the importance of systematic screening for investigating possible neoplasms in this susceptible population. Presentation: 6/1/2024

8657 Thymic Neoplasia in a Pediatric Patient With LI-Fraumeni Syndrome: A Case Report

Abstract Disclosure: M.A. Souza: None. W.M. Lins: None. D. di Matteo: None. J.L. Marcayata: None. A. Kuhn: None. H. Charcar: None. F. Ledesma: None. M.Q. Almeida: None. F. Jatene: None. B.B. Mendonca: None. M.C. Fragoso: None. Introduction: Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant hereditary cancer predisposition syndrome primarily caused by pathogenic variants in the TP53 tumor suppressor gene. The individuals affected are typically young, with a cancer risk of approximately 90% in lifetime. Parents choosing to test their young children face the dilemma of when to disclose their own or the child's status and when to initiate cancer screening if LFS is detected. This process presents psychosocial challenges for both parents and affected children. Both providers and patients question whether the surveillance benefits outweigh the psychological burden of knowing LFS status and screening-related concerns, creating ambivalence toward genetic testing decisions.Case Report: We describe a 6-year-old male with Li-Fraumeni syndrome carrier of the germline pathogenic variant TP53 c.818G>A (p.R273H) in heterozygous (exon 8).In the family history, there are three relatives with advanced tumor cases, with the grandmother already deceased, the mother undergoing chemotherapy treatment, and the cousin being cancer-free for 10 years.The patient in question had no gestational complications. No consanguinity between parents. No signs or symptoms of hormonal hyperfunction. As proposed in the literature, Li-Fraumeni Syndrome patients should undergo frequent screening for early tumor detection, the patient began screening according to the Toronto protocol in 2018, at the age of 1 year and 7 months, through cranial and thoracic MRI, abdominal ultrasound, and annual hormonal assays. In the thoracic MRI conducted in February 2023, an enlarged and heterogeneously signaling thymus was identified, with a nodular formation (absent in previous exams), measuring about 2.5 cm. Facing suspicion of a thymoma, thymic carcinoma, or lymphoma, a biopsy guided by tomography in March 2023 was done. Histological examination was compatible with primary thymic neoplasia. During follow-up, a significant growth of the mass to 9 cm was observed. The patient underwent surgical treatment in August 2023 with resection of the mediastinal mass, and the anatomopathological examination revealed undifferentiated thymic carcinoma, followed in conjunction with the pediatric oncology team. The dilemma is about the adjuvant radiotherapy since the possibility to acquire a new tumor radio-induced such as sarcoma. We proposed to follow with MRI imaging each 3 months and if minimal signal of recurrence he will underwent radiotherapy. Conclusion: In addition to the intrinsic rarity of Li-Fraumeni Syndrome, this case draws attention to the possibility of a thymic tumor, an extremely rare neoplasm in syndrome carriers. In the literature, only scattered case reports show this association. Furthermore, this case reinforces the importance of systematic screening for investigating possible neoplasms in this susceptible population. Presentation: 6/1/2024

8042 A Rare Case of Papillary Thyroid Carcinoma in a Patient with Li-Fraumeni Syndrome

Abstract Disclosure: K.M. Bakhtawar: None. G. Jaiswal: None. Li-Fraumeni syndrome (LFS) is an autosomal dominant syndrome with a high lifetime probability of cancer at an early age. The spectrum of cancers primarily includes osteosarcoma, soft tissue sarcoma, breast cancer, brain tumors, leukemia, and Adenoid cystic carcinoma. Prior studies have estimated the cumulative cancer risk to be about 50% by age 40 and as high as 90% by age 60. As screening for TP53 mutations has improved and more patients are identified, the LFS cancer spectrum has expanded to include thyroid cancer. However, the occurrence of thyroid cancer in LFS has not been extensively assessed in the literature. A recent study examined cancer patients carrying the Brazilian p.R337H TP53 mutation which demonstrated that out of 101 patients, 11 had thyroid cancer (10.9%). In our case, a 45-year-old female with a past medical history of Li-Fraumeni syndrome, Von Willebrand disease, Pulmonary embolism, HER-2 positive invasive ductal carcinoma of the left breast status post chemotherapy, and bilateral mastectomy presented for evaluation of papillary thyroid carcinoma (PTC). An enlarged thyroid was initially identified on physical exam by the PCP with a follow-up thyroid ultrasound showing bilateral nodules. The right upper pole 1.9 x 1.3 x 1.6 cm nodule was biopsied revealing PCT. Following neck ultrasound demonstrated mildly enlarged lymph nodes on the right side, level 2A 1.5 cm and level 3 1.6 cm. The patient subsequently underwent total thyroidectomy and lymph node dissection. The pathology report revealed a 1.4 cm PTC in the upper right pole, a 0.9 cm PCT in the isthmus, and a 0.8 cm PTC in the left midpole. 4/62 lymph nodes were positive with the largest deposit of 1 cm. All margins were negative for carcinoma with no angioinvasion or lymphatic invasion. She was staged as T1bN1bM0. We are awaiting post-operative Thyroglobulin level to assess the need for Radioactive iodine. BRAFV600E and P53 mutation was identified. The patient carries known heterozygous mutation p.R1755H in the TP53 gene with an estimated lifetime cancer risk of 93%. This particular mutation has not been associated with thyroid cancer in prior studies. Although thyroid cancer is an uncommon manifestation of LFS, this case begs the importance of further studies to explore this association which may then lead to early screening and treatment of thyroid cancer in individuals with founder TP53 mutations. Presentation: 6/1/2024

MO27-5 Concurrent leiomyosarcoma and diffuse astrocytoma in a Li-Fraumeni syndrome patient: a case report

MO27-5 Concurrent leiomyosarcoma and diffuse astrocytoma in a Li-Fraumeni syndrome patient: a case report

Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing

We describe the case report of an Osteosarcoma patient, with a Li-Fraumeni Syndrome, presenting with a pathological femoral fracture. The patient was treated with a multidisciplinary approach associating neoadjuvant and adjuvant chemotherapy with excisional surgery. The femoral reconstruction consisted of a ``Capasquelet'' reconstruction combining an induced membrane and a vascularized fibula allograft allowing a good functional result with an early weight-bearing. We managed to complete our histological analysis in this patient, in order to evaluate the tumor vascularization. Indeed, using the syngeneic osteosarcoma MOS-J mouse model, we highlighted previously that CD31+/\ensuremath{\alpha}-SMA+ vessels may be indicators of vasculature normalization and therefore may be used as specific markers of a good therapeutic response. Thus, we search for its interest in this specific case as preliminary work. The aim was to assess the feasibility and technical validity of the vascularization analysis of a human osteosarcoma tumor specimen. Therefore, we propose an immunohistochemistry methodology with multiplexed immunofluorescence to assess the vascularization as a promising marker in human osteosarcoma tissue.

Germline variant affecting p53β isoforms predisposes to familial cancer

Germline and somatic TP53 variants play a crucial role during tumorigenesis. However, genetic variations that solely affect the alternatively spliced p53 isoforms, p53β and p53γ, are not fully considered in the molecular diagnosis of Li-Fraumeni syndrome and cancer. In our search for additional cancer predisposing variants, we identify a heterozygous stop-lost variant affecting the p53β isoforms (p.*342Serext*17) in four families suspected of an autosomal dominant cancer syndrome with colorectal, breast and papillary thyroid cancers. The stop-lost variant leads to the 17 amino-acid extension of the p53β isoforms, which increases oligomerization to canonical p53α and dysregulates the expression of p53’s transcriptional targets. Our study reveals the capacity of p53β mutants to influence p53 signalling and contribute to the susceptibility of different cancer types. These findings underscore the significance of p53 isoforms and the necessity of comprehensive investigation into the entire TP53 gene in understanding cancer predisposition.

Update on Whole-Body MRI Surveillance for Pediatric Cancer Predisposition Syndromes.

Whole-body MRI (WBMRI) is an integral part of screening infants, children, and adolescents for presymptomatic neoplasms in certain cancer predisposition syndromes, which include Li-Fraumeni and constitutional mismatch repair deficiency syndromes, among others. The list of syndromes in which WBMRI adds value, as part of a comprehensive surveillance protocol, continues to evolve in response to new evidence, growing experience, and more widespread adoption. In July 2023, the AACR reconvened an international, multidisciplinary panel to revise and update recommendations stemming from the 2016 AACR Special Workshop on Childhood Cancer Predisposition. That initial meeting resulted in a series of publications in Clinical Cancer Research in 2017, including "Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI." This 2024 review of WBMRI in cancer predisposition syndrome updates the 2017 WBMRI publication, the revised recommendations derived from the 2023 AACR Childhood Cancer Predisposition Workshop based on available data, societal guidelines, and expert opinion. Different aspects of acquiring and interpreting WBMRI, including diagnostic accuracy, are discussed. The application of WBMRI in resource-poor environments, as well as integration of whole-body imaging techniques with emerging technologies, such as cell-free DNA ("liquid biopsies") and artificial intelligence/machine learning, is also considered.

Germline p.R181H variant in TP53 in a family exemplifying the genotype-phenotype correlations in Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline pathogenic/likely pathogenic variants in TP53. Genotype-phenotype correlations are progressively being characterized in LFS with certain TP53 variants associated with attenuated penetrance and phenotypes. We report on a family harboring a TP53 p.R181H variant presenting with a restricted cancer phenotype in adulthood. The proband was a female with breast cancer at the age of 71 years who had three first degree relatives also diagnosed with breast cancer after the age of 40 years (mother, two sisters). Of the nine individuals harboring the variant (6 genetically confirmed, 3 obligate heterozygous), six have not developed malignancies at this time (age range: 36-42). No childhood-onset cancers were reported in this family. A concomitant literature review identified 51 additional individuals harboring the p.R181H variant in TP53, presenting a tumor phenotype dominated by breast cancer. Rare occurrences of other adult-onset cancers (prostate, colorectal and thyroid) and only few childhood onset cancer were documented. These observations are consistent with functional analysis showing that p.R181H retains partial p53 function and suggesting possible reduced cancer penetrance, particularly in the pediatric setting.

A Case of Breast Cancer Patient with Li–Fraumeni Syndrome: Psychosocial Implications and Literature Review

Li–Fraumeni syndrome (LFS) is defined by the early emergence of tumors and is associated with mutations in the tumor suppression gene known as tumor protein 53 ( TP53). Information is scarce regarding the psychosocial challenges encountered by individuals with LFS and how it affects their treatment decisions. A 21-year-old woman developed multiple breast tumors over a period of nine years. Genetic testing identified a heterozygous missense substitution in exon 6 of the TP53 gene, specific variant chr17:7578190T>C c.659A>G (p.Tyr220Cys) listed in the dbSNP database. The report also highlights the psychosocial implications of the diagnosis at a young age and the patient’s reluctance to undergo the recommended bilateral mastectomy. The patient exhibited a significantly higher incidence of secondary tumors, underscoring the importance of comprehensive screening and timely diagnosis for managing LFS. This case highlights the challenges faced and the importance of emotional and psychological support after the diagnosis of hereditary syndromes, especially among young women.

Abstract IA004: Risk of therapy-related subsequent cancers in individuals with germline TP53 variants

Abstract Background. Based primarily on in vitro and animal studies, germline TP53 variants are considered to confer sensitivity to ionizing radiation-induced DNA damage, but data in humans are sparse. We sought to quantify risk of developing radiotherapy and chemotherapy-related subsequent neoplasms by pooling individual-level data from nine cohorts of individuals with confirmed pathogenic/likely pathogenic germline TP53 variants. Methods. 891 individuals were followed from six months after first cancer until diagnosis of a subsequent neoplasm, death or date of last follow-up. Radiotherapy and chemotherapy for each cancer were considered as time-dependent covariates in Cox regression models with age as the time-scale, adjusted for sex and occurrence of prior malignant or benign tumors. Subsequent cancers were classified as in- or out-of-field based on the body region of previous cancers. Results. Among 891 individuals, 643 (72.2%) were female and 297 (33.3%) were diagnosed with a first cancer before age 20 years. Breast cancer was the most commonly diagnosed first cancer (N=371), followed by soft tissue sarcoma (N=131) and central nervous system cancers (N=84). First cancer treatment included radiotherapy for 237 (26.6%) and/or chemotherapy for 421 (47.3%) individuals. Analyses are underway to define the characteristics of subsequent neoplasms (including age at diagnosis, latency, and distribution of diagnosis type) and to calculate relative and absolute risk estimates for radiotherapy and chemotherapy overall and by subsequent neoplasm type. Conclusions. This study will quantify the contribution of radiotherapy and chemotherapy to the risk of subsequent cancers among individuals with Li-Fraumeni syndrome. Understanding the magnitude of this risk will support health care providers and patients in making informed decisions about cancer management. Citation Format: Anita Villani, Payal Khincha, Jessica Hatton, Sara Schonfeld, Catherine Goudie, Leatrisse Oba, Kishan Pithadia, Birte Sänger, Christian Kratz, Anh N. Le, Caitlin Orr, Kara N. Maxwell, Anne Naumer, Jennie Vagher, Wendy Kohlmann, Joshua Schiffman, Elizabeth Santana dos Santos, Orli Michaeli, Jacob J. Carson, Derek S. Tsang, Raymond Kim, Jamie L. Maciaszek, Kim E. Nichols, Victoria E. Goodman, Suzanne P. MacFarland, Lara Reichman, Maria Isabel Achatz, Sharon Savage, David Malkin, Lindsay M. Morton. Risk of therapy-related subsequent cancers in individuals with germline TP53 variants [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA004.