TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 (TP53): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15 families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1–69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2–54)—19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers.

Background: Lung cancer is the leading cause of cancer-related deaths globally, with epidermal growth factor receptor (EGFR) mutations present in approximately 17–39% of non-small cell lung cancer (NSCLC) cases. Osimertinib, a third-generation oral EGFR tyrosine kinase inhibitor (EGFR-TKI), has become a cornerstone in the treatment of EGFR-mutated NSCLC. However, the full scope of its potentially life-threatening adverse effects, particularly cardiomyopathy, remains underexplored. Methods: This retrospective study was conducted using data from a multi-center registry of NSCLC patients with EGFR mutations treated with first-line osimertinib therapy between December 2018 and April 2024. Osimertinib-related cardiotoxicity was defined as a composite of reduced ejection fraction (EF) and cardiac death. Results: The study cohort consisted of 17 patients, and most of the patients had a history of smoking. Cardiac toxicity onset varied from 1 to 28 months following osimertinib initiation, with 70.59% of the patients experiencing symptoms within the first 6 months of treatment. Fourteen patients showed some degree of symptom improvement and EF recovery, although most did not return to baseline EF levels. Comorbidities, including heart failure, hypertension, and dyslipidemia, were prevalent across the cohort. Conclusions: While osimertinib remains an effective treatment for EGFR-mutated NSCLC, its associated cardiac toxicity, particularly in patients with pre-existing conditions, presents a significant challenge. Close monitoring, early intervention, and individualized management strategies are critical in mitigating these risks. Patients with mild cardiac toxicity may be suitable for rechallenge, while those with more severe or persistent toxicity should generally be excluded from further osimertinib treatment.

Introduction Immune checkpoint inhibitors (ICI) have improved outcomes in non-small cell lung cancer (NSCLC). Nevertheless, the clinical benefit of ICI as monotherapy or in combination with chemotherapy remains widely varied and existing biomarkers have limited predictive value. We present an analysis of ENLIGHT-DP, a novel transcriptome-based biomarker directly from histopathology slides, in patients with lung adenocarcinoma (LUAD) treated with ICI and platinum-based chemotherapy. Methods We retrospectively scanned high-resolution H&E slides from pretreatment tumor-tissue samples of 50 patients with metastatic LUAD treated with first-line ICI with (46) or without (4) platinum-based chemotherapy and applied our ENLIGHT-DP pipeline to generate, in a blinded manner, an individual prediction score. ENLIGHT-DP predicts response to ICI and targeted therapies given H&E slide scans in two steps: (1) predict individual messenger RNA expression directly from high-resolution H&E scanned slides using DeepPT, a digital-pathology-based algorithm. (2) Use these values as input to ENLIGHT, a transcriptome-based platform that predicts response to ICI and targeted therapies derived from drug-specific networks of gene expressions. We then unblinded the clinical outcomes and evaluated the predictive value of ENLIGHT-DP in comparison to programmed death ligand (PD-L)-1 and tumor mutational burden (TMB). Results ENLIGHT-DP is predictive of response to treatment with receiver operating characteristic (ROC) area under the curve (AUC) of 0.69 (p=0.01) and outperforms both TMB and PD-L1 expression with ROC AUC of 0.52 and 0.46, respectively. Using a predetermined binary cut-off (established on independent cohorts) for patients predicted to respond to ICI, ENLIGHT-DP achieves 100% positive predictive value (PPV) and 44% sensitivity, superior to both PD-L1>50% (65% PPV and 38% sensitivity) and TMB-high (82% PPV and 26% sensitivity). ENLIGHT-DP was highly predictive in PD-L1<1% and TMB-low outlier groups with ROC AUC of 0.88 and 0.80, respectively (p value<0.05). ENLIGHT-DP is the only biomarker in this cohort significantly correlated with progression-free survival (HR: 0.45, 95% CI: 0.2 to 0.99, p=0.048). Conclusion We demonstrate the application of ENLIGHT-DP, a transcriptome-based biomarker for accurate prediction of treatment of LUAD with ICI and platinum-based chemotherapy, outperforming PD-L1 and TMB, and relying solely on accessible H&E scanned slides. Further studies on different tumor types, ICI monotherapy and bigger NSCLC cohorts are warranted.

SCLC is frequently associated with paraneoplastic syndromes, including dermatomyositis. Patients with malignancy-associated dermatomyositis express a specific autoantibody pattern usually positive for anti–transcription intermediary factor 1-γ (TIF1-γ), suggesting anti–TIF1-γ plays a role in development of malignancy-associated dermatomyositis. We present a case of a patient with SCLC, paraneoplastic dermatomyositis, positive anti–TIF1-γ, and a point mutation in TIF1-γ coding gene, with prominent clinical response to chemoradiation. We suggest that this point mutation is pathogenic, providing evidence for the development of paraneoplastic dermatomyositis through immune cross-reactivity.

The oncogenic role and clinical relevance of BRCA mutations in NSCLC remain unclear. We aim to evaluate the characteristics and clinical outcomes of patients with NSCLC harboring BRCA mutations treated at Hadassah Medical Center (HMC). We retrospectively assessed all patients with advanced NSCLC who underwent next-generation sequencing (NGS) and were found to have pathogenic somatic BRCA mutations (p-BRCA). We compared clinical outcomes in NSCLC patients with wild-type BRCA (wt-BRCA) matched by age, stage, gender, smoking, PDL-1 and driver mutations. Between 2015 and 2022, we evaluated 598 patients with advanced NSCLC using NGS and found 26 patients with p-BRCA, of whom 17 (65.4%) were carriers of germline BRCA variants and represented 1% of all BRCA carriers HMC. The median age of diagnosis was 67 years old (40–78), 13 patients (50%) had a history of smoking and 9 patients (34.6%) had additional driver mutations (EGFR, ALK, BRAF, MET or ERBB2). Objective response rate and median progression-free survival (PFS) for first-line platinum-based chemotherapy in the p-BRCA group compared to wt-BRCA controls were 72.2% and 16 months (CI 95%, 5–22), compared to 47.4% and 7 months (CI 95%, 5–9), respectively, and HR for PFS was 0.41 (CI 95%, 0.17–0.97). Six patients in the p-BRCA group were treated with advanced-line poly (adenosine-phosphate-ribose) polymerase inhibitors (PARPi), with a durable response observed in four patients (66%). In this cohort, patients with NSCLC harboring p-BRCA exhibit high-sensitivity PARPi and a prolonged response to platinum, suggesting some oncogenic role for BRCA mutations in NSCLC. The results support further prospective trials of the treatment of NSCLC harboring p-BRCA with PARPi.