Rinat Bernstein-Molho

Objective: Pheochromocytoma and paraganglioma (PPGL) have high genetic predisposition rates. In this multicenter study, we aimed to identify risk-modulating factors for disease development and aggressiveness in patients carrying pathogenic variants (PPGLgPV) related to PPGL genes. Methods: Observational prospective study including patients with PPGL, family history of PPGL, or suspected PPGL-related hereditary syndrome. Patients underwent clinical and germline PPGLgPV evaluation. Machine-learning analyses were conducted to predict a patient's risk of carrying PPGLgPV, developing PPGL, and developing metastatic or multifocal disease. Results: Of 221 patients (age 33.5 ± 19.9 years, 45.2% males), 143 (64.7%) patients harbored PPGLgPV, and 91 (41.2%) developed PPGL (46 pheochromocytoma, 45 paraganglioma/both, 29 multifocal/metastatic PPGL). Age at diagnosis of 40 years with a solitary PPGL. Pseudohypoxia (PH)-related PPGLgPV carriers were younger at PPGL diagnosis and had an increased risk of multifocal/metastatic disease. Elevated catecholamine metabolites and PH-related PPGLgPV had 80% PPV for metastatic/multifocal disease, vs high NPV for non-elevated catecholamine metabolites with negative family history (100%) or non-PH gene alterations (91%). Patients with PV found incidentally had a lower PPGL risk compared with carriers screened due to a family member with PPGL (P = .026). Conclusions: Machine learning identified combined clinical and genetic characteristics for predicting hereditary PPGL syndromes, and multifocal/metastatic PPGL. This enables personalized risk stratification to guide genetic testing and surveillance in patients with PPGL and their relatives.

Background: We investigated safety of breastfeeding after breast cancer in patients carrying germline BRCA pathogenic or likely pathogenic variants. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including BRCA carriers diagnosed with stage I–III invasive breast cancer at age 40 years or younger between January 2000 and December 2020 (NCT03673306). Locoregional recurrences and/or contralateral breast cancers, disease-free survival (DFS), and overall survival (OS) were compared between patients who breastfed after delivery and those who did not. Results: Among 4732 patients included from 78 centers worldwide, 659 had a pregnancy after breast cancer diagnosis, of whom 474 delivered a child. After excluding patients with uptake of bilateral risk-reducing mastectomy prior to delivery (n = 225) or unknown breastfeeding status (n = 71), 110 (61.8%) breastfed (median duration 5 months) and 68 (38.2%) did not breastfeed. Compared to patients in the no breastfeeding group, those who breastfed were more frequently nulliparous at breast cancer diagnosis (61.8% vs 45.6%) and did not report prior smoking habit (71.8% vs 57.4%). After a median follow-up of 7.0 years following delivery, 7-year cumulative incidence of locoregional recurrences and/or contralateral breast cancers was 29% in the breastfeeding group and 36% in the no breastfeeding group (adjusted subdistribution hazard ratio [HR] = 1.08, 95% CI = 0.57 to 2.06). No difference in DFS (adjusted hazard ratio [aHR] = 0.83, 95% CI = 0.49 to 1.41) nor in OS (aHR = 1.32, 95% CI = 0.31 to 5.66) was observed. Conclusions: Breastfeeding did not appear to be associated with a higher risk of developing locoregional recurrences or contralateral breast cancers, emphasizing the possibility of achieving a balance between maternal and infant needs without compromising oncological safety.

Background: Li–Fraumeni syndrome (LFS) is a rare autosomal‐dominant cancer‐predisposition syndrome caused by germline pathogenic or likely pathogenic variants (P/LPVs) in the TP53 gene. Classical autosomal‐dominant inheritance predicts a 50% transmission rate of TP53 P/LPV from each carrier parent to their offspring. However, clinical observations suggest higher‐than‐expected carrier proportions, indicating a potential transmission ratio distortion (TRD). The objective of this study was to investigate TRD in Israeli LFS families.Methods: Data from families with an LFS diagnosis who were followed at Sheba Medical Center between 2015 and 2024 were reviewed. Families that had complete clinical data and offspring were included. Pedigree analyses classified carriers as confirmed, obligate, or probable. Observed carrier proportions were compared with the expected 50% rate using one‐sample t‐tests.Results: Among 171 individuals from 20 families, 100 (58.5%) were identified as TP53 P/LPV confirmed or obligatory carriers, significantly exceeding the expected 50% inheritance rate (p = .027). A second analysis, which included 11 probable carriers, resulted in a carrier proportion of 64.9% (p < .001). TRD was observed across all phenotypic groups. No significant differences in TRD were observed by sex or variant type.Conclusions: This study revealed significant TRD in TP53 P/LPV inheritance among Israeli LFS families. A potential mechanism involves the role of TP53 in the cell cycle, in which reduced TP53 function may enhance embryonic cell proliferation, offering a survival or implantation advantage. TRD in LFS has implications for genetic counseling, reproductive decision making, and clinical management. These findings underscore the need for further research to validate TRD across diverse populations and elucidate the underlying mechanisms.

Purpose: Our previous data showed that carriers of germline BRCA1/2 pathogenic variants (PV) with breast cancer (BC) treated with mastectomy without post-mastectomy radiation therapy (PMRT) had higher rates of loco-regional recurrence (LRR) compared to those who underwent PMRT or breast-conserving therapy (BCT), despite earlier stage BC. Our aim was to verify our previous findings in a larger cohort. Methods: Clinical data were extracted from the medical records of BRCA1/2 mutation carriers with BC, treated at a single institution between 1/2006 and12/2022. The data included demographics, treatment modalities, and BC outcomes. Results: A total of 464 patients with 484 primary tumors were analyzed. Of these, 48.3% mastectomies were performed: 66% (154) without PMRT (non-PMRT) and 34% (80) with PMRT; 51.8% (250) underwent BCT. The non-PMRT group had earlier disease stages at diagnosis (77.3% were Tis and T1N0 stage) compared to the PMRT and BCT groups (3.8% and 45%, respectively, p < 0.001). During the study period with a median follow-up time of 75 months (range 12–211), the LRR rate was 13% (20/154) in the non-PMRT cohort compared with 1.25% (1/80) in the PMRT group (p = 0.003), and 6.4% (16/250) in the BCT group (p = 0.03). Cumulative incidence of LRR at 5 and 15 years was 14.7%, and 16.6% in the non-PMRT, compared to 5.1% and 35% in the BCT group, respectively (p = 0.081). No significant difference in overall survival was observed (p = 0.202). Conclusions: The timing and rates of LRRs differ according to the loco-regional therapy, which might indicate a different etiology driving these events.