Batha, Lin

629 Background: NENs are a heterogeneous group of tumors with variable clinical behavior. While most NENs occur sporadically, a subset arises in the context of germline cancer predisposition syndromes. The prevalence of GPVs in NENs is increasingly recognized, but the reported frequency and spectrum of genes involved remain inconsistent across studies. Therefore, systematic review and meta-analysis is helpful to clarify the prevalence and clinical significance of PGVs in pts with NENs. Methods: A systematic review with meta-analysis of prospective and retrospective studies reporting germline testing in pts with NENs was conducted according to the PRISMA guidelines. The primary outcome was the prevalence of GPVs. Random-effects models (GLMM) with logit transformation were applied to estimate pooled prevalence with 95% confidence intervals (CIs). Results: Nine studies comprising 1304 patients with NENs were included. The median age was 53.8 (10-88.5) years, 52% were female (n=678/1304), and 56% (n=736/1304) were unselected cohorts (all-comers) and 44% (568/1304) were selected cohorts (testing based on clinical suspicion and high-risk features defined by each study). Across all cohorts, the pooled prevalence of PGVs was 19.6% (95% CI: 10.68–33.15%), with high heterogeneity (I² ≈ 96%). Subgroup analyses demonstrated comparable GPV prevalence between selected (13.2%, 95% CI 6.3–25.8) and unselected cohorts (23.0%, 95% CI 12.0–39.6) (p=0.25). GPV prevalence stratified by pancreatic NENs (17.8%, 95% CI 12.6–24.5) and other NENs (10.6%, 95% CI 6.5–17.0) was also not statistically different (p=0.08). The most altered genes involved DNA repair and cellular signaling pathways, including APC, ATM, BRCA1/2, BAP1, CHEK2, MEN1, MUTYH, VHL, RET, and TSC1/2. Germline variants in mismatch repair (MMR) genes were reported in approximately 2.5% of cases. Conclusions: This study represents the first systematic review and meta-analysis evaluating the prevalence of germline mutations in NENs. Approximately 20% of pts with NENs harbor a germline pathogenic variant, underscoring the importance of genetic counseling and germline testing. The wide variability across studies highlights the need for standardized genetic testing approaches. These findings support routine referral for genetic counseling and panel testing in patients with NENs to guide management and familial risk assessment.

The role of circulating tumor DNA (ctDNA) in gastroesophageal adenocarcinoma (GEA) has expanded in recent years. In resectable disease, postoperative ctDNA is able to detect patients at highest risk of recurrence months before scans. Tumor-informed assays provide the best sensitivity and emerging methylation assays are useful when tissue is scarce. In metastatic GEA, baseline ctDNA burden correlates with prognosis, and a decrease in ctDNA level after treatment initiation reflects therapeutic response. It can also uncover actionable targets, including ERBB2, FGFR2, and MSI-H, and detect resistance that can arise after starting treatment. Limitations include variable assay performance, low shedding in some tumors, clonal hematopoiesis confounding, and a lack of randomized data showing that ctDNA-guided changes improve outcomes. Ongoing trials are testing MRD-guided escalation/de-escalation and ctDNA-directed biomarker therapy. In this review, we evaluate the role of ctDNA in GEA cancers over recent years.