Sahwan, Oudai

Abstract Everolimus 10 mg daily is the standard dose for advanced neuroendocrine tumors (NETs), but adverse events frequently necessitate dose reduction. As a result, oncologists often adopt a dose‐escalation strategy starting at 5 mg and increasing the dose as tolerated. In this multicenter study, we evaluated the effect of reduced dose (RD) and standard dose (SD) everolimus on survival, progression, and toxicity in patients with advanced NETs. We conducted a multicenter retrospective cohort study of patients with advanced NETs treated with everolimus at Mayo Clinic and University Hospitals (Cleveland, OH). Patients were grouped by starting dose (5 mg vs. 10 mg). Primary endpoints were overall survival (OS), real‐world progression‐free survival (rwPFS), and adverse events. Multivariable Cox models, inverse probability of treatment weighting (IPTW), and time‐varying dose sensitivity analysis were used to account for confounding and dose crossover. Among 170 patients (48 started on 5 mg; 122 on 10 mg), the 5 mg cohort was older, had worse ECOG PS, and was more heavily pretreated. Median OS was 43.7 months (5 mg) versus 81.5 months (10 mg; log‐rank p = .02). However, after multivariable adjustment ( N = 124 G1–G2 patients; 51 events), the association was no longer statistically significant (adjusted HR, 0.59; 95% CI, 0.31–1.12; p = .11). Median rwPFS was 7.0 versus 12.4 months (log‐rank p = .05); the adjusted rwPFS difference was not statistically significant (HR, 0.95; 95% CI, 0.56–1.61; p = .84). Nearly half (46.7%) of 10 mg starters required dose reduction. Any‐grade toxicity was more common with 10 mg (89% vs. 75%; p = .05). The apparent survival advantage of standard‐dose everolimus was substantially attenuated after adjustment. These findings do not establish dose equivalence and should be interpreted in the context of limited statistical power. Given its more favorable observed tolerability profile, RD everolimus warrants prospective evaluation as a starting strategy for patients at increased risk of treatment‐related toxicity who may not tolerate SD.

PURPOSE Gastroesophageal carcinoma (GEC) is increasingly managed using biomarker-guided therapies. Although both tissue DNA (tDNA) and circulating tumor DNA (ctDNA) testing are used clinically, the concordance of genomic alterations between primary tumors, metastatic sites, and liquid biopsy remains incompletely understood. METHODS We retrospectively analyzed 345 patients with GEC who underwent ctDNA testing at Mayo Clinic. tDNA next-generation sequencing and immunohistochemistry (IHC) for human epidermal growth factor receptor 2 (HER2)/erb-b2 receptor tyrosine kinase 2 ( ERBB2 ) and mismatch repair (MMR) were collected. Concordance was evaluated between ctDNA and tDNA, ctDNA and IHC, and across all three modalities, using 60-day and 30-day intervals. RESULTS Among 345 patients with ctDNA testing, 186 had tDNA testing, and 310 underwent IHC. ctDNA testing showed a shorter turnaround time than tDNA (median 6 v 13 days). The most frequent alteration in ctDNA, primary tDNA, and metastatic tDNA was TP53. Concordance between ctDNA and primary tDNA was ≥78.8% for key genes; between ctDNA and metastatic tDNA, it was ≥84.8%. IHC-ctDNA concordance was higher in metastatic tumors, with 91.1% for HER2/ ERBB2 and 97.7% for mismatch repair (MMR)/microsatellite instability (MSI) compared with 81.1% and 95.8%, respectively, in primary tumors. Triplet concordance for MSI/MMR was 97.6% in primary tumors and 100% in metastatic tumors, while ERBB2 /HER2 showed 84.4% and 93.9% concordance, respectively. ctDNA temporal heterogeneity analysis revealed 14 patients with fluctuating ERBB2 status and 3 with fluctuating MSI-H status. CONCLUSION ctDNA testing demonstrates high concordance with tDNA and IHC and offers faster turnaround. Given its minimally invasive nature and strong concordance with tissue-based testing, ctDNA is a reliable tool for genomic profiling and longitudinal monitoring in GEC.

PURPOSE Neoadjuvant immune checkpoint inhibitors (nICIs) have demonstrated high response rates in deficient mismatch repair/microsatellite instability–high (dMMR/MSI-H) gastroesophageal adenocarcinoma (GEA). The NEONIPIGA and INFINITY trials demonstrated high rates of pathologic complete response (pCR) in this patient population. Furthermore, the INFINITY trial explored the feasibility of managing these patients nonoperatively, demonstrating promising results. This study aimed to evaluate clinical outcomes of nICIs in resectable dMMR/MSI-H GEA, with a focus on the feasibility of nonoperative management (NOM). MATERIALS AND METHODS This retrospective cohort study included patients with resectable dMMR/MSI-H GEA and treated with nICIs ± surgery at the Mayo Clinic. Patients were identified from institutional records, and clinical data were retrospectively reviewed. Primary outcomes were clinical complete response (cCR) and pCR. Secondary outcomes included event-free survival (EFS), radiologic complete response (rCR), and immune-related adverse events (irAEs). RESULTS A total of 26 patients treated between April 1, 2017, and July 30, 2025, were identified. Nine patients (34.6%) underwent surgery, of whom six (66.7%) achieved pCR. Seventeen patients (65.4%) pursued NOM, with 10 (71.4%) of 14 evaluable patients achieving cCR and 14 (82.4%) of 17 evaluable achieving rCR. One patient who initially achieved cCR had a local recurrence on surveillance endoscopy and underwent salvage endoscopic resection. At a median follow-up of 19.3 months, 15 (88.2%) of 17 patients in the NOM cohort were alive and metastasis-free, with EFS rates of 87.3% at 12 and 24 months for all patients. irAEs occurred in nine patients (34.6%), with no grade ≥3 toxicities. CONCLUSION In this retrospective cohort study, nICIs led to high cCR and pCR rates in resectable dMMR/MSI-H GEA, supporting the use of immune checkpoint inhibitors in this setting and the feasibility of NOM in select patients.