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Immunotherapy with or after chemoradiotherapy (CRT) vs CRT alone in limited-stage small cell lung cancer (SCLC): Meta-analysis of randomized controlled trials.
e20140 Background: Limited-stage SCLC is treated with curative-intent concurrent chemoradiation (CRT). However, relapse is still common. We evaluated the efficacy and safety of adding immune checkpoint inhibitors (ICI) versus CRT control. Methods: PubMed, Embase, Cochrane Library and ClinicalTrials.gov were searched for randomized controlled trials enrolling adults with limited-stage SCLC treated with definitive concurrent CRT and randomized to ICI versus no-ICI control. Trials evaluated ICI given either concurrently with or as adjuvant therapy after CRT with atezolizumab, or as post-CRT consolidation/maintenance therapy with durvalumab in one trial and nivolumab plus ipilimumab in another, each compared to no-ICI control. One eligible RCT was available as an ASCO 2025 abstract (Grønberg et al.; NCT03540420). Primary endpoint was overall survival (OS); secondary endpoint was progression-free survival (PFS). Safety outcomes included grade ≥3 adverse events (AEs), grade ≥3 pneumonitis, and fatal events as reported (treatment-related death or AEs with outcome of death). Time-to-event outcomes were pooled as hazard ratios (HRs), and binary outcomes as risk ratios (RRs), using a DerSimonian and Laird for random-effects, heterogeneity was assessed with I². Safety event counts are summarized in Table 1. Results: Four RCTs (N = 1,371) were included. Overall, immunotherapy did not significantly improve OS HR 0.93 (95% CI 0.77-1.14; I² = 28.7%) or PFS HR 0.89 (95% CI 0.78-1.03; I² = 0%). There was a statistically higher incidence of grade ≥3 pneumonitis RR 1.98 (95% CI 1.02-3.84; I² = 0%) and fatal events RR 3.29 (95% CI 1.47-7.36; I² = 15.5%). Grade ≥3 AEs were non-significantly higher in the ICI group RR 1.29 (95% CI 0.86-1.95; I² = 87.4%). Conclusions: In limited-stage SCLC, adding immunotherapy did not improve OS or PFS. High-grade (grade ≥3) adverse events were non-significantly increased, whereas pneumonitis and fatal events were significantly increased. Safety outcomes across included RCTs (events/total; ICI vs control). Trial Grade ≥3 AEs Grade ≥3 Pneumonitis Fatal Events Peters et al, 2022 48/78 vs 19/75 7/78 vs 1/75 4/78 vs 1/75 Cheng et al, 2024 64/262 vs 64/265 3/262 vs 2/265 7/262 vs 5/265 Grønberg et al, 2025 Not Reported 2/85 vs 2/85 3/85 vs 0/85 Higgins et al, 2026 253/264 vs 242/257 16/264 vs 8/257 24/264 vs 4/257 Total 365/604 vs 325/597 28/689 vs 13/682 38/689 vs 10/682
SYNERGY: A phase 1b/2 study of nenocorilant, a selective glucocorticoid receptor antagonist, plus nivolumab in patients with advanced solid malignancies.
TPS2695 Background: Acting through the glucocorticoid receptor (GR), glucocorticoids (GCs) suppress the anticancer immune response by decreasing antigen presentation, exhausting CD8+ T-cell effector function, and increasing the immunosuppressive function of regulatory T cells and tumor-infiltrating myeloid cells. The use of GCs with anti-programmed death (ligand) 1 (anti-PD[L]1) therapy is associated with poor outcomes in several solid tumor types. Selective GR antagonists (SGRAs) inhibit the effects of GCs at the GR and show synergistic activity with cytotoxic chemotherapy, as demonstrated by the phase 3 ROSELLA study in patients with platinum-resistant ovarian cancer (Olawaiye Lancet 2025). SGRAs enhance tumor growth inhibition when combined with anti-PD1 therapy in syngeneic mouse tumor models that are refractory to immune checkpoint inhibition (Greenstein Int Immunopharmacol 2023). We hypothesize that GR antagonism with nenocorilant, an SGRA, may enhance or restore sensitivity to anti-PD(L)1 therapy and provide clinical benefit for patients with solid malignancies. Methods: This phase 1b/2, open-label, multicenter study (NCT07276373) is evaluating nenocorilant + nivolumab in patients with advanced solid malignancies. Key eligibility criteria for phase 1b include having received standard-of-care therapies, no prior immune-related adverse events (AEs) grade ≥3 or leading to anti-PD(L)1 discontinuation, no ongoing requirement for GCs, and evaluable disease (per Response Evaluation Criteria in Solid Tumors version 1.1). Treatment will continue until disease progression or discontinuation criteria are met. Nenocorilant will be given orally once daily in escalating doses (starting at 200 mg) across 3 cohorts of 10 patients each. Nivolumab 240 mg will be given intravenously once every 2 weeks. If ≤3 patients in a cohort experience dose-limiting toxicities (DLTs) during the 28-day evaluation period, enrollment will proceed to the next cohort at a higher dose of nenocorilant. Primary objectives include characterizing safety/tolerability (DLTs, AEs, serious AEs, dose modifications, and treatment discontinuations due to AEs) and determining the maximum tolerated dose and/or optimal dose/schedule. Secondary objectives are to characterize the anticancer activity, pharmacokinetics, and corrected QT interval effects of this combination. Safety endpoints will be summarized using descriptive statistics and time-to-event endpoints will be estimated using Kaplan-Meier methods. Data from the currently enrolling phase 1b part of the study will inform the dosing regimen for phase 2, which will further characterize the anticancer activity and safety of nenocorilant + nivolumab in specific solid malignancies. Clinical trial information: NCT07276373 .
VISTA: Targeted combination immunotherapy for suppression of breast cancer metastasis and recurrence.
1137 Background: Triple-negative breast cancer (TNBC) has limited treatment options and poor outcomes, with ~12% 5-year overall survival in stage IV. In early-stage TNBC (II/III), recurrence remains substantial among patients without pathological complete response after chemo-immunotherapy. Current PD-1/PD-L1 inhibitors show limited efficacy in metastatic TNBC (median OS ~23 months) and infrequent durable responses. Novel immune targets are urgently needed to overcome resistance and prevent metastasis. V-domain Ig suppressor of T-cell activation (VISTA) is a next-generation checkpoint with distinct biology, enriched in tumor-infiltrating immune cells in TNBC. Methods: Comprehensive bioinformatic analyses of VSIR (VISTA) and ligands were performed across multi-cohort TNBC datasets spanning early and advanced stages, including pre-treatment, post-treatment, and progression samples. Spatial single-cell profiling of stage III TNBC tumors with recurrence versus non-recurrence was conducted using NanoString CosMx. VISTA expression in tumor tissue and circulating tumor cells (CTCs) was assessed by optimized immunofluorescence and digital pathology. Clinically relevant TNBC mouse models evaluated VISTA-mediated immune modulation alone and combined with chemo- or immunotherapy. Results: Single-cell bioinformatic analyses revealed enrichment of VSIR and ligands SELPLG/LGALS9 in post-treatment and progression-stage TNBC versus pre-treatment, observed in tumors and liquid biopsies. VSIR/SELPLG were enriched in progenitor and terminally exhausted immune subsets, whereas early-stage TNBC showed broader immune distribution. Digital pathology identified VISTA in metastasis-initiating tumor cells and dysfunctional immune cells, with induction following anti–PD-1 therapy in TNBC mouse models. Spatial profiling of recurrence-associated tumors showed co-enrichment of VSIR/SELPLG with inhibitory receptors TIM3, LAG3, and TIGIT across immune niches in recurrence-associated tumors. VISTA targeting with a novel antibody, HMBD-002, enhanced anti-tumor immunity, synergized with chemo- and immunotherapy, and suppressed recurrence and metastatic burden in preclinical models. Conclusions: VISTA is a treatment-emergent checkpoint associated with T-cell exhaustion, recurrence, and metastasis in TNBC. Its enrichment in exhausted T-cell niches, metastasis-initiating tumor cells, and CTCs post–chemo-immunotherapy supports its role in adaptive resistance. VISTA expression in tissue and liquid biopsy CTCs represents a clinically actionable biomarker for patient selection and response monitoring. These data provide strong rationale for early-phase clinical trials of combination VISTA blockade with ICIs in high-risk early-stage TNBC with residual disease and metastatic TNBC after prior ICI exposure.
Integrated tumor-informed and tumor-agnostic ctDNA molecular residual disease (MRD) assessment with imaging in early breast cancer.
11130 Background: Accurate ctDNA-based MRD detection in early breast cancer is limited by tumor heterogeneity, clonal evolution and methodological issues, limiting tumor-informed (TI) assays reliant on predefined variants. Tumor-agnostic (TA) approaches, while broader, are susceptible to false positives from clonal hematopoiesis and reduced sensitivity in low–tumor burden settings. Methods: We analyzed a single-center cohort of 74 female patients with stage I–III breast cancer undergoing post-treatment surveillance after completion of curative-intent therapy (surgery, radiation, and adjuvant systemic therapy as appropriate). Plasma samples collected post-treatment were analyzed using an integrated MRD assay combining TI ddPCR and TA NGS ctDNA detection strategies. CHIP filtering was incorporated to improve analytical robustness. MRD status was correlated with clinicopathologic features and contemporaneous imaging. MRD positivity was defined as detection by either TI or TA component. Results: At the time of ctDNA assessment, which was performed during standard post-treatment surveillance following completion of curative-intent therapy, 94.6% (70/74) of patients were imaging-negative. MRD was detected in 31.1% (23/74) of patients overall. All imaging-positive patients (4/4) were MRD-positive. Notably, among imaging-negative patients, 27.1% (19/70) were MRD-positive, indicating molecular residual disease not captured by conventional imaging. No imaging-positive cases were MRD-negative. MRD positivity was observed across all stages, including early-stage disease (I–II: 26%, 14/54), with the highest prevalence in stage III (47.4%, 9/19); one case had unknown staging. MRD was detected in 33.3% (18/54) of HR + /HER2 - , 25% (2/8) of TNBC, and 25% (3/12) of HER2 + tumors, demonstrating applicability across biological subtypes. Importantly, the hybrid approach increased detection sensitivity significantly. Among MRD-positive patients (n=23), 47.8% were detected exclusively by TA component, 43.5% by the TI component alone, and only 8.7% were detected by both. Reliance on a single MRD strategy would have failed to identify 91.3% (21/23) of MRD-positive cases, highlighting substantial biological complementarity between the two approaches. At early follow-up (median 113.5 days), MRD was detected in 23 patients, including 19 who were imaging-negative; among those with subsequent imaging-confirmed recurrence (n=4), the median MRD–imaging interval was 9.75 months. Conclusions: A hybrid TI and TA ctDNA MRD platform detects clinically occult molecular disease beyond imaging in stage I–III breast cancer. The complementary performance of TI and TA approaches substantially improves MRD detection and supports the use of hybrid MRD testing for early risk stratification and MRD-guided clinical trials.
Time on treatment for systemic therapies for patients with hormone receptor-positive breast cancer and <i>BRCA1</i> , <i>BRCA2</i> , or <i>PALB2</i> pathogenic variants.
1096 Background: For patients with hormone receptor-positive/HER2- (HR+) metastatic breast cancer and pathogenic variants (PVs) in BRCA1 , BRCA2 or PALB2 ( mBRCA), data suggests longer cancer-specific survival compared to patients without PVs (wtBRCA). One hypothesis is that their innate DNA repair deficiency improves response to cytotoxic therapy, as seen in poly (ADP-ribose) polymerase inhibitors (PARPi), which results in longer progression free survival (PFS). However, it remains unclear whether mBRCA is associated with a longer PFS with other therapies such as endocrine therapies (ET), including aromatase inhibitors (AI) and Selective Estrogen Receptor Degraders (SERDs). Some data suggests a shorter PFS with CDK 4/6-inhibitors (CDK4/6i) for mBRCA. Therefore, we compared time-on-treatment (TOT), a real-world surrogate for PFS, for mBRCA vs wtBRCA treated with ET, CDK4/6i, or PARPi. Methods: DNA and RNA somatic sequencing were performed on tumors submitted to Caris Life Sciences. HR+ was defined by IHC per ASCO/CAP. TOT was calculated from first to last of treatment time based on insurance claims. Univariable Cox-proportional hazard analyses were utilized to assess TOT between mBRCA vs wtBRCA for each therapy (ET, PARPi and CDK4/6i). Protocol was approved prior by Caris research committee. Results: From 8263 HR+ breast cancer patients, 628 were mBRCA+ (median age: 57 years; range 23-90; 96% Female, 4% Male), and 7635 were wtBRCA (median age: 63 years; range 22-89; 98% Female, 2% Male). PVs were BRCA2 : 66%, BRCA1 : 19% and PALB2 : 15%. As shown in Table 1, there was a shorter TOT for AI, SERDs and CDK4/6i, but a longer TOT with PARPi among mBRCA. Patients with mBRCA and high tumor mutational burden (TMB-Hi ≥10 mutations/Mb) had shorter TOT across all analyzed treatments vs low TMB (27.9 vs 35.8 mos, HR=1.47 95%CI 1.14-1.89; p = 0.003), except AI where TMB-Hi had longer TOT (23.5 vs 16.9 mos; HR=0.79, 95%CI 0.62-1.021; p = 0.07). Conclusions: This real-world data analysis demonstrates distinct TOT patterns among ET, CDK4/6i and PARPi for mBRCA patients when compared to wtBRCA. This calls for further studies in this specific patient population to understand the various treatment responses, associated tumor biology and immunologic landscape of mBRCA. TOT comparisons by therapy between mBRCA and wtBRCA patients. Therapy TOT (months)mBRCA TOT (months)wtBRCA Hazard Ratio (HR), Confidence Interval (CI) at 95% Samples collected at all sites (including breast) AI 21.7 25.8 HR=1.16 (CI 1.04-1.29 p=0.009 SERDs 7.6 11.1 HR=1.40 (CI 1.21-1.62) p<0.00001 CDK4/6i 10.3 13.6 HR=1.39 (CI 1.22-1.59) p<0.001 PARPi 5.8 2.1 HR=0.51 (CI 0.36-0.73) p<0.001 Samples collected at metastatic sites AI 25.2 28.3 HR=1.14 (CI 0.994-1.30; p=0.06 SERDs 6.4 11.5 HR=1.40 (CI 1.20-1.68; p<0.0001 CDK4/6i 10.3 13.6 HR=1.31 (CI 1.12-1.54; p<0.001 PARPi 5.8 1.8 HR=0.46 (CI 0.31-0.70; p<0.001
Accuracy and consensus strategies for large language model abstraction of axillary surgery type from a breast cancer oncologic history text.
e13702 Background: Accurate abstraction of axillary surgery from unstructured oncologic history is essential for breast cancerresearch, quality assessment, and downstream data modeling. Large language models (LLMs) offer ascalable approach but vary in performance and reliability. We evaluated multiple LLMs and ensemblestrategies for high-confidence axillary surgery abstraction from real-world clinical texts. Methods: Unedited oncologic history narratives were manually copied verbatim from clinical oncologichistory section for 100 breast cancer cases (EPIC EHR) with varied note complexities and adjudicatedaxillary surgery outcomes (sentinel lymph node biopsy [SLNB], axillary lymph node dissection [ALND], orno axillary surgery [NONE]). Two physician abstractors (TD, DH) independently labeled all cases toestablish a finalized ground-truth benchmark. Four contemporary LLMs from different vendors (Gemini-3,GPT-5.2, Claude-4.5, Grok-4) were evaluated using an identical single-pass prompt instructing models toclassify as SLNB, ALND, or NONE with abstention permitted. Model outputs were compared against thebenchmark. Performance metrics included coverage, overall accuracy, and conditional accuracy (amongnon-abstaining predictions), with class imbalance considered. Ensemble strategies used increasingagreement thresholds (≥2/4, ≥3/4, unanimous 4/4). All data were de-identified and analyzed under IRB.This was a proof-of-concept evaluation of abstraction reliability and ensemble confidence strategies. Results: Ground-truth distribution was SLNB 68%, NONE 19%, ALND 13%. Physician accuracy vs.finalized label was TD 92%, DH 96%; when agreed (88% cases, κ = 0.748), conditional accuracy was100%. Among LLMs, Gemini-3 and Grok-4 achieved highest performance (88% overall accuracy each;100% coverage). Claude-4.5 abstained in 12% but had 91% conditional accuracy. GPT-5.2 showed 60%overall accuracy. Ensembles revealed precision–coverage tradeoff: unanimous 4-of-4 agreement auto-labeled 51% cases with 96% conditional accuracy; 3-of-4 auto-labeled 88% with 92% conditionalaccuracy. ≥2-model agreement did not exceed best individual models. Unanimous failures were rare(3%), with manual review identifying temporal anchoring to prior procedures and incomplete OncologicHistory summaries, reflecting real world documentation limitations. Conclusions: LLMs can accurately abstract axillary surgery from unstructured text, approaching but notmatching expert performance, with model-specific error modes. Ensemble agreement supports selectiveautomation, auto-labeling high-confidence cases while routing ambiguities for human review. Multi-modelunanimity yields low-error subsets suitable for clean data generation. These findings support human-in-the-loop frameworks for scalable oncology data abstraction.
Intratumoral injection of IP-001 following thermal ablation in patients with advanced solid tumors: A multicenter phase Ib/IIa trial with expansion cohorts in melanoma and soft tissue sarcoma patients (SAKK 66/17).
2610 Background: This trial combines the novel adjuvant immunomodulator IP-001, a glycan polymer, with laser ablation in patients with relapsed solid tumors. Methods: This is a non-randomized, open-label multicenter phase Ib/IIa trial with a dose-finding part 1 and a dose expansion part 2 in advanced melanoma and soft tissue sarcoma (STS). Primary objectives include the safety and tolerability of up to six 4-weekly cycles of intratumoral IP-001 following laser ablation (TRANBERG Thermal Therapy System, Clinical Laserthermia System AB), and 12-week disease control rate (12w-DCR) according to RECIST v1.1 in advanced melanoma. The dose-finding part used 4 mL of IP-001 (10 mg/mL). The activity endpoint for advanced melanoma used the 1 st stage of a Simon 2-stage design, with 12w-DCR ≤20% (H0) vs. ≥40% (H1) (type-I error 0.05, power 80%). Results: We treated 15 melanoma and 10 STS patients, including 4 in part 1 (n=28). Median age was 62 years, 57% were male, all patients had metastatic disease, including 60% with liver metastases. Most patients (78%) had received ≥3 prior lines of systemic treatment, including 79% with prior immunotherapy. Treatment was well tolerated with no dose-limiting toxicity, and a recommended IP-001 dose of 4 mL. Patients received a median of 2 (range 1 to 6) cycles of study treatment. Reasons for treatment discontinuation included physician’s decision (39%) and disease progression (25%). 27 patients (96%) experienced treatment-emergent adverse events (TEAE). IP-001-related TEAE occurred in 16 (57%) patients, including 5 (17%) patients with severe IP-001-related TEAE. Severe TEAE occurred in 20 (71%) patients overall. Most frequent mild IP-001-related TEAE included fever (36%), fatigue (21%), rash (14%), hypotension (11%), injection site reactions (11%) and flu-like symptoms (7%); 2 cases (7%) of severe allergic reactions were reported, including one serious reaction. Allergic reactions occurred at cycle 3 in both patients and resolved without sequelae. Treatment discontinuation for TEAE occurred in a single patient (4%). 12w-DCR in advanced melanoma was 21% (3/14 evaluable patients) (2-sided 90% CI: 6%, 46%), with stable disease in 50% and partial remission (PR) in one (7%) melanoma patient. 15 (53%) patients had radiological tumor shrinkage in ≥1 untreated tumor lesion. Median progression-free survival (PFS) in advanced melanoma was 3 months, with a 12-month PFS rate of 33%, indicating preliminary evidence of disease control beyond the 12-week primary endpoint window. Conclusions: Intratumoral IP 001 at a dose of 4 mL following thermal ablation is well tolerated, with mainly mild, transient immune-related events. Although the pre-specified activity endpoint was not met, the observed DCR and PFS support further evaluation of this novel immuno-oncologic strategy. Clinical trial information: NCT03993678 .
Age and HIV status as survival predictors in HHV8-positive diffuse large B-cell lymphoma: The largest population-based analysis to date.
7084 Background: HHV8-positive Diffuse Large B Cell Lymphoma (HHV8+ DLBCL) is a rare and aggressive subtype of Non-Hodgkin Lymphoma that is frequently associated with HHV8-positive Multicentric Castleman Disease (MCD). Due to its rarity, population-based studies have been limited to small cohorts or have focused primarily on demographic features without survival analysis. This study explores demographic features, treatment pattern and prognostic factors affecting survival in patients diagnosed with (HHV8+ DLBCL) in the United States. Methods: Following IRB approval, we analyzed the largest cohort of HHV8+ DLBCL to date (n=262) using the National Cancer Database (NCDB) (2010-2023). Patients with histologically confirmed HHV8+ DLBCL (ICD-O-3 9738/3) were included. Univariable Cox regression identified factors associated with survival; significant variables were included in multivariable cox regression with backward elimination (p<0.05). Data was analyzed using SAS version 9.4. Results: Among 262 patients with HHV8+ DLBCL, (mean age 52.6 years), 65.6% were <60 years, 76.7% were male, and 66.0% were white. Primary site was predominantly nodal (78.6%), with extranodal involvement in 21.4%. 19.2% were HIV-positive, and 63.3% had no comorbidities (Charlson-Deyo score 0). The majority received systemic therapy (84.6%). Among treated patients, 62.2% received chemotherapy and 43.1% received immunotherapy. Median overall survival was 133 months, with 1-, 3- and 5-year survival rates of 68.2%, 63.1%, and 59.9%, respectively. On multivariable Cox regression analysis, age ≥60 years (HR 2.20, p=0.0004), higher Charlson-Deyo score (HR 1.67, p=0.0090), HIV-positive status (HR 2.56, p=0.0026), and absence of systemic treatment (HR 2.16, p=0.0016) was independently associated with worse overall survival. Conclusions: In conclusion, HHV8+ DLBCL is a rare and aggressive lymphoma with poor long-term survival, frequently associated with multicentric Castleman disease, mainly affecting males with nodal involvement. Age ≥60 years, higher Charlson-Deyo score, HIV-positive status, and lack of systemic treatment independently predicted worse survival. Our study provides the largest cohort analysis of HHV8+ DLBCL to date. Nevertheless, further prospective studies with larger sample sizes are necessary to gain deeper insight into the pathogenesis and optimize treatment of this rare lymphoma. Multivariable Cox regression for overall survival in patients with HHV8+ DLBCL. Factor HR (95%CI) p-value Age Age <60 (ref) Age ≥60 12.20(1.42-3.40) 0.0004 Charlson Deyo ScoreNo morbidities (ref)≥1 Morbidities 11.67(1.14-2.44) 0.0090 Systemic Treatment Status No TreatmentReceipt of Treatment (ref) 2.16(1.34-3.48)1 0.0016 HIV Negative (ref) Positive Unknown 12.56(1.39-4.71)0.96(0.59-1.56) 0.00260.8601
EPCORE NHL-6: Phase 2 study of subcutaneous (SC) epcoritamab as outpatient treatment for 2L+ relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).
e19003 Background: Epcoritamab, a CD3×CD20 bispecific antibody approved for R/R DLBCL, is administered SC with inpatient monitoring for 24 h after the first full dose (FFD). Previous report from NHL-6 (NCT05451810) demonstrated feasibility of outpatient dosing and monitoring of epcoritamab in 2L+ DLBCL after FFD, with 92% of patients (pts) monitored outpatient after FFD (Vaidya SOHO 2025 Abstract ABCL-1224). Here we present longer follow-up data. Methods: Pts aged ≥18 y with R/R DLBCL, ECOG PS 0–2, who received ≥1 prior line of therapy (LOT), including immunochemotherapy with anti-CD20 antibody, were enrolled in academic and community centers of US and Puerto Rico. Pts received epcoritamab in 28-day (D) cycles (C): 0.16-mg and 0.8-mg C1 step-up doses, 48-mg full dose C1D15 onward (C1–3, QW; C4–9, Q2W; C≥10, Q4W). Safety education materials and mandatory cytokine release syndrome (CRS) prophylaxes were given in C1. Primary endpoints were grade ≥3 CRS, immune effector cell–associated neurotoxicity syndrome (ICANS), and neurologic events. Secondary endpoints were efficacy and safety. Results: At the 11 Nov 2025 cutoff, 92 pts received ≥1 dose of epcoritamab and the baseline characteristics have been reported previously (Vaidya SOHO 2025 Abstract ABCL-1224). The median number of treatment cycles was 6 (range 1–35). At 17.3-mo median follow-up (95% CI 15.4–18.9), all pts experienced ≥1 treatment-emergent adverse event (TEAE), with 22.8% leading to treatment discontinuation (5.4% DLBCL disease progression reported as TEAE). Grade 3–4 TEAEs occurred in 81.5%, Grade 5 TEAEs in 17.4% of pts (7.6% DLBCL disease progression, 5.4% infections [3.3% COVID-19]), and serious adverse events in 65.2%. Infections and infestations were reported in 68.5% of pts, including 26.1% that were serious. The incidence and severity of CRS and ICANS were consistent with prior reports. With extended follow-up, the overall response rate (ORR) and time to response remained consistent with earlier analyses. Higher complete response rates (CRR) were observed with epcoritamab in 2L vs overall (Table). Median duration of response (mDOR) was 25.8 mo and median duration of complete response (mDOCR) was not reached (NR). Median progression-free survival (mPFS) was 7.9 mo. Median overall survival (mOS) was 27.2 mo. Conclusions: With longer follow-up, the overall safety profile remained consistent with previous report, with no new safety signals identified. Responses observed with epcoritamab were durable and mOS was 27.2 mo. Higher CRR observed in the 2L group suggested enhanced benefit with using epcoritamab in earlier LOTs. Clinical trial information: NCT05451810 . EPCORE NHL-6 efficacy outcomes. Outcome, 95% CI 2L (n=42) Overall (n=92) ORR % 66.7, 50.5–80.4 64.1, 53.5–73.9 CRR % 57.1, 41.0–72.3 48.9, 38.3–59.6 mPFS mo 11.4, 5.5–NR 7.9, 4.2–NR mDOR mo NR, 8.7–NR 25.8, 25.8–NR mDOCR mo NR, NR–NR NR, 24.8–NR mOS mo NR, NR–NR 27.2, 13.4–NR
Interrupting HEG1/Cx43 interaction to promote cuproptosis via inhibiting gap junction to overcome glioblastoma radioresistance.
2047 Background: Glioblastoma (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. Its intrinsic radioresistance leads to suboptimal therapeutic outcomes. A prior clinical trial by our team revealed that mutations in the HEG1 gene lead to upregulated protein expression, a key factor limiting the benefit from standard radiotherapy in GBM patients. As a form of non-classical programmed cell death induced by radiotherapy, we hypothesized that high HEG1 expression reduces the susceptibility of GBM cells to cuproptosis, thereby promoting radiotherapy resistance. Methods: Cellular functional assays were performed to evaluate the impact of HEG1 expression on cuproptosis sensitivity and radiotherapy response in GBM cells. Molecular techniques were used to assess intracellular and intercellular copper ion flow. Co-immunoprecipitation and inhibition of protein degradation pathways were employed to investigate the direct interaction between HEG1 and the gap junction protein Connexin 43 (Cx43), and its inhibitory effect on Cx43 degradation via the endolysosomal pathway. Structural modeling combined with virtual screening of a drug library was conducted to identify potential compounds disrupting the HEG1-Cx43 interaction. Site-directed mutagenesis and kinase activity modulation were used to elucidate the mechanism by which c-Kit kinase promotes HEG1-Cx43 binding by phosphorylating HEG1 at tyrosine residue Y1350. Functional validation was performed both in vitro and in vivo using GBM models. Results: High HEG1 expression facilitated intercellular copper ion flow, dampened intracellular copper ion fluctuations, and consequently blocked the propagation of cuproptosis. Mechanistically, HEG1 directly interacted with Cx43, inhibiting its degradation via the endolysosomal pathway and sustaining gap junction establishment. Virtual screening identified several multi-target tyrosine kinase inhibitors capable of disrupting the HEG1-Cx43 interaction. Mechanistic studies revealed that c-Kit kinase promoted this interaction by phosphorylating HEG1 at Y1350. Both in vitro and in vivo functional validation demonstrated that targeting the HEG1-Cx43 interaction reactivated cuproptosis and sensitized GBM to radiotherapy. Conclusions: Our findings elucidate the regulatory role of the "HEG1-Cx43-cuproptosis" axis in GBM radioresistance, offering new insights for treatment. The combination of multi-target tyrosine kinase inhibitors and cuproptosis inducers may represent a promising novel therapeutic strategy for GBM.
Ocular toxicity and safety profile of mirvetuximab soravtansine in ovarian cancer: A systematic review and meta-analysis of clinical trials and real-world studies.
5558 Background: Mirvetuximab soravtansine (MIRV) is a folate receptor alpha (FRα)–targeting antibody–drug conjugate approved for FRα-positive, platinum-resistant ovarian cancer. Ocular adverse events are a characteristic toxicity of MIRV; however, the incidence and severity of ocular and selected non-ocular toxicities across clinical trials and real-world studies have not been comprehensively synthesized. Methods: This systematic review and meta-analysis study was conducted according to PRISMA guidelines and registered in PROSPERO (CRD420251270297). MEDLINE/PubMed, Embase, Scopus, and CENTRAL were searched from inception through December 2025 for prospective phase I–III trials and real-world observational studies evaluating MIRV in epithelial ovarian, fallopian tube, or primary peritoneal cancer. Two reviewers independently screened studies and extracted data. Primary outcomes included any-grade and grade ≥3 ocular adverse events, as well as ocular toxicity–related dose reductions and treatment discontinuations. Secondary outcomes included grade ≥3 pneumonitis and thrombocytopenia. Clinical trial and real-world data were analyzed separately. Random-effects meta-analyses of proportions were performed using logit transformation, with heterogeneity assessed using the I² statistic. Analyses were conducted in R version 4.5.2. Results: Fourteen studies comprising approximately 750 patients were included. In pooled analyses of clinical trials, any-grade ocular adverse events were common (56.2%; 95% CI, 5.2–96.8) with substantial heterogeneity contributing to wide confidence intervals, whereas grade ≥3 ocular adverse events were rare (1.41%; 95% CI, 0.47–4.13) with no observed heterogeneity. Dose reduction due to ocular toxicity occurred in 31.2% (95% CI, 18.0–48.4) of patients, while treatment discontinuation due to ocular adverse events was less frequent (9.98%; 95% CI, 0.70–63.58). Severe non-ocular toxicities were uncommon, with pooled incidences of 1.41% (95% CI, 0.47–4.13) for grade ≥3 pneumonitis and 1.44% (95% CI, 0.09–19.44) for grade ≥3 thrombocytopenia. Across three real-world studies involving 289 patients, treatment discontinuation due to ocular adverse events was rare (0.35%; 95% CI, 0.00–20.54), with safety findings consistent with those from clinical trials. Conclusions: MIRV is associated with frequent, but predominantly low-grade, ocular adverse events, which are commonly managed with dose modification, while severe ocular and non-ocular toxicities are rare. Real-world evidence supports the tolerability profile observed in clinical trials, highlighting the importance of proactive ocular monitoring to optimize treatment continuity.
Integrated expression analysis of microRNA and its associated gene network in thyroid cancer.
e18042 Background: Thyroid cancer, the most common endocrine malignancy, is increasing in incidence globally, underscoring the need for novel diagnostic and prognostic biomarkers. This study aimed to evaluate the expressional patterns of miR-296-3p and the DDHD2 gene and their potential role in thyroid carcinogenesis. Methods: This study was conducted on histopathologically confirmed thyroid cancer patients and both cancerous tissue and their adjacent normal tissues were collected after surgery. Demographic and clinical data including age, gender, thyroid function status (TSH, T3, and T4 levels), tumor size, cancer stage, and family history were recorded. While gene and miRNA expression levels were assessed using quantitative real-time PCR (qRT-PCR). Results: Demographic analysis showed a mean patient age of 40 years, with majority of patients were female which is consistent with known epidemiological trends and tumors were predominantly detected at early stages with moderate sizes. Hormonal analysis showed that the majority of patients had mean TSH (2.9 mIU/L), T4 (9.92 µg/dL), and T3 (2.57 pg/mL) levels within normal ranges. Family history revealed that most cases were sporadic, with limited familial links. Molecular analysis showed significant upregulation of miR-296-3p in tumor tissues in thyroid cancer. Although miR-296-3p is reported as a tumor suppressor in several previously reported studies like on NSCLC and colorectal cancer, in this study (and in glioblastoma), its overexpression suggests a possible oncogenic role in thyroid cancer. Similarly, the DDHD2 gene was also significantly upregulated in thyroid cancer, aligning with prior findings of its involvement in lipid signaling and tumor progression in papillary thyroid cancer and breast cancer. A moderate positive correlation between miR-296-3p and DDHD2 was observed in thyroid cancer, suggesting a possible co-regulation mechanism. Conclusions: These results highlight the potential of miR-296-3p and DDHD2 as diagnostic biomarkers and therapeutic targets in thyroid cancer. This study provides critical insight into the molecular landscape of thyroid cancer within the Pakistani population and supports further validation through large-scale studies.
Age-related disparities in catastrophic health expenditures among cancer survivors in the United States: Evidence from MEPS, 2018-2022.
e23108 Background: Cancer survivorship carries substantial financial burden, yet age-related differences in catastrophic health expenditure (CHE) remain poorly characterized. We examined age-specific patterns and determinants of CHE among U.S. cancer survivors. Methods: We conducted a pooled cross-sectional analysis of adult cancer survivors using MEPS 2018-2022. Survivors aged 18-39 (&lt;40) were compared with those ≥65 years. CHE was defined as out-of-pocket spending ≥10% of household income (CHE10); progressive CHE (CHE_PROG) applied income-adjusted thresholds (≥5% for poor/near-poor, ≥10% for middle/high-income). Survey-weighted logistic regression adjusted for sociodemographics, insurance, poverty level, and dual Medicare-Medicaid coverage. Results: Among 8,504 cancer survivors weighted N = 17.7 million), pooled prevalence of CHE10 was 9.1% among those aged ≥65 and 4.8% among those aged < 40 (p = 0.002). Progressive CHE prevalence was higher overall, affecting 13.2% of survivors aged ≥65 and 6.7% of those aged < 40 (p < 0.001). Year-specific analyses demonstrated consistently higher CHE prevalence among older survivors across all study years. In adjusted models, survivors aged < 40 had significantly lower odds of CHE10 (aOR 0.36, 95% CI 0.19-0.66) and CHE_PROG (aOR 0.28, 95% CI 0.16-0.49) compared with those aged ≥65. Poverty showed strong graded associations, with poor survivors having 25-fold (CHE10) and 49-fold (CHE_PROG) higher odds than high-income survivors. Dual Medicare-Medicaid eligibility was protective (CHE10: aOR 0.29, 95% CI 0.20-0.44; CHE_PROG: aOR 0.25, 95% CI 0.18-0.36), representing 71-75% reduced odds. No significant temporal trend was observed (p = 0.58). Conclusions: Catastrophic health expenditure disproportionately affects older cancer survivors. Although younger survivors experienced lower CHE prevalence, income level and dual insurance eligibility, rather than age alone, were the dominant drivers of financial toxicity. The strong protective effect of dual insurance coverage underscores the importance of comprehensive insurance. Policies improving affordability for low-income and older survivors are essential to mitigate financial hardship.
A randomized phase II study of pembrolizumab plus paclitaxel with or without bevacizumab in PD-L1–positive recurrent triple-negative breast cancer previously treated with perioperative immune checkpoint inhibitors: WJOG16522B (PRELUDE) trial.
TPS1163 Background: Perioperative pembrolizumab combined with chemotherapy has become a standard of care for patients with early-stage triple-negative breast cancer (TNBC). However, a substantial proportion of patients experience disease recurrence after perioperative immune checkpoint inhibitor (ICI)–based therapy, and the optimal systemic treatment for this population remains undefined. Angiogenesis has been implicated as a potential mechanism of resistance to immunotherapy. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), may enhance antitumor immunity through vascular normalization and modulation of the tumor microenvironment. The PRELUDE trial was designed to evaluate whether the addition of bevacizumab to pembrolizumab plus paclitaxel improves clinical outcomes in patients with PD-L1–positive recurrent TNBC previously treated with perioperative ICIs. Methods: PRELUDE is a multicenter, open-label, randomized phase II trial conducted in Japan. Eligible patients have recurrent TNBC with PD-L1 expression (combined positive score ≥10 using 22C3) and prior exposure to perioperative ICI-containing chemotherapy. Patients are randomized 1:1 to receive pembrolizumab plus paclitaxel with or without bevacizumab. Pembrolizumab is administered at 400 mg every 6 weeks, paclitaxel at 90 mg/m² on days 1, 8, and 15 every 4 weeks, and bevacizumab at 10 mg/kg on days 1 and 15 every 4 weeks in the experimental arm. Treatment is continued until disease progression or unacceptable toxicity. Tumor assessments are performed according to RECIST v1.1. Exploratory biomarker analyses using tumor tissue and peripheral blood samples are planned. The primary endpoint is progression-free survival. Secondary endpoints include overall response rate, disease control rate, overall survival, and safety. Exploratory endpoints include translational biomarker analyses to investigate mechanisms of response and resistance. Enrollment is currently ongoing. ClinicalTrials.gov: NCT06976944, jRCT2031250076.
Primary cutaneous diffuse large B-cell lymphoma, leg type: A systematic review of morphological mimics and atypical anatomical presentations.
e19078 Background: Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type (PCDLBCL-LT) is characterized by an aggressive clinical course and a distinct molecular profile. While the Leg Type designation captures the most common clinical pattern, this creates a significant knowledge gap when the malignancy deviates from this expected pattern. When the disease manifests in atypical locations or adopts morphologies that overlap with common inflammatory conditions, the resulting diagnostic complexity can lead to a gap in timely intervention, which is critical given the subtype's poor ~50% five-year survival rate. With this we systematically analyze documented deviations from the classic clinical pattern of PCDLBCL-LT to better define the full clinical spectrum of the disease. Methods: A systematic review was conducted using the PubMed (MEDLINE) database to identify case reports related to Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type (PCDLBCL-LT). The search strategy employed terms targeting atypical anatomical presentations and analogous words (n=70). Inclusion criteria focused on confirmed cases of PCDLBCL-LT (n=47). After exclusion of treatment-based cases, review papers, and non-English reports, the literature (n=22) revealed a consistent pattern of diagnostic camouflage across three domains: anatomical heterogeneity, morphological mimicry, and atypical systemic presentations. Results: Anatomical heterogeneity was noted in a significant subset of cases, with primary lesions appearing on the periorbital region, cheek, and trunk. Morphological mimicry created substantial overlap with benign or chronic conditions, such as verrucous stasis dermatitis, chronic venous ulcers, and erythema nodosa. Finally, atypical systemic presentations, including fever of unknown origin (FUO) and hematological precursors, highlight a gap where the disease may remain invisible or mimic systemic inflammatory syndromes before classic cutaneous tumors emerge. Conclusions: The clinical challenges associated with PCDLBCL-LT are largely driven by the tension between the disease’s name and its broad biological potential. This research is critical because it systematically organizes the scattered clinical knowledge on atypical PCDLBCL-LT, transforming rare extra-leg presentations and morphological mimics from diagnostic pitfalls into recognizable patterns for clinicians. The study empowers oncologists to facilitate appropriate and early diagnosis for patients who might otherwise face fatal delays. This early intervention is the only proven method to improve the poor survival rate associated with this aggressive subtype, as it ensures high-risk patients receive immediate systemic staging and treatment.
Overcoming immunotherapy resistance in advanced melanoma through radiotherapy: A prospective observational study.
e21501 Background: Outcomes for patients with advanced melanoma have improved since the integration of immune checkpoint inhibitors (ICIs). Despite these advances, most experience disease progression and succumb to their illness, making strategies to overcome resistance to immunotherapy an area of active investigation. Radiotherapy can induce an immune-mediated abscopal effect resulting in regression of non-irradiated tumors after localized radiotherapy. However, in melanoma, response rates and benefits with concurrent ICIs remain unclear. This prospective study assessed radiotherapy’s impact on advanced melanoma patients receiving immunotherapy, evaluating responses in both irradiated and non-irradiated lesions using RECIST 1.1. Methods: This ongoing IRB approved study enrolls adult patients with metastatic melanoma receiving standard of care immunotherapy. Upon disease progression, stereotactic radiotherapy was delivered to a selected target lesion (TL). Additional non-targeted lesions (NTL) were identified for monitoring. Radiation regimens included either 8–10Gy x 3 fractions or a single fraction of 8 Gy. Tumor responses were evaluated using RECIST 1.1 criteria. Objective response was defined as a ≥30% reduction in the sum of diameters of the lesions. Results: Five patients with metastatic melanoma were included in this interim analysis. All patients received nivolumab; one patient also received pembrolizumab, and two patients received ipilimumab. The median follow-up duration was 8.2 months (range 5.8– 34.5 months). In three patients (60%), TL remained stable in size following radiotherapy for a median duration of 6.9 months. Two patients (40%) demonstrated a reduction >30%. For NTL, four patients (80%) showed stable or decreased in size, with a median duration of response of 4.2 months. Four patients developed new metastatic lesions, resulting in the designation of progressive disease. The median time to progression due to new lesions was 4.8 months. Three patients died from disease progression at 5.8, 10.1, and 17.4 months from consent. Two patients remain alive at 34.5 months. Conclusions: Combining radiotherapy with ICIs represents a promising strategy to overcome immunotherapy resistance by augmenting antitumor responses. In this interim analysis, our small cohort demonstrated evidence of clinical benefit following combined therapy, with stabilization or reduction of both irradiated target lesions (100%) and non-irradiated lesions (80%). These findings suggest a transient synergistic effect in disease control, as most patients later developed metastatic lesions. The emergence of metastases may reflect the outgrowth of tumor clones with antigenic profiles distinct from the irradiated lesions suggesting sequential or repeated radiotherapy targeting new lesions could be explored as a strategy to re-induce local and systemic responses.
Belzutifan plus lenvatinib versus cabozantinib in post–PD-(L)1 renal cell carcinoma (RCC): Health-related quality-of-life (HRQoL) outcomes in the phase 3 LITESPARK-011 study.
e23270 Background: Belzutifan + lenvatinib significantly improved PFS and ORR vs cabozantinib, and had manageable safety, in participants (pts) with advanced RCC that progressed on or after anti–PD-(L)1 therapy in the phase 3 LITESPARK-011 study (NCT04586231). We report HRQoL outcomes from LITESPARK-011. Methods: Adults (≥18 y) with advanced RCC that progressed on or after anti–PD-(L)1 therapy as the immediate prior treatment were randomly assigned 1:1 to receive belzutifan 120 mg + lenvatinib 20 mg PO QD or cabozantinib 60 mg PO QD. HRQoL was evaluated in pts who received ≥1 dose of study treatment and completed ≥1 patient-reported outcome (PRO). Prespecified exploratory end points included time to deterioration (TTD) and least squares mean (LSM) change from baseline in FKSI-DRS, and EORTC QLQ-C30 global health status/quality of life (GHS/QoL), physical functioning (PF), and role functioning (RF) subscales. Questionnaires were completed electronically on day 1 of wk 1, 3, 5, and 9, Q4W thereafter, at treatment discontinuation, and 30 days after last dose. The analysis timepoint was wk 45 (last timepoint where completion and compliance rates of ~60% and ≥80%, respectively, were observed). PROs were not formally statistically tested. Results: The PRO analysis population included 731 pts (n = 365, belzutifan + lenvatinib; n = 366, cabozantinib). At data cutoff (Apr 9, 2025), median study follow-up was 29.0 mo (range, 19.3-49.2). Completion rates for FKSI-DRS and QLQ-C30 were > 85% at baseline (compliance > 86%) and > 55% at wk 45 (compliance > 89%) in each arm. TTD and LSM change from baseline in FKSI-DRS, QLQ-C30 GHS/QoL, PF, and RF scores were similar between arms (Table). Conclusions: Belzutifan + lenvatinib had similar TTD for FKSI-DRS, and GHS/QoL, PF, and RF vs cabozantinib. LSM changes in HRQoL and disease-specific symptoms from baseline to wk 45 were also similar for both arms. Combined with efficacy and safety data, results support belzutifan + lenvatinib as a new treatment option for advanced RCC that progressed after anti–PD-(L)1 therapy. Clinical trial information: NCT04586231 . Median TTD, mo(95% CI) Median TTD, mo(95% CI) LSM change from baseline (95% CI) LSM change from baseline (95% CI) Belzutifan + lenvatinib Cabozantinib Belzutifan + lenvatinib Cabozantinib FKSI-DRS 13.8 (6.4-20.3) 10.6 (7.4-20.2) −0.05 (−0.57-0.48) −0.23 (−0.75-0.30) HR 1.02 (95% CI, 0.82-1.28) - Difference 0.18 (95% CI, −0.51-0.87) - QLQ-C30 GHS/QoL 7.9 (5.5 to 13.1) 10.1 (6.5-19.3) −4.13 (−6.39-−1.87) −4.35 (−6.60-−2.11) HR 1.07 (95% CI, 0.86-1.34) - Difference 0.23 (95% CI, −2.70-3.15) - QLQ-C30 PF 7.9 (5.5-13.8) 11.6 (6.9-16.6) −5.66 (−7.78-−3.55) −3.96 (−6.06-−1.86) HR 1.13 (95% CI, 0.91-1.40) - Difference −1.70 (95% CI, −4.58-1.17) - QLQ-C30 RF 3.7 (2.8 to 6.5) 6.4 (4.6-8.2) −5.62 (−8.61-−2.63) −6.96 (−9.93-−3.98) HR 1.10 (95% CI, 0.90-1.35) - Difference 1.34 (95% CI, −2.59-5.26) -
Neighborhood-level disadvantage and disparities in treatment and recurrence in tenosynovial giant cell tumor.
e23528 Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm arising from the synovial lining of the joint, bursa, and tendon sheath. Although socioeconomic conditions negatively affect many rare cancers, its impact on TGCT is unknown. Real-world data are needed to define how neighborhood-level disadvantage, a composite measure of socioeconomic conditions derived from United States (US) census block data, affects TGCT treatments and outcomes. Methods: A total of 574 US adults enrolled in the TGCT Support Patient Registry (Oct 2022-Dec 2024). Residential addresses were geocoded to Area Deprivation Index deciles and grouped as more (ADI ≥ 8) or less disadvantaged (ADI < 8). 1:2 Propensity score matching (PSM; caliper 0.02) was performed based on sex, TGCT subtype, and tumor location. Conditional logistic regression models were adjusted for surgeries, recurrences, and surgical technique. Models were further adjusted for access to academic multidisciplinary teams (MDTs). Results: Among 574 eligible patients included, PSM resulted in 334 matched patients: 117 more disadvantaged and 217 less disadvantaged patients. Baseline demographic and clinical variables were similar except for education and employment. More disadvantaged patients were significantly less likely to receive systemic therapy (OR: 0.5; 95% CI 0.3-0.9; p = 0.04), more likely to undergo arthroplasty (OR: 3.6; 95% CI 1.5-8.5; p = 0.03), and numerically more likely to receive radiotherapy (OR: 1.8; 95% CI 0.6-5.1; p = 0.26) compared to less disadvantaged patients. After additional adjustment for MDT access, disparities in systemic therapy (OR: 0.9; 95% CI 0.4-2.0; p = 0.76), arthroplasty (OR: 1.7; 95% CI 0.9-3.7; p = 0.14), and radiotherapy (OR: 1.3; 95% CI 0.5-3.6; p = 0.58) attenuated. In contrast, more disadvantaged patients had significantly higher odds of local recurrence than less disadvantaged patients after full adjustment (OR 1.9; 95% CI 1.1-3.2; p = 0.02). Conclusions: This real-world analysis suggests that inequitable access to MDTs and neighborhood-level deprivation contribute to disparities in treatments and local recurrence rates among US TGCT patients. Treatments by disadvantage status using matched, adjusted conditional logistic regression. Less Disadvantaged (ref; n=217) (n, %) More Disadvantaged (n=117) (n, %) Adjusted OR (95% CI) p value Adjusted OR for Access to MDTs (95% CI) p value Systemic Therapy 52 (24.0) 18 (15.4) 0.5 (0.3, 0.9) 0.04 0.9 (0.4, 2.0) 0.76 Pexidartinib 41 (18.9) 13 (16.2) 0.5 (0.3, 1.0) 0.05 0.9 (0.4, 2.0) 0.72 Imatinib 17 (7.8) 8 (6.8) 0.7 (0.2, 1.8) 0.36 0.9 (0.3, 3.2) 0.91 Arthroplasty 11 (5.1) 18 (15.4) 3.6 (1.5, 8.5) 0.03 1.7 (0.9, 3.7) 0.14 Radiotherapy 11 (5.1) 8 (6.8) 1.8 (0.6, 5.1) 0.26 1.3 (0.5, 3.6) 0.58 Prior Surgery n=204 n=102 Recurrence(s) 103 (50.5) 66 (64.7) 1.6 (2.7, 1.0) 0.045 1.9 (1.1, 3.2) 0.02 No Recurrence 101 (49.5) 36 (35.3)
Actionable germline findings in endometrial cancer from a large multigene panel tested cohort.
10611 Background: Although most endometrial cancers (EC) are sporadic, 2–6% arise in the setting of Lynch syndrome (LS) or Cowden syndrome. The prevalence and clinical correlates of other germline pathogenic/likely pathogenic variants (PVs) remain incompletely characterized. We assessed the prevalence of potentially actionable germline PVs in EC and their clinicopathologic associations. Methods: This retrospective cohort included 3,844 EC patients (pts) who underwent pan-cancer germline multigene panel testing at a single diagnostic laboratory (2018–2025). Pts < 18 years, with mosaic results, or unclear pathology were excluded. Clinical and pathologic variables were compared between pts with and without PVs using appropriate statistical methods, including multivariable logistic regression. Results: The final cohort comprised 3,693 females; 46.6% were non-Hispanic White and 8.3% African American. Median age at testing was 62 years and median age at diagnosis was 57 years. Overall, 20.8% (n = 804) harbored a PV in a high- or moderate-penetrance gene. Among 852 PVs identified, 46.9% occurred in DNA damage response (DDR) genes, 37.0% in LS genes, and 16.1% in other genes. The most frequent DDR PVs were BRCA2 (12.6%), CHEK2 (9.2%), BRCA1 (8.0%), ATM (7.5%), PALB2 (3.1%). PTEN accounted for 3.2% of the PV. PV carriers were younger at testing (60 vs 62 years; p = 0.014) and diagnosis (54 vs 57 years; p < 0.001), more often African American (12.4% vs 7.2%; p < 0.001), and had higher rates of colorectal cancer (7.7% vs 3.4%; p < 0.001) and multiple primary cancers (41.7% vs 36.8%; p = 0.012). In multivariable analysis, younger age at EC diagnosis (OR 0.99; p = 0.028) and personal history of colorectal cancer (OR 1.84; p < 0.001) remained independently associated with PV status. Histologic subtype distribution differed between LS and DDR groups (p < 0.001); endometrioid tumors were more frequent in LS (26.6% vs 22.7%), whereas serous carcinoma (7.3% vs 1.1%) and carcinosarcoma (4.2% vs 1.8%) were more frequent in DDR. Among pts with available immunohistochemical (IHC) data (n = 810), 51.2% (n = 415) showed mismatch repair protein loss. Of these, 96 (23.1%) had PVs in LS genes, 13 (3.1%) in DDR genes, and 9 (2.2%) in other genes; 297 (71.6%) had no germline PV. Notably, among 161 pts with MLH1/PMS2 loss and confirmed MLH1 promoter methylation, 25 (15.5%) still harbored PVs; 4 (2.5%) in LS genes, 16 (9.9%) in DDR genes and 5 (3.1%) in other genes. Conclusions: Germline PVs were identified in over 20% of EC cases, extending beyond LS or Cowden syndrome. The presence of PVs in MLH1 -methylated tumors—traditionally considered sporadic—is a critical finding that challenges current tumor-only triage. These results support universal multigene germline testing in EC. A complementary case–control analysis including cancer-free controls and an independent validation cohort will be presented.
5–aminolevulinic acid fluorescence-guided surgery vs conventional white-light resection in glioma: A systematic review and meta-analysis.
e14076 Background: Gliomas are the most common primary malignant brain tumors, for which maximal safe surgical resection is a cornerstone of management to improve survival outcomes. The infiltrative nature of these tumors, however, makes distinguishing neoplastic from healthy tissue challenging with conventional white-light microsurgery. Fluorescence-guided surgery (FGS) using 5-aminolevulinic acid (5-ALA) has emerged as a tool to enhance intraoperative tumor visualization, but its long-term impact requires clarification. This systematic review and meta-analysis aims to evaluate the efficacy and safety of 5-ALA-guided resection compared to conventional surgery for newly diagnosed gliomas. Methods: A systematic literature search was conducted across multiple databases up to July 2025, including randomized controlled trials (RCTs) and cohort studies that compared 5-ALA FGS with standard white-light microsurgical resection in patients with newly diagnosed glioma. The primary outcomes were the rate of gross total resection (GTR), progression-free survival (PFS), and overall survival (OS). The incidence of new postoperative neurological deficits was assessed as a primary safety outcome. Data were pooled for meta-analysis using random-effects models. Results: Thirteen studies, comprising three RCTs and ten retrospective studies, were included in the final analysis, with a total of 2,211 patients. The meta-analysis revealed that the use of 5-ALA was associated with a significantly higher rate of GTR compared to the control group (Risk Ratio [RR] = 1.73, 95% Confidence Interval [CI] 1.57–1.91, p < 0.0001). This improvement in resection correlated with a significant benefit in 6-month PFS (RR = 1.46, 95% CI 1.08–1.99, p = 0.026) and 12-month OS (RR = 1.21, 95% CI 1.07–1.37, p = 0.0027). No significant difference was observed for 12-month PFS (p = 0.417) or the incidence of new neurological deficits between the two groups (RR = 1.29, 95% CI 0.62–2.69, p = 0.435). Conclusions: This meta-analysis provides strong evidence that 5-ALA fluorescence-guided surgery significantly increases the rate of gross total resection in patients with newly diagnosed glioma. This translates into improved short- and medium-term survival outcomes without an increased risk of postoperative neurological morbidity. These findings support the integration of 5-ALA as a standard of care in the surgical management of high-grade gliomas to maximize the extent of resection and improve patient outcomes.