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Comprehensive genomic profiling of adenoid cystic carcinoma using the AACR Genie Database.
6072 Background: Adenoid cystic carcinoma (ACC) is a rare neoplasm of the secretory glands, comprising <1% of head and neck tumors. While most commonly arising in salivary glands, ACC has also been reported in the skin, breasts, prostate, and female genital tract. Despite multimodal treatment, no standardized therapeutic approach exists, and prognosis remains poor, with a 5-year survival rate of 50-60%. This study utilizes the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database to characterize the genomic landscape of ACC and identify prognostic biomarkers and therapeutic targets. Methods: The AACR GENIE database was accessed via cBioPortal (v18.0-public) on December 12, 2025, to identify ACC cases. Frequently mutated genes, demographic associations, and patterns of mutual exclusivity were evaluated using two-sided t-tests and non-parametric analyses with Benjamini-Hochberg false discovery rate correction. Results: A total of 540 samples from 500 patients were analyzed, of whom 229 (45.8%) were male, and 266 (53.2%) were female. The cohort included 334 (66.8%) non-Hispanic patients and 39 (7.8%) Hispanic patients. By race, 334 (66.8%) were White, 46 (9.2%) Asian, and 42 (8.4%) Black. Most tumor samples were metastatic (293, 54.3%), followed by primary tumors (217, 40.2%). The most frequently mutated genes were NOTCH1 (n=152; 28.1%), KDM6A (n=59; 10.9%), ARID1A (n=54; 10.0%), BCOR (n=52; 9.6%), KMT2C (n=44; 8.1%), and KMT2D (n=42; 7.7%). Sex-stratified analysis demonstrated FH mutations occurring exclusively in females (n=4, p<0.001), and a higher prevalence of KMT2C in female patients (n=25 vs n=8, p<0.001). TET2 alterations were more frequent in males (n=8 vs n=1). Race-based analysis identified GATA3 mutations exclusively in Asian patients (n=2; p=0.002) and a higher frequency of FGFR3 alterations in Asians compared with non-Asian patients (n=2 vs n=1; p=0.0447). Co-occurrence was observed between NOTCH1 and ARID1A (n=21/106; p<0.001), CREBBP (n=17/98; p<0.001), and KDM6A (n=22/117; p=0.003). Additional co-occurrence was noted between KDM6A and ARID1A (n=14/80; p<0.001), and CREBBP with PIK3CA (n=8/50; p=0.001). Mutations in APC (n=6; p<0.001), CDK12 (n=4; p=0.05), ELF3 (n=4; p<0.05), MDM2 (n=4; p<0.05), and JAK2 (n=4; p<0.05) were observed exclusively in primary tumors. Conclusions: To our knowledge, this is the first comprehensive analysis of ACC using the GENIE database. Our findings corroborate prior reports implicating CREBBP , NOTCH1 , and KDM6A in ACC while identifying a novel demographic association with GATA3 mutations exclusive to Asian patients. These findings highlight CREBBP , NOTCH1 , KDM6A, and GATA3 as potential targets for future therapeutic development.
Financial toxicity and care access barriers among adolescent and young adult versus older melanoma survivors: A population-based analysis of 2021-2024 National Health Interview Survey data.
e21592 Background: Adolescent and young adult (AYA) cancer survivors may experience disproportionate financial toxicity and barriers to care as compared to older cancer survivors. Contemporary national estimates in melanoma survivorship are limited. We aimed to estimate financial toxicity and care barriers among AYA and older melanoma survivors. Methods: We pooled National Health Interview Survey (NHIS) 2021–2024 data and identified adults with a history of melanoma and known age at the time of melanoma diagnosis. Survivors were classified as AYA diagnosis (15–39 years) or older diagnosis (≥40 years). Outcomes included delayed medical care due to cost, inability to afford needed medical care, no usual place for medical care, worry about medical bills (very/somewhat vs not at all), and cost-related medication nonadherence (CRN; delayed filling, taking less, or skipping doses) among those reporting prescription use in the past year. We estimated survey-weighted prevalences and fit parsimonious survey-weighted log-link models to obtain adjusted prevalence ratios (aPRs) for older vs AYA diagnosis, adjusting for sex, insurance (Private/Public/Other), poverty (< 200% vs ≥200% Federal Poverty Level ), and survey year. Results: The analytic sample included 755 melanoma survivors (unweighted): AYA n = 124 and older n = 631. Prescription use was common (n = 688 unweighted). Weighted prevalence was higher in AYA vs older survivors for CRN among prescription users (7.5% vs 4.3%), delayed care due to cost (4.5% vs 3.8%), inability to afford needed care (5.3% vs 3.6%), no usual place for care (3.2% vs 1.4%), and worry about medical bills (33.8% vs 30.5%). In adjusted models, older vs AYA diagnosis was associated with lower prevalence for CRN (aPR 0.67, 95% confidence interval [CI] 0.25–1.80) and no usual place for care (aPR 0.38, 95% CI 0.07–2.07), though the estimates were uncertain. Adjusted differences were similarly uncertain for delayed care due to cost (aPR 1.44, 95% CI 0.52–3.97), inability to afford needed care (aPR 0.98, 95% CI 0.33–2.92), and worry about medical bills (aPR 1.16, 95% CI 0.83–1.63). Conclusions: AYA-diagnosis melanoma survivors demonstrated consistently higher national point estimates of financial and access barriers compared with older-diagnosis survivors. Although adjusted comparisons were imprecise, these findings support targeted survivorship interventions addressing medication affordability and care navigation for AYA melanoma survivors.
U.S. patient enrollment in pivotal clinical trials that supported FDA oncology approvals from 2020 to 2025.
e23030 Background: Adequate enrollment of U.S. patients in pivotal clinical trials designed to support applications for FDA approval help support applicability of trial results to the U.S. population. We sought to characterize contemporary patterns of U.S. patient enrollment in pivotal clinical trials supporting FDA oncology approvals. Methods: Pivotal clinical trials that supported FDA approvals of oncology indications and/or new patient populations for drug and biologic products from January 1, 2020, to December 31, 2025, were included in this analysis. Clinical trials of cellular and gene therapies were excluded. U.S. patient enrolment was summarized by trial type, product type, cancer type, and treatment setting. FDA review documents for these approvals were examined for documentation of factors supporting applicability of these pivotal trials’ results to the approved U.S. patient populations. Results: A total of 309 pivotal randomized controlled trials (RCTs) and non-RCT cohorts that supported 281 FDA oncology approvals of drugs and non-cellular biologics were included in this analysis. Characteristics of these pivotal trials are summarized in Table 1. In 18 (6.4%) of these approvals, no U.S. patients were enrolled across their pivotal trials. Documented factors that supported applicability of those trials’ results to their relevant U.S. patient populations included: conduct as multiregional clinical trials; similarity of known intrinsic and extrinsic factors in the trial and U.S. patient populations; and absence of trial conduct and/or data integrity issues. Conclusions: This exploratory analysis demonstrates that most FDA oncology approvals are based on pivotal clinical trials that enrolled U.S. patients, albeit with relatively lower U.S. patient enrollment in RCTs, and in pivotal trials in certain cancers and cancer settings. Pivotal trials for oncology indications that do not enroll U.S. patients may have limited applicability to U.S. patients. U.S. patient enrollment in pivotal trials that supported FDA approvals for oncology indications from 2020 to 2025. N Median US enrollment, % 0% US enrollment, % >0% to <10% US enrollment, % ≥10% to <50% US enrollment, % ≥50% US enrollment, % All Trials 309 16.1 6.2 30.7 40.8 22.3 Trial type RCT 177 8.9 7.9 46.3 34.5 11.3 Non-RCT 132 39.5 3.8 9.8 49.2 37.1 Product type Biologics 149 11.1 9.4 37.6 38.9 14.1 Non-biologics 160 24.0 3.1 24.4 42.5 30.0 Cancer type* Lung 49 7.3 8.2 53.1 28.6 10.2 Breast 22 13.4 0 36.4 50.0 13.7 Non-Hodgkin Lymphomas 22 18.6 0 31.8 45.5 22.7 Multiple Myeloma 17 5.0 11.8 41.2 35.3 11.8 Tumor Agnostic 17 37.9 0 5.9 70.6 23.5 Acute Leukemias 16 16.7 12.5 18.8 37.5 31.3 Urothelial 16 16.9 0 23.5 47.1 29.4 Treatment setting CIS/(neo)adjuvant 23 13.1 4.2 33.3 58.3 4.2 1 st line advanced/metastatic 135 11.3 9.6 37.5 34.6 18.4 2 nd and later-line advanced/metastatic 144 24.8 2.8 24.3 45.1 27.8 *Cancers with ≥15 trials; CIS=carcinoma in-situ; N =number of trials.
Clinical outcomes in <i>TP53</i> -mutated clonal hematopoiesis: Single-center retrospective study.
6594 Background: Clonal hematopoiesis (CH), including CH of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), is defined by myeloid neoplasm (MN)-associated somatic mutations in the absence of known hematologic malignancy and may precede MNs, such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). TP53 -mutated ( TP53 m) CH has been assumed to be high risk, but clinical outcomes are poorly characterized. Methods: We retrospectively evaluated patients (pts) with TP53 m CH seen at a tertiary cancer center. Inclusion required pathogenic or likely pathogenic TP53 mutations of presumed hematopoietic origin identified on bone marrow, peripheral blood, or plasma next-generation sequencing. Results: 62 pts with TP53 m CH were included; 26 (42%) CHIP and 36 (58%) CCUS. Median age was 68 years (range, 23–81) with 30 male pts (48%). History of tobacco, alcohol, and illicit drug use was noted in 30 (48%), 31 (50%), and 7 (11%) pts, respectively. Common comorbidities included cardiovascular disease (n=51, 82%), diabetes (n=17, 27%), and rheumatologic disorders (n=13, 21%). 53 pts (85%) had a history of non-myeloid malignancy, with 41 (77%) receiving prior cytotoxic chemotherapy, 20 radiation (32%), and 13 (21%) stem cell transplant/cellular therapy (SCTCT). By CH Risk Score (CHRS), 4 (7%), 38 (61%), and 20 (32%) pts were considered low-, intermediate-, and high-risk of myeloid transformation. The 36 CCUS pts were classified as 10 (28%) low, 9 (25%) intermediate, and 17 (47%) high risk by Clonal Cytopenia Risk Score (CCRS). Median TP53 VAF was 5% (range, 1–54), and 30 pts (46%) had additional somatic mutations. 12 pts (19%) were TP53 double-hit. Median time from prior malignancy to CH detection was 42.3 months (mo; range, 0.2–365.0). With a median follow-up time of 60.1 mo (95% confidence interval [CI], 43.0–70.5), median overall survival (mOS) from CH detection was 67.5 mo (95% CI, 59.0–not estimable [NE]). A total of 15 pts (24%) progressed to MNs (12 MDS [80%], 3 AML [20%]) with a median time to transformation of 20.2 mo (95% CI: 6.8–53.9). mOS from time of MN diagnosis was 20.1 mo (95% CI, 7.3–NE) for MDS and 0.3 mo (95% CI, 0.3–NE) for AML pts. Pts who transformed to MNs were more likely to have had tobacco (p=0.026) or illicit drug use (p=0.031), higher comorbidity burdens (p=0.031), rheumatologic disorders (p=0.016), previous SCTCT (p=0.042), and CCUS (p=0.035). No differences were observed by TP53 VAF. Of those who transformed, 7 (47%) were intermediate- and 8 (53%) high-risk by CHRS. CCRS showed low, intermediate, and high risk in 4 (33%), 1 (9%), and 7 (58%) of the 12 TP53 m CCUS pts who progressed to MNs, respectively. Conclusions: TP53 m CH is associated with significant comorbidity burdens and oncologic history. Existing risk stratification tools poorly predict myeloid transformation in these pts. Further clinicopathologic characterization of TP53 m CH is warranted.
Suicide gene therapy for recurrent glioblastoma using allogeneic bone marrow–derived mesenchymal stem cell gene delivery (MSC/CD): A first-in-human, dose-escalation phase I clinical trial.
2071 Background: Glioblastoma (GBM) remains an incurable brain tumor characterized by complex heterogeneity and poor prognosis, even with maximal multimodal therapy. Innovative treatments for recurrent GBM are urgently needed to complement existing therapies. This study explores the feasibility, safety, and efficacy of a novel suicide gene therapy using allogeneic mesenchymal stem cells (MSCs) expressing cytosine deaminase (CD) in combination with 5-fluorocytosine (5-FC). Methods: A Phase 1, single-center, non-randomized, dose-escalating study was conducted to evaluate the safety and efficacy of mesenchymal stem cell expressing cytosine deaminase (MSC/CD) therapy in 10 patients with recurrent GBM. Patients received intratumoral injections of MSC/CD followed by oral 5-FC. Pharmacokinetic profiling, pharmacodynamic analysis, targeted panel sequencing, whole transcriptome analysis, integrative omics analysis, and multiplexed immunofluorescence imaging were performed to assess drug conversion and identify predictable candidate biomarkers. Safety and survival outcome were monitored by evaluating adverse events (AEs) and clinical data. Results: MSC/CD therapy was well-tolerated, with most AEs being mild to moderate. There was no drug toxicity related with dose escalation. Severe AEs (≥ Grade 3) were rare and unrelated to the study drug. Effective conversion of 5-FC to 5-fluorouracil (5-FU) was observed in the brain, with detectable levels in the cerebrospinal fluid, confirming the feasibility of intracranial drug delivery. The median progression-free survival was 5.4 months, and the overall survival was 16.3 months. RNA transcriptomic analysis revealed two molecular subclusters with distinct biological characteristics, correlating with different progression-free survival outcomes. The integrative omics analysis revealed that specific cell cycle-related genes were found to be highly expressed in the non-responder group of patients, suggesting that elevated levels of these genes may be associated with resistance to treatment. Conclusions: This study demonstrates that MSC/CD therapy is a feasible, safe, and potentially effective treatment for recurrent GBM. The identification of distinct molecular subtypes and candidate genes offers a potential biomarker for patient selection and therapeutic targeting. Further studies are warranted to validate these findings and optimize therapeutic strategies. Clinical trial information: NCT04657315 .
Clinical and molecular landscape of MTAP-deleted thoracic tumors across Western and Asian cohorts: Implications for synthetic lethal targeting.
e20713 Background: Methylthioadenosine phosphorylase (MTAP) deletion creates a synthetic lethal vulnerability to protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferase 2A (MAT2A) inhibition. While early-phase trials targeting this pathway are ongoing, the clinicogenomic context of MTAP-deleted tumors remains incompletely characterized across diverse populations, despite its importance for optimizing patient selection and combination strategies. We utilized large-scale data to characterize MTAP deficiency in US and Japanese cohorts. Methods: We retrospectively analyzed genomic profiling data from two independent nationwide cohorts: AACR Project GENIE (United States; evaluable n = 11,091) and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT; Japan; evaluable n = 4,851). MTAP copy number alterations were assessed in lung, pleural, and thymic tumors. Analyses included histology-specific prevalence, co-mutation patterns with CDKN2A/B and other genes, associations with clinically actionable drivers, tumor mutational burden (TMB), and overall survival stratified by molecular subgroup. Results: In lung cancer, MTAP deletion occurred at comparable frequencies between adenocarcinoma and squamous cell carcinoma within each cohort (GENIE: 8.1% vs 9.8%; C-CAT: 19.6% vs 16.5%) but was rare in small cell lung cancer (GENIE: 1.0%; C-CAT: 1.9%). In thymic tumors, MTAP deletion was observed predominantly in thymic carcinoma (9.7%; 25.6%) and was uncommon in thymoma (0%; 3.2%). MTAP deletion was strongly associated with CDKN2A/B deletions and was rare in their absence. MTAP deletion frequently co-existed with actionable driver alterations, including EGFR mutations, ALK fusions, and ERBB2 alterations. A robust inverse association with RB1 mutations was observed in both cohorts. While MTAP deletion appeared associated with lower TMB (p < 0.01) and shorter overall survival in EGFR-mutated lung cancer (HR 1.73 [1.24-2.41], p < 0.01), these associations were largely attributable to enrichment of oncogenic drivers and concurrent CDKN2A loss, respectively. Conclusions: MTAP-deleted thoracic tumors exhibit reproducible clinical and molecular features across Western and Asian populations, characterized by frequent co-occurrence with actionable drivers and mutual exclusivity with RB1 alterations. Careful consideration of co-existing driver alterations and CDKN2A status is essential for interpreting prognosis and immunotherapy-related biomarkers. Our findings support the rational, globally applicable development of PRMT5/MAT2A-targeted synthetic lethal strategies in thoracic malignancies, particularly in combination with molecular targeted agents.
Liquid biopsy to stratify metastatic breast cancer progression risk using multi-analyte cell subtyping prior to systemic therapy.
e15060 Background: In metastatic Breast Cancer (mBC) Circulating Tumor Cells (CTCs) are an established prognostic indicator of patients (pts) with highly aggressive disease, poor clinical outcomes, and poor response rates to therapy. However, CTCs are typically found in < 20% of mBC pts and many pts without CTCs also progress. Cancer associated macrophage-like cells (CAMLs) are inflammatory tumor macrophages also found in blood, in > 90% of mBC, and are indicators of poor clinical outcomes independent of CTCs. We conducted a prospective study to model CTC & CAML subtypes from 212 mBC pt blood samples prior to induction of new systemic therapies to optimize and validate risk models based on 2-year outcomes of Progression-free survival (PFS) & Overall survival (OS). Methods: An observational multi-institutional prospective study was conducted on 212 mBC pts prior to induction of a new line of therapy who were progressing on their current therapy. Anonymized (7.5ml) whole blood samples were taken prior to therapy induction and filtered by CellSieve filtration. Quantities and subtypes of CTCs & CAMLs were categorized by their expression of CK+/CD45+/CD14+ for CAMLs and CK+/CD45-/CD14- for CTCs. PFS (RECIST v1.1) and OS hazard ratios (HRs) were calculated by censored univariate & multivariate analysis at 2 years. Results: Pt median age was 51 years (range 25-92); TNBC (44%), ER/PR+ (30%), HER2+ (15%). Pts were treated with chemotherapy alone (18%), immune checkpoint inhibitor (46%), targeted (40%), hormone (8%) and unknown (5%). 38% (81/212) pts had ≥1 CTCs which correlated with significantly poorer PFS (HR = 1.9; 95%CI 1.3-2.7; p = 0.0016) and OS (HR = 2.0; 95%CI, 1.3-3.0; p = 00025), with the most significant risk at ≥8 CTCs (14% pts), PFS (HR = 3.8; 95%CI, 2.1-6.9; p < 0.0001) and OS (HR = 7.2; 95% CI, 3.4-14.9; p < 0.0001). Independently, 93% (n = 196/212) of pts had ≥1 CAML, with a threshold of >40um size (84% pts) had significantly poorer PFS (HR = 2.0; 95% CI, 1.2-3.1; p = 0.0032), but not OS (HR = 1.5; 95%CI, 0.9-2.7; p = 0.1169). However, a threshold of >125um size CAML (43% pts) also had significantly poorer PFS (HR = 1.8; 95% CI, 1.2-2.7; p = 0.0013) and OS (HR = 1.6; 95% CI, 1.0-2.5; p = 0.0233). By combining models, the best outcomes were seen in pts with 0 CTCs & 0 CAMLs (mPFS = 12.6 & mOS = 21.3), followed by 0 CTCs & ≥40um CAMLs (mPFS = 5.2 & mOS = 17.5) and 0 CTCs & ≥125um CAMLs (mPFS = 4.9 & mOS = 15.2). Poorer outcomes were seen with ≥1 CTCs (mPFS = 3.3 & mOS = 13.5) and the worst outcomes with ≥8 CTCs (mPFS = 2.5 & mOS = 4.8). Conclusions: CTCs were uncommon in mBC pts but correlated with very poor clinical outcomes. In parallel analysis, CAMLs were common with CAML size correlating with increasingly poorer outcomes. By combining CTC & CAML subtypes, mBC pts were more accurately stratified by risk of progression and death. Additional multivariate studies correlating treatment class and tumor response rates are ongoing.
Cost-saving analysis of neoadjuvant versus adjuvant immunotherapy in clinical stage III melanoma: A real-world Brazilian perspective.
e21544 Background: Neoadjuvant immunotherapy has become a new standard for resectable clinical stage III melanoma, driven by improved event-free survival and high pathological response rates in randomized trials. In addition to clinical benefit, this strategy may reduce cumulative treatment exposure compared with conventional adjuvant anti–PD-1 therapy. However, real-world economic evaluations comparing neoadjuvant and adjuvant approaches remain limited, particularly in middle-income countries. We estimated and compared direct medical costs of a neoadjuvant strategy based on the NADINA protocol versus standard adjuvant anti–PD-1 therapy in clinical stage III melanoma. Methods: This cost-saving estimate analysis evaluated direct medical costs related to medications and exams using the care pathway of A.C.Camargo Cancer Center, a Brazilian private cancer center. Neoadjuvant and adjuvant treatment protocols, including dosages and frequencies, were defined according to expert opinion and contemporary clinical literature. Drug costs were based on the hospital’s 2025 mean acquisition prices, and exam costs reflected institutional delivery costs without profit margin. Cost differences were calculated per complete treatment cycle. All costs were collected in Brazilian reais (R$) and converted to US dollars (US$). Results: In the neoadjuvant scenario, patients received 2 cycles of nivolumab (240 mg) plus ipilimumab (80 mg), with 40% requiring additional adjuvant therapy consisting of 10 cycles of nivolumab (480 mg). In the adjuvant scenario, all patients received 12 cycles of nivolumab (480 mg). Exam frequency was identical between scenarios, except for one additional PET/CT in the neoadjuvant strategy. Total estimated cost per treatment cycle was R$ 365,949 (US$ 69,177) for the neoadjuvant approach and R$ 581,595 (US$ 109,942) for the adjuvant approach, yielding an estimated cost saving of R$ 215,645 (US$ 40,764) per cycle. Conclusions: A neoadjuvant immunotherapy strategy based on the NADINA protocol was associated with meaningful direct cost savings compared with standard adjuvant anti–PD-1 therapy in clinical stage III melanoma. Reduced exposure to prolonged adjuvant treatment offset the higher upfront costs of combination immunotherapy. These findings suggest that neoadjuvant immunotherapy may offer not only clinical advantages but also improved economic efficiency in real-world practice. Prospective health economic analyses incorporating long-term outcomes are warranted to further inform policy and reimbursement decisions.
Clinical factors associated with durable response to atezolizumab in extensive-stage small-cell lung cancer: A real-world analysis in Moscow.
e20160 Background: Atezolizumab (A) in combination with platinum-etoposide chemotherapy represents the current standard of care for the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC). However, sustained clinical benefit is achieved only in a limited cohort of patients (pts). Identifying predictors of long-term response may optimize patient selection and improve understanding of immunotherapy outcomes in SCLC. Methods: This retrospective real-world study included 335 consecutive pts with ES-SCLC (stage III – 34 pts, stage IV – 301 pts) who received first-line treatment with atezolizumab in combination with platinum-etoposide chemotherapy. Long responders (LRs) were defined as pts achieving progression-free survival (PFS) 12 months or longer. Baseline demographic, clinical, radiological and laboratory characteristics were collected and compared between LRs and pts without durable response using chi-square tests with Yates correction and t-tests. Results: Seventy-five pts (22.4%) were classified as LRs. Median age in the overall cohort was 63 years (range 26–82), 61 years in LRs (range 36–82). In the entire population median PFS was 6.9 months (95% CI, 6.4–7.4), with a 1-year PFS rate of 26.4%; median overall survival (mOS) was 12.1 months (95% CI, 10.2–13.9), with a 1-year OS rate of 50.3%. LRs demonstrated a markebly prolonged OS compared with non–long responders (non-LRs): mOS 47.9 vs 8.6 months. 10 pts (13,3%) in LRs-group had st III disease. Favorable ECOG performance status (0–1) was more common among LRs (53.3% vs 35.8%, p = 0.013). Disease burden was higher in non-LRs group: liver metastases (40.0% vs 14.7%, p < 0.001), bone metastases (28.5% vs 14.7%, p = 0.023), and elevated lactate dehydrogenase (LDH) above the upper limit of normal (65.6% vs 34.3%, p < 0.01). No significant differences were observed between LRs and non-LRs in the incidence of brain metastases, age ≥65 years, gender, or laboratory parameters including transaminase elevation, serum calcium, C-reactive protein, and albumin levels. Conclusions: In this real-world ES-SCLC cohort, approximately one-fifth of pts achieved durable benefit from atezolizumab beyond 12 months. Favorable ECOG performance status (0–1) and non-elevated LDH may suggest a benefit from using atezolizumab with platinum-etoposide agents while other features (ECOG 2-3, liver and bone mts and elevated LDH) reflect aggressive disease biology and associates with lack of long-term response. These readily available clinical factors may help identify patients less likely to derive durable benefit from immunotherapy and warrant prospective validation.
Real-world efficacy and safety of sintilimab combined with nab-paclitaxel and S-1 as first-line treatment for locally advanced or metastatic pancreatic ductal adenocarcinoma: A single-center retrospective study.
e16373 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis, and effective first-line treatment options remain limited. This study evaluated the real-world efficacy and safety of sintilimab combined with nab-paclitaxel and S-1 (AS) in patients with locally advanced or metastatic PDAC. Methods: This single-center retrospective study included patients with PDAC who were treated with sintilimab in combination with nab-paclitaxel and S-1 at Harbin Medical University Cancer Hospital between January 2023 and May 2025. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). Results: A total of 37 patients were enrolled, with a median follow-up of 16.2 months. The median OS (mOS) was 12.2 months (95% CI, 9.9–14.5), and the median PFS (mPFS) was 8.6 months (95% CI, 5.6–11.6). All patients were evaluable for treatment response, with an ORR of 40.5% and a DCR of 91.9%. Four patients subsequently underwent curative-intent surgery, including one patient who achieved a pathological complete response (pCR). Exploratory circulating tumor DNA (ctDNA) methylation analysis in seven patients showed decreased methylation levels after two treatment cycles compared with baseline. Stratification according to CA19-9 trajectories at 6 weeks revealed significant differences in OS and PFS among patient subgroups (OS: P < 0.0001; PFS: P = 0.0001). Patients with a marked CA19-9 decline (≥50%) exhibited the most favorable survival outcomes (median OS not reached; median PFS, 10.2 months). Two patients experienced Grade ≥3 irAEs, which were manageable. The remaining irAEs were Grade 1–2, most commonly hypothyroidism (18.9%), elevated transaminases (5.4%), diarrhea (5.4%), and rash (5.4%). Conclusions: Sintilimab combined with nab-paclitaxel and S-1 demonstrated promising antitumor activity and an acceptable safety profile in patients with locally advanced or metastatic PDAC. Blood-based ctDNA methylation may serve as a potential predictive biomarker for treatment response. Further validation in large-scale phase III clinical trials is warranted.
Has racial and ethnic representation in oncology clinical trials changed?: A 30-year systematic analysis using artificial intelligence.
11079 Background: Despite societal emphasis on racial and ethnic representation in oncology trials, it remains unclear whether participant diversity has meaningfully changed over time. Recent advances in large language models (LLMs) enable scalable extraction of data from PDF documents, facilitating high-throughput research. Methods: We identified all oncology clinical trials published in The Lancet and The New England Journal of Medicine (NEJM) between 1995 and 2025, and retrieved full-text PDFs from the journals' websites. Using an LLM (Gemini-2.5-Flash), structured variables, including trial phase, cancer type, enrollment countries, and participant race and/or ethnicity, were automatically extracted from texts, tables, and figures. Trials were stratified by decade (1995–2005, 2006–2015, and 2016–2025) to evaluate temporal trends. Results: We identified 1,385 oncology trials between 1995 and 2025, including 334, 448, and 603 for the three decades, respectively. The proportion of phase III trials increased steadily over time (68%, 72%, and 76%). Trials also became more globally distributed, with multi-continental studies rising from 27% to 46% and 58%. Most notably, Asian countries were increasingly involved among trial enrollment sites, rising from 14% to 25% and 45%. Reporting of race/ethnicity increased over time, from 16% to 29% and 47% of publications across decades. Among studies that reported race, non-White enrollment increased, with the median percentage per study rising from 10% in both earlier decades to 21% in 2016–2025. However, after excluding Asian participants, the median non-White percentage declined across decades (7.5%, 5.3%, and 4.3%). In pooled analyses across all trials, non-White patients comprised 15%, 11%, and 15% of total enrollment, respectively; excluding Asian patients, this decreased from 13.2% to 6.2% and 6.9%. Black enrollment declined over time, with the median percentage falling from 6.8% to 2.4% and 1.5%. Among trials reporting ethnicity, Hispanic enrollment remained consistently low (5.4%, 4.0%, and 4.6%). Conclusions: Globalization and race/ethnicity reporting in oncology trials improved, but the observed increases in diversity were largely attributable to the expansion of trial enrollment in Asia. In contrast, Black and Hispanic representation remained low or declined across decades. 1995-2005, n (%) 2006-2015, n (%) 2016-2025, n (%) Total Studies 334 448 603 Clinical Trial Phase Phase 1 78 (23) 86 (19) 55 (9) Phase 2 25 (7) 38 (8) 87 (14) Phase 3 228 (68) 323 (72) 460 (76) Major Cancer Types Breast 55 (17) 64 (14) 78 (13) Hematologic 54 (16) 77 (17) 114 (19) Colorectal 49 (15) 40 (9) 29 (5) Lung 17 (5) 37 (8) 66 (11) Continents Africa 16 (5) 29 (6) 16 (3) Asia 47 (14) 113 (25) 274 (45) Europe 158 (47) 272 (61) 403 (67) North America 102 (31) 219 (49) 361 (60) South America 0 (0) 5 (1) 19 (3) Oceania 43 (13) 134 (30) 203 (34)
Characteristics and survival of 4N and non-4N metastatic neuroblastoma across treatment eras: A report from the International Neuroblastoma Risk Group Task Force.
10007 Background: Patients with metastatic neuroblastoma confined to distant lymph nodes (4N) were identified as a subgroup with superior outcomes to those with metastases to other sites. Over the past two decades, outcomes for high-risk neuroblastoma have improved from increasingly effective and intense therapy, while intermediate-risk patients have maintained excellent outcomes with biology and response-based therapy. We aimed to determine if 4N patients remained a favorable subgroup with contemporary therapy. Methods: Patients with International Neuroblastoma Staging System (INSS) stage 4 disease in the International Neuroblastoma Risk Group Data Commons diagnosed between 1990-2020 were evaluated. Those with metastases only to the distant lymph nodes were defined as 4N. All other patients were defined as non-4N. Treatment eras included: 1999 and prior, 2000-2009, 2010 and later which correspond to standardization of multimodal therapy, stem cell transplant, and anti-GD2 immunotherapy for high-risk patients. Differences between 4N and non-4N patients were assessed with chi-square, Wilcoxon rank sum, and t-tests. Five-year Kaplan-Meier estimates of survival with 95% confidence intervals and multivariable Cox proportional hazards modeling were used to evaluate event-free (EFS) and overall (OS) survival. Results: The analytic cohort included 107 4N and 5976 non-4N patients. There were no clinical differences between 4N and non-4N patients apart from unfavorable histology (74.2% [4N] versus 60.1% [non-4N]; p=0.02). 5-year EFS and OS were higher for 4N compared to non-4N patients (p=0.001 and 0.001, respectively). Though survival estimates for 4N were higher in each era, the difference was not statistically significant for patients diagnosed from 2000-2009 nor 2010 and beyond; (1999 and prior: EFS 58.7% (40.9-72.7%) versus 31.8% (29.7-33.9%) p=0.001; OS, 66.2% (48.1-79.3%) versus 37.9% (35.7-40.1%) p=0.002, 2000-2009: EFS, 47.9% (34.0-60.5%) versus 36% (34.1-37.9%) p=0.179; OS, 55.4% (40.7-67.8%) versus 45.1% (43.1-47.1%) p=0.122, and 2010 and later: EFS, 63.6% (29.7-84.5%) versus 42.8% (39.9-45.6%) p=0.178; OS, 71.6% (35.0-89.9%) versus 52.3% (49.2-55.3%) p=0.207. Log-rank calculations may have been underpowered in part due to small sample sizes (n=39, 56, and 12) of each 4N subgroup, respectively. 4N patients had superior EFS (HR=0.48; p=0.0004) and OS (HR=0.49; p=0.0009) in a model which included age, MYCN -amplification status, treatment era, ferritin, and LDH. A sensitivity analysis using only high-risk patients age >18 months yielded similar results. Conclusions: Patients with stage 4N neuroblastoma are a rare subgroup which appears to continue to have favorable outcomes with contemporary therapy. Additional studies to identify opportunities to reduce therapy intensity for this subgroup are warranted.
Health-related quality of life.
1109 Background: Trials typically pool patient-reported outcomes across demographics, assuming baseline differences reflect normal variation. When adequate enrollment permits disaggregation, nuanced patterns emerge across quality-of-life domains. Methods: Individual participant data meta-analysis of 15 breast cancer trials (N=12,656). HRQoL domains (Physical, Emotional, Social, Role, Cognitive) and breast symptoms assessed via EORTC QLQ-C30/FACT-B at baseline, treatment, and post-treatment. Comparisons: Hispanic vs Not-Hispanic; White vs Asian vs Black vs Other. Dual approach: 1) direct between-group comparisons, 2) pooled within-group trajectories revealing between-group mean differences and absolute changes. Results: Population: 2.3% Black, 9.6% Hispanic, 19.9% Asian. Baseline disparities were substantial and domain-specific. Hispanic demonstrated higher cognitive functioning (MD 2.72, p<0.05). Black had superior role functioning versus White (84.11 vs 67.19, MD -7.80, p<0.001); all minority groups scored lower on emotional functioning (Black MD -4.76, Asian MD -3.34, Other MD -1.88, all p<0.001). During treatment, Hispanic maintained physical (MD 1.99, p<0.05) and role functioning (MD 3.67, p<0.05); Asian showed less role decline (MD 2.61, p<0.01). All groups experienced similar symptom improvement and cognitive decline. Post-treatment divergence: Black patients' breast symptoms worsened (change +1.27) while Asian showed highest improvement (change -2.09, p<0.05). Hispanic cognitive advantage eroded (MD -1.77, p<0.05), and treatment resilience disappeared. Uniform 60% attrition across all groups. Conclusions: Equal treatment response does not equal equity when groups enter with disparate baselines and experience differential post-treatment trajectories. Post-treatment divergence was striking: Black patients' symptoms worsened while Asian improved most—invisible in binary White vs Not-White comparisons. Hispanic treatment resilience disappeared in survivorship and cognitive advantages eroded. Uniform 60% attrition demonstrates recruitment, not retention, is the barrier requiring redirection of diversity initiatives. Even pooling 15 trials, Black and Hispanic representation remained inadequate. Equal treatment perpetuates existing disparities from unequal starting points or creates new disparities through differential recovery. Trial equity requires adequate diverse enrollment and interventions addressing pre-enrollment disparities and post-treatment survivorship needs.
Real-world outcomes of immune checkpoint inhibitors in patients aged 65–74 versus ≥75 years with non-small cell lung cancer.
e20642 Background: Immune Checkpoint Inhibitors (ICIs) have shown significant survival benefit in the treatment of Non-Small Cell Lung Cancer (NSCLC). However, adults ≥75 years, remain under-represented in clinical trials despite comprising a growing proportion of patients with cancer and are often grouped as “older adults” (≥65 years), which may overlook age related physiological and pathophysiological complexity. Methods: We conducted a multicenter retrospective cohort study using the TriNetX network to compare real-world ICI outcomes in patients aged 65–74 years with those ≥75 years. Inclusion criteria included ICD 10-code for malignant neoplasm of the bronchus and lung, and treatment with pembrolizumab, nivolumab, cemiplimab, atezolizumab, durvalumab, and/or ipilimumab. Exclusion criteria consisted of patients on chemotherapy and those with small cell lung cancer, neuroendocrine tumors, carcinoid tumors, hematological/lymphoid malignancies, ulcerative colitis, Crohn’s disease, microscopic colitis, and history of organ transplant. There is no specific ICD-10 code for NSCLC, but these cohorts aim to reflect real-world NSCLC treatment regime, as ICIs are not routinely used in small cell lung cancer. Patients were divided into two cohorts: 65–74 years (Cohort 1) and ≥75 years (Cohort 2). Index date was defined as the first documented ICI administration. Propensity score matching (1:1) was performed on demographic variables, measure of association analysis was used to calculate outcome proportions and survival outcomes were analyzed using Kaplan-Meier analysis. Primary outcome was all-cause mortality. Secondary outcomes included ICU admission, systemic corticosteroid initiation, incidence of pneumonitis, gastrointestinal colitis, hepatitis, myocarditis, and ICD-10 code adverse effects of ICI (T45.AX5 A/D/S). Results: After propensity score matching, each cohort included 4,300 patients. All-cause mortality was significantly lower in patients aged 65-74 compared to those ≥75 years (41.2% vs 51.5%). Risk Difference (RD) was −10.3% (95% CI −0.124 to −0.082; p < 0.001), and odds ratio was 0.660 (95% CI 0.606–0.718). Gastrointestinal colitis/enterocolitis occurred more frequently in patients 65–74 than in those ≥75 years (9.7% vs 7.9% - RD of 1.8% 95% CI 0.006-0.030%; p = 0.003). No significant differences were observed in ICU admission, pneumonitis, myocarditis, systemic corticosteroid initiation, or ICD-10–coded ICI adverse effects. Conclusions: The higher rate of mortality in patients aged ≥75 years with NSCLC treated with ICIs but with lower rates of gastrointestinal colitis/enterocolitis, highlights the heterogeneity and complexity in outcomes in the older adult population. Due to increasing proportion of geriatric patients among individuals with cancer, focus on age-stratified research may improve prognostication and guide treatment plans.
Major adverse cardiovascular events in androgen receptor signaling inhibitor–treated patients with metastatic castration-sensitive prostate cancer.
5107 Background: Cardiovascular disease is highly prevalent in the predominantly older male population with metastatic castration-sensitive prostate cancer (mCSPC). Androgen receptor pathway inhibitors (ARPIs) form the backbone of contemporary doublet and triplet treatment strategies, but—as with any systemic therapy—may influence patients’ underlying cardiovascular risk. This study compares the incidence of major adverse cardiovascular events (MACE) in real-world mCSPC patients treated with darolutamide versus abiraterone. Methods: This retrospective cohort study included patients in the nationwide VA healthcare system initiating doublet or triplet abiraterone or darolutamide for newly diagnosed mCSPC. After inverse probability of treatment weighting (IPTW), 1-year cumulative MACE incidence was estimated via Kaplan-Meier analysis. Doubly robust multivariable Cox regression using IPTW and multivariable competing risk regression with death as a competing risk assessed the association between treatment and MACE. All analyses were adjusted for age, race, prior MACE, NCI Charlson Score, smoking status, and prior hypertensive combination treatment. Results: Among 11,788 patients initiating darolutamide or abiraterone for mCSPC, 9,952 received abiraterone doublet, 936 received darolutamide doublet, 374 received abiraterone triplet, and 526 received darolutamide triplet therapy. In the weighted cohort, the 1-year cumulative incidence of MACE was lower in patients receiving darolutamide (7.2%, 95% confidence interval [CI] 5.6-9.0%) versus abiraterone (10.7%, CI 10.0-11.4%) doublet therapy. For triplet therapy, 1-year MACE incidence was 5.3% (CI 3.4-7.4%) with darolutamide and 9.6% (CI 5.9-13.6%) with abiraterone. In doubly robust multivariable Cox models, darolutamide doublet was associated with a lower hazard of MACE compared to abiraterone doublet (hazard ratio [HR] 0.78, CI 0.62-0.96, P=0.03). For triplet, patients receiving darolutamide had a HR of 0.73 for MACE (CI 0.39-1.31, p=0.29) compared to patients receiving abiraterone triplet therapy. Competing risk models showed consistent results. Conclusions: Darolutamide, particularly in doublet therapy, was associated with lower MACE risk than abiraterone. A similar point estimate in triplet therapy warrants validation in larger cohorts. These findings may inform treatment selection or prophylactic management to improve cardiovascular outcomes in mCSPC.
PUNCH03: Preliminary results from a phase II study of disitamab vedotin combined with tislelizumab and Bacillus Calmette-Guerin (BCG) in Her2-positive high-risk non-muscle-invasive bladder cancer (HR NMIBC).
4597 Background: Disitamab vedotin (RC48) was a novel antibody drug conjugate that targets the Her2 protein. The KEYNOTE-057 study has supported the benefits of PD-1 inhibitor in HR NMIBC patients (pts). Our study was established to evaluate the efficacy and safety of RC48 combined with tislelizumab and BCG as a bladder-preserving treatment for Her2-positive HR NMIBC pts. Methods: This open-label phase II study enrolled BCG-naïve HR NMIBC pts with multiple papillary tumors (high-grade Ta or T1 tumors), and all pts were Her2-positive (IHC 2+ or 3+). Firstly, the papillary tumors should be removed all visible lesions by transurethral resection of bladder tumor (TURBT). Secondly, pts were administered RC48 (2.0 mg/kg, ivgtt), every 2 weeks for 1 cycle, and were administered tislelizumab (200 mg, ivgtt), every 3 weeks for 1 cycle. Then, pts received second TURBT. Finally, pts received at least 1 year of tislelizumab (200 mg, Q3W, ivgtt). Meanwhile, pts were administered 3 - 5 cycles of RC48 (2.0 mg/kg, Q2W, ivgtt) and received 18 instillations of BCG. Specifically, pts were started on an induction course of BCG with 6 instillations every week, followed by maintenance with 3 instillations every 2 weeks and 9 instillations every 4 weeks. The primary end point was recurrence-free survival (RFS) rate at 12 months (defined as no reappearance of high grade or T1 tumors or clinical stage development after the therapy). Secondary end points were bladder-preservation rate, OS and safety. Our study estimated a RFS rate at 12 months was no less than 85% and the study would enroll 38 pts. Results: By Aug. 2025, 24 eligible pts were enrolled and analyzed (male 87.5%; median age 63 years (38-85); IHC 2+ =58.3%, IHC 3+ =41.7%; tumor size≥3 cm (50%); cT1=100.0%; 75.0% multiple papillary tumours. Median follow-up was 6.1 months (3.1-14.2), the median number of tislelizumab cycles was 10 (4-16) and RC48 cycles was 6 (4-8). All pts completed tislelizumab and RC48 treatment during the induction therapy. During the follow-up, only two pts showed reappearance and one pt received radical cystectomy. The bladder-preservation rate was 95.8% (95%CI, 90.7%-100%). The common treatment related adverse events (TRAEs) of any grade were fatigue (54.2%), alopecia (33.0%), anorexia (33.0%) and peripheral neuropathy (16.8%). None 3-5 grade of TRAEs were observed. Conclusions: Our preliminary results supported the use of disitamab vedotin combined with tislelizumab and BCG as a bladder-preserving therapy for Her2-positive HR NMIBC pts. Clinical trial information: ChiCTR2400093839.
Assessment of recurrence risk in stage IIB/C melanoma across time: Implications for stratification and surveillance.
9568 Background: Stage IIB/C cutaneous melanoma is associated with high recurrence risk, however stratification of risk in relation to time after surgery has not been comprehensively evaluated. We evaluated recurrence-free survival (RFS) at key time points, stratified by clinicopathologic factors, to identify patients (pts) at higher recurrence risk and personalize postoperative surveillance strategies. Methods: In this multi-institutional, international retrospective cohort study from the Sentinel Lymph Node Working Group database, we included pts with pathologic T3b/T4a/T4b and N0 disease who underwent surgical resection and sentinel node biopsy from 1994-2025. The type of first recurrence (local, regional, distant) was characterized based on time category (0-12, 12-24, 24-60, and 60+ months after surgery). Restricted mean survival time (RMST) analysis was used to measure the average survival time up to a specified time point (6-, 12-, 24-, and 60-months after surgery), and associations of clinicopathologic variables (age, sex, Breslow thickness, ulceration and lymphovascular invasion [LVI]) with RFS. Results: We included 2514 stage IIB/C pts from 19 sites in 4 countries, with a median follow-up of 53 (stage IIB) and 49 (stage IIC) months. 675 (27%) pts experienced a recurrence (92 [14%] local, 238 [35%] regional and 345 [51%] distant), and 400 (59%) recurrences occurred within 24 months. The proportion of distant recurrences as the first recurrence increased significantly with time, comprising 39%, 50%, 62%, and 59% of recurrences in the 0-12, 12-24, 24-60, and 60+ month time categories respectively (χ 2 p<0.001). No significant differences were observed for the included clinicopathologic variables for 6-month RMST estimates. At 12 months, RMST estimates for thickness ≥4 mm (11.2 vs 11.6 months for thickness 2-3.99 mm, p<0.001) and presence of LVI (10.7 vs 11.4 months, p=0.009) were significantly different. 24-month RMST estimates differed for male sex (20.7 vs 21.5 months vs females, p=0.002), thickness ≥4 mm (20.5 vs 21.9 months, p<0.001), and presence of LVI (19.0 vs 21.1 months, p<0.001). Lastly, 60-month RMST estimates differed for male sex (42.0 vs 45.2 months, p=0.001), thickness ≥4 mm (41.5 vs 46.2 months, p<0.001), LVI (36.0 vs 43.7 months, p<0.001), and age >65 years (41.5 vs 46.4 for age <42, p=0.022). Conclusions: In this real-world, multi-center analysis of pathologic stage IIB/C melanoma pts, recurrence patterns varied based on time after surgery. Breslow thickness, LVI, male sex, and age were significantly associated with earlier recurrence at different time intervals on RMST analysis. Additionally, given that >50% of first recurrences 12+ months after surgery were distant, active surveillance for distant relapses may be warranted.
The impact of surgery and the type of immune check point inhibitors (ICI) in patients with locally advanced head and neck squamous cell carcinoma (LA HNSCC) receiving immunotherapy: An updated systematic review and meta-analysis of randomized controlled trials.
e18081 Background: Locally advanced head and neck squamous cell carcinoma (LA HNSCC) remains a clinical challenge with high recurrence rates despite standard-of-care definitive or perioperative therapy. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of recurrent or metastatic disease, their efficacy in the curative-intent setting for LA HNSCC is less clear. This meta-analysis evaluates the efficacy of ICIs in this setting, specifically examining the impact of surgical intervention and the distinct roles of PD-1 versus PD-L1 blockade. Methods: A systematic search of MEDLINE and EMBASE was conducted through January 10, 2026, to identify Phase II and III randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors (ICIs) in locally advanced head and neck squamous cell carcinoma (LA HNSCC). Clinical trials also covered both definitive (non-surgical) and perioperative (surgical) settings. To explore biological drivers of efficacy, trials were stratified by ICI target: PD-1 inhibitors (Pembrolizumab, Nivolumab) and PD-L1 inhibitors (Avelumab, Durvalumab, Atezolizumab). The primary endpoints were progression-free survival (PFS), event-free survival (EFS) or disease-free survival (DFS). Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects inverse variance model. Study heterogeneity was evaluated using Cochran’s Q and the I² statistic. Results: A total of seven trials (n=3605), one phase II (GORTEC 2015-01 PembroRad) and six phase III (NRG-HN004, KEYNOTE-412, NIVOPOSTOP, JAVELIN Head and Neck 100, KEYNOTE-689, and IMvoke010) were included in the primary analysis. In the overall cohort, adding ICIs did not significantly improve PFS, EFS, or DFS (HR 0.90; 95% CI, 0.77–1.06; p=0.20) or OS (HR 0.95; 95% CI, 0.80–1.14; p=0.59). However, significant differences emerged upon segregation. A significant PFS benefit was observed in the perioperative/surgical group (HR 0.75; 95% CI, 0.64–0.88; p=0.0003), but not in the definitive/non-surgical group (HR 1.01; 95% CI, 0.84–1.22; p=0.89). PD-1 inhibitors significantly improved PFS (HR 0.78; 95% CI, 0.69–0.89; p=0.0001). PD-L1 inhibitors provided no significant benefit (HR 1.12; 95% CI, 0.92–1.36; p=0.26). Conclusions: The addition of ICIs to standard therapy for LA HNSCC does not provide a universal survival benefit. The therapeutic efficacy of ICIs in this setting appears to be restricted to patients undergoing surgical resection and those treated with PD-1 rather than PD-L1 inhibitors. Further research is required to refine patient selection and optimize treatment sequences for high-risk LA HNSCC populations.
Building a patient-driven, integrated research infrastructure to accelerate therapeutic advances in colorectal cancer.
e15615 Background: Despite major scientific advances, colorectal cancer (CRC) remains a leading cause of cancer-related mortality. Progress toward improved outcomes has been constrained by siloed datasets, limited inclusion of diverse patient populations, and slow translation of discovery science into clinical impact. To address these challenges, the Colorectal Cancer Alliance initiated Project Cure CRC in 2023 as a national, patient-centered research infrastructure designed to integrate data, clinical investigation, and collaborative discovery. The initiative seeks to shorten the path from biological insight to effective therapies while improving survival and equity in CRC care. Methods: Project Cure CRC integrates four complementary pillars into a unified ecosystem. First, an adaptive clinical trial framework evaluating perioperative, neoadjuvant, and minimal residual disease (MRD) strategies across CRC subtypes. Second, BlueLake serves as a real-world evidence and data integration platform, linking clinical, molecular, and patient-reported outcomes to support hypothesis generation and care optimization. Third, BlueHQ provides a digital engagement environment that enables patient navigation, peer connection, longitudinal data contribution, education, and participation in research. Fourth, a competitive and peer-reviewed funding program supports early-career investigators, senior investigators, pilot studies, and team science initiatives, with an explicit mandate to feed discoveries into the adaptive clinical trial and BlueLake for rapid validation and translation. Results: Since inception, Project Cure CRC has reviewed more than 525 research proposals and allocated over $15 million in funding to 33 projects spanning biomarker development, translational science, and health equity. The program has engaged more than 150 academic investigators, 20 industry collaborators, and a growing cohort of patient participants, establishing the largest philanthropic CRC research network in the United States. Governance structures supporting FDA submission of the adaptive trial platform have been completed, and in 2025 a diverse patient advisory council was launched to guide ecosystem development and ensure patient-centered priorities. Conclusions: Project Cure CRC represents a scalable model for aligning patients, data, and discovery within an integrated research infrastructure. By combining adaptive clinical trials, real-world data, sustained patient engagement, and targeted research investment, the initiative is accelerating translational progress and redefining how colorectal cancer research is conducted. This ecosystem approach offers a blueprint for advancing cures across complex disease landscapes.
Role of VISTA/TIM3 heterodimerization and macrophage metabolic reprogramming in microsatellite stable colorectal cancer.
e15586 Background: Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibodies, represent a major paradigm shift in cancer management. However, microsatellite stable (MSS) colorectal cancer (CRC), which accounts for over 95% of CRC cases, exhibits a dismal response rate of less than 5%. Increasing evidence suggests that heterogeneity and complex crosstalk among immune checkpoints limit the efficacy of monotherapy strategies. This study aims to break through current therapeutic bottlenecks by systematically profiling the immune checkpoint landscape of MSS CRC to identify core drivers of immune tolerance and explore novel intervention strategies. Methods: We collected tumor tissues from a multicenter cohort of treatment-naive MSS CRC patients. The immune checkpoint landscape was constructed using flow cytometry, multiplex immunofluorescence, and integrated analysis of public single-cell RNA sequencing and TCGA datasets. To elucidate molecular mechanisms and metabolic characteristics, we employed tumor-bearing mouse models combined with metabolomics, co-immunoprecipitation, and site-directed mutagenesis assays. Results: We identified four distinct immune checkpoint patterns in MSS CRC, among which the VISTA/TIM3 co-expression pattern (14.6%) was most strongly associated with poor prognosis and CD8 + T cell exhaustion. Clinical validation confirmed a specific enrichment of VISTA + TIM3 + tumor-associated macrophages (TAMs) in the tumor microenvironment of approximately 14% of patients (n = 35), where these cells constituted over 50% of the macrophage population. Notably, patients with high VISTA + TIM3 + TAM infiltration exhibited significantly shorter overall survival compared to those with low infiltration ( P = 0.019). Mechanistically, we discovered that VISTA and TIM3 do not function independently on macrophages but physically interact to form a heterodimer complex. This complex induces metabolic rewiring to favor succinate accumulation, thereby promoting protein succinylation and sustaining an immunosuppressive macrophage phenotype. In vivo and in vitro experiments demonstrated that disrupting the VISTA-TIM3 interaction or combining therapy with succinylation inhibitors significantly reversed the immunosuppressive function of VISTA + TIM3 + TAMs and restored sensitivity to anti-PD-1 therapy. Conclusions: This study is the first to reveal that "metabolic-immune" crosstalk mediated by the VISTA-TIM3 heterodimer is a key mechanism driving immune tolerance in MSS CRC. Targeting VISTA + TIM3 + TAMs and their downstream succinate metabolic pathway represents a promising breakthrough strategy to overcome immunotherapy resistance in MSS CRC.