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TUC-TOC phase II trial (NCT05955170): Tucatinib in combination with oral etoposide (VP16) and trastuzumab in patients with metastatic HER2-positive breast cancer (HER2+ mBC).

TPS1145 Background: Patients with HER2-positive metastatic breast cancer (HER2+ MBC) have limited therapeutic options after progression on tucatinib–trastuzumab–capecitabine. There is a need for later-line regimens combining chemotherapy with dual HER2 targeting. TUC-TOC was designed to evaluate the efficacy and safety of tucatinib combined with oral etoposide (VP16) and trastuzumab in this setting. Oral VP16 was selected because (i) topoisomerase II inhibitors are rarely used in HER2+ MBC, (ii) TOP2A and ERBB2 are frequently co-amplified, and (iii) it enables an almost all-oral regimen. A prior retrospective analysis suggested favorable activity and tolerability of VP16 plus trastuzumab in heavily pretreated HER2+ MBC (PMID: 35565244). Methods: TUC-TOC (NCT05955170) is an open-label, multicenter, academic phase II trial. Eligible patients have histologically-confirmed HER2+ MBC with disease progression on tucatinib-trastuzumab-capecitabine or a contraindication to capecitabine, measurable disease per RECIST v1.1, and adequate cardiac function. Patients with brain metastases are eligible unless urgent local treatment is required. The study includes a safety run-in followed by an expansion phase. In the safety run-in, six patients received oral VP16 50 mg/d on days 1–14 of a 3w cycle, tucatinib 300 mg PO BID, and trastuzumab 600 mg SC q3w. The primary endpoint of this phase was the rate of dose-limiting toxicities (DLTs). The primary endpoint of the expansion phase is the objective response rate (ORR), defined as the best overall response within 24 weeks according to RECIST v1.1. Secondary endpoints include PFS, OS and safety. A total of 55 evaluable patients is planned. As of 01.2026, the safety run-in phase has been completed and enrollment into the expansion phase is ongoing. Clinical trial information: NCT05955170 .

A triage-forward outpatient diagnostic pathway for cancer evaluation: Early experiences from a Suspicion of Cancer clinic.

e23252 Background: The UCSD suspicion of cancer (SoC) clinic was developed to address the systemic reliance on inpatient care for urgent malignancy workups, and reduce avoidable hospital admissions by providing an accelerated outpatient diagnostic pathway. The goal of the clinic was to utilize physician-led triage and expedited diagnostics prior to the initial consultation visit at the SoC clinic. This proactive model ensures that comprehensive diagnostic data is available at the time of the appointment, facilitating immediate clinical decision-making. Methods: This retrospective descriptive analysis reflects early operational data from the clinic launch using this new triage and referral workflow to evaluate its feasibility. Crucial components of this clinic model included creation of an SoC referral order set permitting referrals only from emergency department providers, inpatient providers, and specialty oncology clinics. When additional diagnostic data were required, the triaging SoC physician ordered or referred patients for expedited outpatient testing prior to clinic evaluation, if appropriate. Results: Between December 2025 and January 2026, 20 patients were referred to the SoC clinic. The average age was 65 years (range 31–91); 65% were female, with a racial distribution of 15% Asian, 35% White, and 50% other (40% identifying as Hispanic). Median time from referral to first contact by the SoC clinic was 3.5 days. Through physician-led triage, SoC ordered and coordinated expedited outpatient diagnostics for 7 patients (35%), including CT imaging, interventional radiology–guided biopsies, thoracentesis, nuclear medicine bone scans, and MRI, following ED or inpatient discharge. Once sufficient diagnostic information was obtained (or previously obtained testing had resulted), 11 of 20 patients were redirected to appropriate disease-specific oncology clinics or to primary care (for 2 patients with benign findings) without requiring an in-person SoC clinic visit. Nine patients were scheduled for SoC visits; one patient no-showed and one visit was declined due to insurance. Among the scheduled patients, the average time from referral to visit was 10.8 days, inclusive of time required to complete additional testing. Conclusions: Implementation of a physician-led triage within the SoC workflow facilitated early clinical assessment of referrals, expedited outpatient diagnostic testing pathway, and rapid redirection of patients to appropriate disease-specific oncology clinics without requiring in-person SoC visits. This model supports care coordination for urgent but non-emergent patient cases and judicious use of inpatient resources. Future work may assess how this impacts SoC clinic volume and sustainability, longitudinal evaluation of diagnostic timelines, and best practices for staffing SoC clinics with representatives from each oncologic group.

Risk of immune checkpoint inhibitor–related pneumonitis in non-small cell lung cancer patients with chronic obstructive pulmonary disease: A propensity score–matched analysis.

e20596 Background: Immune checkpoint inhibitors (ICIs) are standard therapy for non-small cell lung cancer (NSCLC) but can cause immune-related pneumonitis. Patients with chronic obstructive pulmonary disease (COPD) may be at increased risk, though real-world data are limited. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network to identify adults with NSCLC who initiated ICI therapy between 2015-2022. Patients were stratified by COPD status. Exclusion criteria include secondary malignancies, autoimmune disease, or pre-existing pneumonitis. Propensity score matching (1:1) was performed based on age, sex, race, ethnicity, comorbidities (hypertension, ischemic heart disease, cerebrovascular disease, chronic kidney disease), and prior radiation therapy. The primary outcome was pneumonitis within 2 years of ICI initiation. Secondary outcomes included all-cause mortality, all-cause hospitalization, and ICU admission. Results: Before matching, 3,234 patients with COPD and 5,967 patients without COPD were identified. After propensity score matching, 2,914 patients were included in each cohort. Baseline characteristics and comorbid conditions were well-balanced between the two cohorts: mean age 73 years, 55% male, hypertension (51%), ischemic heart disease (21%), cerebrovascular disease (12%), and chronic kidney disease (11%). Pneumonitis occurred in 8.6% (n = 251) of patients with COPD versus 4.2% (n = 122) without COPD. COPD was associated with significantly increased risk of pneumonitis (HR 1.88, 95% CI 1.51-2.33; log-rank p<0.001). All-cause mortality and hospitalization rates were similar between cohorts; however, ICU admission was more common in patients with COPD (9.4% vs 6.0%; hazard ratio 1.44, 95% CI 1.19–1.75; p < 0.001). Conclusions: Among patients with NSCLC treated with ICIs, pre-existing COPD was associated with nearly 2-fold increased risk of pneumonitis. These findings highlight the need for enhanced monitoring and risk-stratified management of patients with COPD receiving immunotherapy.

Intrathecal chemotherapy and central nervous system relapse in acute lymphoblastic leukemia.

e23063 Background: Central nervous system (CNS) involvement is a rare but devastating complication of acute lymphoblastic leukemia (ALL). While intrathecal (IT) chemotherapy is routinely used for CNS prophylaxis, substantial variation exists across protocols regarding dosing and timing, and the relationship between IT chemotherapy administration patterns and CNS relapse risk remains poorly described. Methods: To address this gap, we conducted a single-institution retrospective study of factors associated with CNS relapse in patients with ALL. Patients were included if they received IT chemotherapy between 2014 and 2024 at the University of Chicago and all first-line (1L) IT doses were known, regardless of age, cell lineage (B-ALL vs T-ALL/T-LBL) or Philadelphia chromosome status (Ph-negative, Ph-like, or Ph-positive). Total 1L IT doses and CNS relapse status were compared by sociodemographic, biologic, and clinical factors using Wilcoxon rank-sum, ANOVA, and Fisher’s exact tests. Multivariable logistic regression model assessed which factors were associated with CNS relapse, and Youden index predicted an IT dose cutoff. Results: Among 321 patients, median age was 24 years (IQR 8–54); 45% were female, 21% Black, 25% Hispanic, and 31% uninsured or Medicaid-insured. Clinically, 84% had B-ALL (69% Ph-negative, 9% Ph-like, and 22% Ph-positive), while 19% had cytogenetic risk factors for CNS relapse (abnormal 17p, MLL rearrangement, or translocation 9;22) and 4% had CNS disease at diagnosis. Patients received a median of 14 1L IT doses (IQR 7-21) with fewer doses for the 16% who had a stem cell transplant (median 7 vs 16, p<0.001). Patients with T-cell lineage received more IT doses than B-cell (median 19 vs 13, p=0.004), even when accounting for transplant. B-cell had fewer IT doses for Ph-like (8) and Ph-positive (9) than Ph-negative (17, p<0.001). CNS relapse occurred in 18 patients (6%) but did not significantly differ by cell lineage, Ph status, cytogenetic features, or CNS disease status at diagnosis. CNS relapse was higher among males (10% vs 0%, p< 0.001) and Hispanic patients (12% vs 3%, p=0.02). CNS relapse was associated with receipt of fewer 1L IT doses (median 7.5 vs 14, p=0.049). In our multivariable model, only number of 1L IT doses was associated with CNS relapse (aOR 0.90, p=0.02). A cutoff of 15 IT doses had a sensitivity of 75% and specificity of 64%. Conclusions: Only 6% of patients with ALL developed CNS relapse, with higher risk among males and Hispanic patients. Patients with T-ALL did not have higher CNS relapse rate, possibly due to receiving more 1L IT doses. CNS relapse was associated with fewer 1L IT doses, with a predicted cutoff of 15 doses having limited discrimination. Future work is needed to evaluate protocol adherence to IT chemo doses to determine the optimal number to prevent CNS relapse while avoiding unnecessary neurocognitive toxicity.

Screening and comprehensive analysis of endoplasmic reticulum stress-related biomarkers in atherosclerosis

Atherosclerosis (AS) is a chronic inflammatory vascular disorder in which endoplasmic reticulum stress (ERS) plays a crucial regulatory role. However, the biological and translational relevance of ERS-related gene networks in AS remains largely unexplored. This study aimed to identify a robust ERS-related gene signature for AS. We integrated multiple GEO datasets and applied machine learning algorithms, including least absolute shrinkage and selection operator (LASSO) regression, support vector machine-recursive feature elimination (SVM-RFE), and random forest (RF). Five ERS-related signature genes (TRIM25, CYBB, CYBA, MYOC, and PRKAA2) were identified and showed favorable discriminatory performance in the integrated discovery cohort (combined AUC = 0.946). The expression patterns of these genes were further examined at both the mRNA and protein levels by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) in an oxidized low-density lipoprotein (ox-LDL)-induced endothelial injury model. Gene set enrichment analysis and immune infiltration analysis indicated that the identified genes were primarily involved in oxidative stress and immune-related pathways. Collectively, this study identifies a machine learning–derived ERS gene signature associated with AS. These findings improve our understanding of ERS-related vascular injury in AS and provide candidate biomarkers for further tissue-level and mechanistic validation.

Computational (DFT) and experimental analysis of green-synthesized TiO₂ NPs: Characterizations and sustainable approach for photocatalytic and biomedical applications

OS benefit with first-line datopotamab deruxtecan in advanced-stage TNBC

Heterogeneity-aware personalised federated learning for household energy forecasting on multi-source real-world smart meter data

Abstract Residential and building-level electricity forecasting is increasingly based on smart-meter streams, but direct data pooling is often difficult because load traces are private, geographically dispersed and statistically different across households and buildings. This paper studies the effect of such client heterogeneity in federated energy forecasting. A multi-source benchmark is constructed by combining processed Smart, CU-BEMS, UCI Household and AMPds clients, giving 22 usable clients and 1,522,510 observations at 15-minute resolution. The benchmark compares non-federated baselines (Persistence, Ridge, LocalOnly and Centralised training), standard federated baselines (FedAvg, FedProx and FedPer) and the proposed HAPFL framework over 1-step, 12-step and 24-step forecasting horizons. HAPFL separates a shared temporal encoder from client-specific prediction heads and combines proximal stabilisation, latent prototype alignment and difficulty-aware aggregation. In the reported benchmark protocol, HAPFL gives the lowest mean MAE and the highest mean $$R^2$$ at all three horizons. At horizon 1, mean MAE improves from 0.208 to 0.196 and mean $$R^2$$ improves from 0.741 to 0.769 relative to centralised training, while the worst-10% client MAE is reduced from 0.301 to 0.274. At horizons 12 and 24, the corresponding MAE reductions over centralised training are 6.11% and 7.60%, respectively. The results indicate that vanilla federated averaging is not adequate for strongly non-identically distributed energy clients, while personalised and heterogeneity-aware federated learning is a more suitable direction for decentralised household and building load forecasting.

Herpes simplex virus alkaline nuclease interacts directly with ubiquitin-specific protease 15 through a conserved C-terminal domain

Differences in central versus local lab PD-L1 classification in the ALCHEMIST Alliance A151216 non–small cell lung cancer (NSCLC) study.

8057 Background: The NCI Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST) study tested resected stage II-IIIB(N2) NSCLC for targetable EGFR and ALK alterations and PD-L1 expression to screen patients for biomarker-driven adjuvant therapy trials (NCT02194738). Local lab results were requested when available for comparison to central lab results. Methods: We identified patients with both central and local PD-L1 results in the ALCHEMIST adjuvant immunotherapy study screening population. Discrepancies in tumor proportion score (TPS) between central and local PD-L1 were defined using prespecified cut-points (granular: <1%, 1-<5%, 5-<10%, 10-<20%, 20-<30%, 30-<40%, 40-<50%, 50-60%, 60-<70%, 70-<80%, 80-<90%, 90-<100%; clinical: <1%, 1-<50%, 50-100%). Large discrepancies were defined as ≥ 50 percentage point differences; for these cases, local PD-L1 and hematoxylin & eosin-stained slides were requested. These and all central slides were digitally scanned at 40X. Three expert pathologists reviewed the scanned slides in a blinded fashion. Differences between patient or tumor characteristics were assessed by Chi-square and Wilcoxon rank sum tests. Percent agreement was computed within and between the reviewers. Results: Central and local PD-L1 results were available for 497 patients. 177 cases (36%) had discrepancies that placed patients in different clinical TPS categories (<1%, 1-<50%, 50-100%). Among these, 43 cases had large TPS discrepancies; 14 had available local testing slides. 46 of the 320 cases without discrepancy were randomly selected as controls. No patient or tumor characteristics were associated with discrepancy, including tumor location, histology, grade or cancer stage (p > 0.05). Pairwise comparisons of TPS according to three pathologists re-reading the same scanned PD-L1 slides showed similar levels of disagreement in clinical TPS category whether there was initial discrepancy between central and local results (24%, 34%, and 23%; mean 27%) or not (33%, 30%, and 20%; mean 28%). Among the 14 cases with large initial discrepancies and local slides available, there was agreement in clinical TPS category when the anonymized central and local scanned slides were re-read by the pathologists in 54%, 38%, and 43% of cases, despite 100% non-agreement in initial reads. There were higher rates of agreement when the tested slides both originated from the same (100%) versus different (35%) blocks, when the same (48%) versus different (40%) PD-L1 antibodies were used, and when the cases were of non-squamous (52%) versus squamous (14%) cell carcinoma. Conclusions: There are substantial differences in PD-L1 TPS read by pathologists that can result in placement of patients in different categories commonly used for clinical management. These differences have clear implications in clinical trials and routine patient care.

Association between mammary adipocyte diameter and survival outcomes in breast cancer patients.

e12720 Background: Obesity is associated with poorer breast cancer outcomes, yet body mass index (BMI) has limitations in assessing adiposity and metabolic dysfunction. Mammary adipocyte hypertrophy may better reflect the biological impact of obesity on tumor behavior and breast cancer prognosis. We examined if mammary adipocyte diameter is associated with overall and recurrence-free survival in breast cancer patients, independently of BMI. Methods: Women with newly diagnosed invasive, non-metastatic breast cancer were recruited at the Centre des Maladies du Sein (Quebec, Canada) between 2000-2012. Mean mammary adipocyte diameter (μm) was measured on hematoxylin- and eosin-stained tissue sections located ≥1 cm from the tumor using automated segmentation in ImageJ. Patients were followed through December 31, 2023. Hazard ratios (HR) and 95% confidence intervals (CI) from adjusted multivariate Cox models estimated associations of mean adipocyte diameter (per 10 μm) with overall survival (OS) and recurrence-free survival (RFS). Analyses were also stratified by combined estrogen receptor (ER) and progesterone receptor (PR) status, in line with previous findings in the literature. Results: Among 2,211 women (median follow-up: 13.2 years), mean adipocyte diameter was 75.0 μm (range: 46.3-116.4), and 804 deaths occurred (36.4%) and 1,069 recurrences (48.3%) were observed. In adjusted analyses, each 10 μm increase in adipocyte diameter was associated with poorer OS (HR = 1.08; 95% CI: 1.00-1.17; p = 0.047) particularly among patients whose tumors were ER+/ PR- (HR = 1.25; 95% CI: 1.01-1.55; p = 0.041). However, these associations were attenuated and no longer significant after adjusting for BMI (HR = 1.01; 95% CI: 0.93-1.10; p = 0.80 and HR = 1.10; 95% CI: 0.85-1.41; p = 0.47, respectively). No significant association with RFS was observed, regardless of BMI adjustment. Conclusions: Larger mammary adipocyte diameter was associated with poorer overall survival, specifically in patients with ER+/PR- tumors. While BMI accounted for much of this association, adipocyte size may be related to other clinical outcomes in the cancer care continuum, such as the long-term metabolic effects of cancer treatments. Further research is needed to explore these relationships and their potential value in improving survivorship and tailoring patient care in breast cancer.

Targeting metastatic sites with radiation and outcomes in high-risk pediatric rhabdomyosarcoma.

10002 Background: Outcomes for pediatric patients with metastatic rhabdomyosarcoma (RMS) remain poor despite therapy intensification and novel agents. RMS13 (NCT01871766) was a phase II prospective multicenter trial evaluating a response-based approach to metastatic site radiotherapy (RT). We report outcomes related to metastatic disease management in this high-risk (HR) population. Methods: Event-free survival (EFS) and metastatic site control were analyzed for HR patients treated with interval compressed chemotherapy, risk-adapted RT to primary and metastatic site, and maintenance therapy. EFS was defined from therapy start to relapse, progression, death or last follow-up. Metastatic RT was delivered between interval-compressed and maintenance therapy for non–bone marrow metastatic sites without complete response (CR). RT omission criteria included PET negativity, lesion size <1 cm, or complete surgical resection with negative margins. Metastatic RT used protons: 25 Gy in 5 or 50.4 Gy in 28 fractions, by lesion size. Primary tumor control consisted primarily of proton RT, with limited use of surgery plus adjuvant RT. Results: From 2015 to 2020, 39 HR patients were enrolled (median age 9.5 years). Most patients were FOXO1 fusion–positive (64%), had nodal involvement (74%), and an Oberlin score >1 (67%). Median follow-up was 23.1 months overall (78.5 months for non-progressors). Five-year EFS was 31.6% (95% CI, 19.7-50.6%), differing by Oberlin score >1 – 16.2% (95% CI, 6.6–39.8%), ≤1 - 61.5% (95% CI, 40-94.6%). Twenty-six patients relapsed: 22 had distant failure (DF), 6 had local failure (LF), and 2 had both DF and LF. The 5-year cumulative incidence of LF was 14.4% (95% CI, 5–28), and 54% for DF (95% CI, 36–69), establishing DF as the predominant pattern of failure. Twenty-six patients reached the protocol window for metastatic-site RT (weeks 47–54): 11 soft-tissue metastases, 6 bone, 8 both, and 1 bone marrow only, with a 5-year EFS of 42.3% (95% CI 23.3-61.3%). Among 21 patients achieving CR at metastatic sites without RT, 5-year EFS was 38.1% (95% CI 17.3–58.9%), and cumulative incidence of any DF was 57.1% (95% CI 35.9–78.3%). Seven patients (33%) recurred at initially involved metastatic sites, primarily soft tissue. In-site recurrence occurred in 7/17 (41%) non-irradiated soft-tissue sites versus 1/12 (8%) bony sites. Only one recurrence occurred among irradiated soft-tissue sites. Conclusions: Soft-tissue metastatic sites in CR that were not irradiated had high recurrence rates, while bony sites achieved durable control without RT. Future trials should consider consolidative RT for soft-tissue metastases regardless of response in HR RMS. Clinical trial information: NCT01871766 . Recurrence by metastatic site. CR, no RT (N) Recurrence, non-RT, N(%) PR, RT (N) Recurrence, No RT, N (%) Bone metastases (n=14) 12 1 (8) 2 0 Soft-tissue metastases (n=19) 17 7 (41) 2 1 (5.9) CR, complete response; PR, partial response; RT, radiotherapy.

Contemporary real-world patterns of precision medicine in metastatic NSCLC.

e20665 Background: Precision medicine has become an essential part of lung cancer care over the last several years. The International Association for Study of Lung Cancer (IASLC) analyzed the ASCO CancerLinq database to investigate biomarker testing and treatment for stage IV NSCLC patients from 2010 to 2018. Our study aims to expand this analysis with an updated cohort from 2019 to 2023 as more biomarkers and precision oncology treatments have been incorporated into NSCLC care. Methods: The ASCO CancerLinq Discovery database was analyzed to identify patients diagnosed with stage IV NSCLC from the years 2019 to 2023. All analyses were descriptive in nature. Patient demographics, tumor characteristics, biomarker testing patterns, and treatment utilization were summarized using counts, percentages, means, medians, and standard deviations, as appropriate. Time intervals from biomarker testing to initiation of first-line therapy were calculated at the patient–biomarker level and summarized overall and by biomarker type. Data extraction was conducted using SQL-based cohort definitions, and summary statistics were generated using Microsoft Excel. Results: Among 10,658 patients with stage IV NSCLC identified in the updated analysis (2019–2023), 25% (n = 2,679) had documented biomarker testing, compared with 22% (n = 8,357) in the prior IASLC analysis. Demographic distributions were similar between cohorts (Table 1), with 70.7% White and 11.9% Black patients in the current cohort versus 66.6% and 13.1%, respectively, in the IASLC cohort; gender distribution was also comparable (51.8% female, 48.2% male vs 53.4% and 46.6%). The mean interval from biomarker testing to initiation of first-line therapy was 29.7 days (SD 93.6). Among patients with documented biomarker testing, 25.2% received targeted therapy, representing an increase compared with 8.1% in the IASLC analysis. Targeted therapies were directed against nine actionable oncogenic drivers whereas earlier analyses were largely limited to EGFR and ALK alterations. Conclusions: This updated real-world analysis demonstrates the continued evolution of precision medicine in metastatic NSCLC, with expanded use of targeted therapies across nine actionable genomic alterations in a real-world population. Although biomarker testing rates appear modest, this likely reflects known limitations in capturing molecular diagnostics within real-world databases rather than true testing gaps. Ongoing analyses will evaluate survival outcomes and treatment patterns to better define the clinical impact of precision oncology in modern NSCLC care. Comparison of cancerlinq database: IASLC vs UIC. IASLC (2010-2018) UIC (2019-2023) Total Number of Patients 37917 10658 Biomarker Testing 8357 (22%) 2679 (25%) Female 4462 (53.4%) 1388 (51.8%) Male 3894 (46.6%) 1291 (48.2%) Black 1095 (13.1%) 319 (11.9%) White 5566 (66.6%) 1875 (70.7%) Targeted Therapy 676 (8.1%) 675 (25.2%)

Bowel function after sphincter-preserving treatment with neoadjuvant therapy for low rectal cancer.

3665 Background: Neoadjuvant therapy (NAT) is important for locally advanced rectal cancer, including neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant chemotherapy alone (nCT). Based on the tumor response, sphincter-preserving treatment such as low anterior resection (LAR) or watch and wait (WW) strategy can be implemented. The effects of these therapy combinations on functional outcomes for low rectal cancer remain unclear. Methods: We conducted a retrospective study recruiting patients who were treated at The Sixth Affiliated Hospital of Sun Yat-sen University between 2010 and 2023. Patients who underwent sphincter-preserving treatment after NAT for low rectal cancer with no distant metastasis were eligible. Low rectal cancer was defined as the tumor height no more than 5 cm from the anal verge. Patients with multiple primary carcinoma or familial adenomatous polyposis were excluded. The incidence of low anterior resection syndrome (LARS) was assessed using the LARS score. Oncological outcomes included overall survival (OS), disease-free survival (DFS), and stoma-free survival (SFS). Functional and oncological outcomes were evaluated based on Wilcoxon signed-rank test and Kaplan-Meier survival analysis. The difference of baseline characteristics in different treatment groups was analyzed using propensity scores with inverse probability treatment weighting (IPTW). Results: We enrolled 590 patients: 49 in nCRT+WW group, 181 in nCT+LAR group and 360 in nCRT+LAR group. Median follow-up was 3.4 years (IQR 2.8-4.4), 5 years (IQR 4.3-7.1) and 7.3 years (IQR 4.8-9.3), respectively. After IPTW, all baseline characteristics were similar in the three groups. 3-year OS was 91.0% (95% CI 81.6-100.0) for nCRT+WW group, 89.3% (84.5-94.5) for nCT+LAR group, 93.2% (90.7-95.7) for nCRT+LAR group. 3-year DFS was 62.5% (95% CI 45.6-85.7), 71.0% (64.1-78.6) and 77.5% (77.3-81.9), respectively. There was no differences in oncological outcomes. The incidence of major LARS in the three groups was 0% (0/18.6), 34.1% (35.2/103.2) and 45.9% (104.2/226.8). 3-year SFS without IPTW was 95.2% (20/21) for nCRT+WW, 91.0% (152/167) for nCT+LAR, and 79.7% (244/306) for nCRT+LAR. Conclusions: This retrospective study shows similar oncological outcomes in the three sphincter-preserving strategies for low rectal cancer, while nCRT+WW presented with superior bowel function. Functional outcomes are inversely correlated to the intensity of local therapy. Outcomes for the three therapy combinations after IPTW. nCRT+WW nCT+LAR nCRT+LAR Tumor Height, cm 2.71 (1.20) 3.74 (0.83) 3.60 (0.91) Clinical Stage III, % 75.4 69.1 70.3 3-year OS, % 91.0 89.3 93.2 3-year DFS, % 62.5 71.0 77.5 Major LARS, % 0 34.1 45.9 Minor LARS, % 22.5 22.9 24.1 None LARS, % 77.5 43.0 30.0 3-year SFS*, % 95.2 91.0 79.7 *Without IPTW.

Territorial Oncology L’Aquila ASL1 Abruzzo, Italy: 11 years of experience in a complex organization integrating innovative outpatient oncologic treatment and care models.

e13582 Background: We report 11 years organization from 2014 and overall results of Oncology Territorial Care (OTC) Unit L’Aquila, Italy ASL1 Abruzzo, Innovative Strategic Project “Integrated Personalized and Territorial Oncology”, with primary aims of humanize and personalize oncologic cure and care, integrating territorial and hospital clinical activities. Methods: OTC Unit performs outpatient clinical activities (OCA) services (OS) at operative center, San Salvatore Hospital L’Aquila, consisting of Ambulatorial Oncologic Therapies (AOT), intravenous (PAC2) and non infusional (PAC1), out-patient visits (OV), specifically First Access (FA), Follow up (FU), Prevention and Cancer Predisposition (PreV), periodic on-/off-treatment (PV) settings, integrated with ASL1 Abruzzo Territorial Ambulatories (TA) in the Province of L’Aquila, since 2/2015 at L’Aquila, Avezzano, Sulmona health Districts, 9/2017 Tagliacozzo and 5/2018 Castel di Sangro territorial Hospitals. Oncologic clinical activities are also integrated with Multidisciplinary Oncologic Groups and Oncology Territorial Network (OTN), including Territorial General Medicine and Home Care, Health Residential Care, Palliative Care and Hospice. Results: From 10/2014 to 9/2025, overall 3610 patients were followed, prevalently affected by gastrointestinal cancer 47.3%, breast 14.5%, urologic 9.7%, gynecologic 5.9%, and 57661 OCA OS performed: OV 41065 (71.2%), prevalently FA 2564 (6.3%), PV 29796 (72.5%), FU 8493 (20.7%), PreV 212 (0.5%). From 8/2016, AOT, first Oncologic Unit in Abruzzo Region Italy, all prescribed and administered at operative center, were 16596 (28.8%), PAC2 13185 (79.4%), PAC1 3411 (20.6%). According to the sequential activation of TA in L’Aquila Province, overall 8869 (21.6%) territorial OV were performed, representing for each setting: FA 397 (4.5%), 15.5% overall FA; PV 909 (10.2%), 3% overall PV; FU 7399 (83.4%), 87.1% overall FU, at L’Aquila District 5125 (69.3%) and other territorial ambulatories 2274 (30.7%); PreV 164 (1.8%), 77.4% overall PreV. Conclusions: Complex organization of OTC L’Aquila Italy, dinamically integrating innovative outpatient oncologic treatment and hospital/territorial care models links AOT with territorial OV gaining overall 21.6%, according to patients’ home proximity, specifically for FU 87.1% overall (83.4% territorial OV), FA 15.5% overall (4.5% territorial OV), PV 3% overall (10.2% territorial PV) for management of metastatic chronic patients integrated with OTN, thus contributing to assure continuity and equity of access to oncologic cure and care, and public health sustainability; it will also integrate territorial OV specifically addressing oncologic clinical pathway, cancer predisposition/prevention, AOT/PAC1 non intravenous.

NSABP FC-13 (EMPIRE): A phase II platform study of cemiplimab monotherapy or cemiplimab-based combinations in patients with colorectal cancer and minimal residual disease (MRD) after definitive therapy.

TPS3685 Background: Patients with microsatellite-stable (MSS) colorectal cancer (CRC) who are ctDNA-positive following surgery and chemotherapy have a high risk of recurrence and limited treatment options. Immune checkpoint blockade with PD-1/PD-L1 inhibitors, alone or with other immune modulators, may be most effective in early-stage disease or in patients without liver metastases. However, no approved therapies currently exist for patients with MSS CRC and ctDNA-positivity after curative-intent therapy, making this high-risk population an area of critical unmet need and opportunity for new drug development. NSABP FC-13 (EMPIRE) is a Phase II platform trial evaluating cemiplimab alone or in combination with novel agents in this high-risk MRD setting, wherein ctDNA clearance serves as an early surrogate marker of therapeutic activity. Methods: This multicenter Phase II platform study randomizes patients with MSS stage II–III or oligometastatic stage IV CRC who are ctDNA-positive within 12 weeks of completing definitive therapy (surgery ± chemotherapy/chemoradiotherapy) to one of three arms: (1) Cemiplimab 350 mg IV q3w × 1 year; (2) Cemiplimab 350 mg + fianlimab 1600 mg IV q3w × 1 year; (3) Cemiplimab 350 mg + REGN7075 2700 mg IV q3w × 1 year. Eligibility includes ECOG 0–1, adequate organ function, and absence of radiographic recurrence at enrollment. Assessments include serial tumor-informed ctDNA testing (Signatera, Natera, Inc.), imaging, labs, and safety monitoring. The primary endpoint is ctDNA clearance at 12 weeks without radiographic recurrence. Secondary endpoints include recurrence-free survival (RFS), safety, ctDNA kinetics, and patterns of recurrence. Statistical design: Arm 1 follows a Simon two-stage design with up to 33 patients (α=0.047, power=0.80), and Arms 2 & 3 enroll up to 23 patients each (single-stage; α=0.05, power=0.78). Status: Enrollment began in September 2025 across NSABP Foundation sites and is ongoing. Clinical trial information: NCT07058012 .

Association of <i>FBXW7</i> mutation with prolonged survival in microsatellite instability–high colorectal cancer treated with immune checkpoint blockade.

3657 Background: Colorectal cancer (CRC) remains a major cause of cancer-related mortality. Biomarkers of response to novel therapies may improve treatment selection and outcomes. Microsatellite instability (MSI-H) is a predictor of response to immune checkpoint blockade (ICI); however, less than half of patients with MSI-H CRC have a durable response to ICI. FBXW7 mutations ( MT) are common in CRC but their prognostic significance in patients treated with ICI is not well studied. Here, we characterized FBXW7 -MT in CRC and their association with ICI outcomes. Methods: A total of 29,446 CRC (MSS, n = 27,323; MSI-H, n = 2,123) samples were tested by next generation sequencing (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). TMB was assessed by nonsynonymous mutations/Mb (high ≥10). Immune cell proportions were estimated using WTS deconvolution (Quantiseq). Real-world median overall survival (mOS) data were derived from insurance claims, calculated from tissue collection or treatment (chemotherapy: CAPEOX, Capecitabine, FOLFIRI, FOLFIRINOX, Fluorouracil, Irinotecan, Oxaliplatin; ICI: Nivolumab, Pembrolizumab) initiation to last contact, and analyzed using Kaplan-Meier. Statistical significance was assessed by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q&lt;0.05). Results: FBXW7 -MT was enriched in MSI-H (29.6% (n=608) vs 9.2% (n=3,025), p&lt;0.05) compared to MSS tumors. Among MSI-H tumors, FBXW7 -MT had higher median TMB (40 vs 37, q&lt;0.05) and numerically higher TMB-high frequency (99.2% vs 97.9%, p=0.05) compared to FBXW7 -WT. Analysis of inferred immune cells revealed that FBXW7 -MT MSI-H CRC had lower median cell fraction (%) of M2 macrophages (2% vs 2.5%) compared to FBXW7 -WT. In MSI-H CRC, FBXW7 -MT patients had better mOS when treated with ICI (48.3 vs 34.2 months, HR 0.68, 95% CI 0.52 – 0.9, p=0.006) compared to FBXW7 -WT, whereas there was no difference in mOS in MSI-H CRC treated with chemotherapy (HR 0.95, p = 0.67) compared to FBXW7 -WT. FBXW7 -MT was not associated with OS in MSS CRC. In MSI-H CRC, R465C / H/L/S (20.6%), R505C/H/L/G (7%) and R479Q/G (3.4%) were the most common FBXW7 hotspot mutations. R465C / H/L/S had better mOS with ICI (HR 0.61, p=0.04) compared to FBXW7 -WT. Multivariable Cox analysis adjusted for TMB and PD-L1 showed FBXW7- MT is an independent predictor of improved OS with ICI in MSI-H CRC (HR 0.69, 95% CI 0.53 – 0.9, p=0.007). Conclusions: This large study is the first to report a positive association with FBXW7 mutation and OS in MSI-H CRC treated with PD1/PD-L1 blockade. While requiring validation in independent cohorts, our findings suggest that FBXW7 -MT is a biomarker of response to ICI and that targeting FBXW7 may be an effective way of augmenting the clinical activity of ICI in MSI-H CRC.

Role of cystine/glutamate transporter SLC7A11 in breast cancer brain metastatic cells.

e13123 Background: Brain metastases in patients with triple-negative breast cancer (TNBC) pose many challenges due to their aggressive nature and limited treatment options. These tumors are able to grow and survive despite living in this unique low-lipid brain environment. To combat metabolic stress within the brain, breast cancer brain metastatic (BCBM) cells become more efficient at synthesizing fatty acids to use as their main energy source. These tumors rely on converting acetate to acetyl-CoA via acetyl-CoA synthetase 2 (ACSS2) in order to generate lipids. We have found that by targeting ACSS2, either genetically or pharmacologically, we can induce a form of cell death called ferroptosis in BCBM cells. Additionally, ACSS2 correlated to the regulation of the ferroptosis regulator protein SLC7A11. SLC7A11 is a cystine/glutamate transporter that protects cells from ferroptosis. We wanted to test the sensitivity of BCBM cells to the inhibition of SLC7A11. Methods: We stably knocked down SLC7A11 expression using RNAi in BCBM cells and confirmed the knockdown using Western blot. Soft agar assay was performed to assess the anchorage-independent cell growth of BCBM cells in vitro. Cell growth was also assessed in BCBM cells using an ex vivo model. Results: Soft agar assay showed that reducing SLC7A11 levels in BCBM cells blocks anchorage-independent cell growth in vitro . Additionally, targeting SLC7A11 in BCBM cells also blocks growth ex vivo . Conclusions: Thus, our data suggests that SLC7A11 may serve as a therapeutic target for treating BCBM tumors.

Multicenter phase Ib/II study of neoadjuvant zolbetuximab plus docetaxel, oxaliplatin, and S-1 (DOS) followed by adjuvant zolbetuximab/S-1 in patients with CLDN18.2-positive resectable gastric or gastroesophageal junction adenocarcinoma (NEOCLAUD).

TPS4250 Background: Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2), has demonstrated significant survival benefit in advanced gastric or gastroesophageal junction adenocarcinoma (G/GEJA) in the phase 3 SPOTLIGHT and GLOW trials, validating CLDN18.2 as a therapeutic target. The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy improved progression-free survival (PFS) and overall survival (OS) compared with surgery followed by adjuvant S-1 for patients with resectable locally advanced gastric cancer (LAGC). Building on this evidence, we designed NEOCLAUD to evaluate whether adding zolbetuximab to neoadjuvant DOS chemotherapy, followed by adjuvant zolbetuximab/S-1, improves outcomes in patients with CLDN18.2-positive LAGC. Methods: This open-label, multicenter, phase Ib/II trial will enroll up to 57 patients with newly diagnosed, resectable G/GEJA positive for CLDN18.2 (≥75% moderate–strong membranous staining by VENTANA 43-14A). Eligible patients must have clinical stage T3–4/N0 or T2–4/N+ disease (AJCC 8th), ECOG 0–1, and no distant metastasis. Primary endpoints are recommended phase II dose (RP2D) (phase Ib) and the pathologic complete regression (pCR) rate (phase II). Phase Ib uses a 3+3 design to determine the RP2D. Phase II will test whether adding zolbetuximab increases the pCR rate from 10% (historical control) to 25%; the primary endpoint will be met if ≥8/40 patients achieve pCR (A’Hern single-stage design, α = 0.05, power = 80%). Secondary endpoints include PFS, OS, objective response rate, disease control rate, R0 resection rate, and safety. Exploratory endpoints include artificial intelligence-based histopathology modeling, spatial transcriptomics, single-cell RNA sequencing, and circulating tumor DNA minimal residual disease analysis. Neoadjuvant therapy consists of zolbetuximab 800 mg/m² on cycle 1 day 1 (C1D1) followed by 600 mg/m² on C2D1/C3D1, with DOS (docetaxel 50 mg/m², oxaliplatin 100 mg/m² IV D1; S-1 40 mg/m² PO BID D1–14) every 3 weeks ×3 cycles. Surgery (D2 gastrectomy) is performed 1–4 weeks post-neoadjuvant therapy. Adjuvant therapy (initiated 3–8 weeks post-surgery) includes zolbetuximab 600 mg/m² D1/D22 Q6W ×8 cycles plus S-1 PO D1–28 Q6W ×8 cycles. Enrollment has been ongoing since February 2025 across multiple sites in Korea. Clinical trial information: NCT06732856 .

Clinicopathologic differences in early- vs. late-onset pancreatic cancer: A retrospective cohort study.

e16397 Background: Pancreatic cancer diagnosed in patients younger than 50 years has become increasingly common over the past two decades. In the United States, early-onset pancreatic cancer (EOPC) increased from approximately 1.1 to 1.4 per 100,000 between 2013 and 2022, with similar rising trends reported internationally, particularly in high-income countries compared to late-onset pancreatic cancer (LOPC). With this notable increase in incidence, characterizing EOPC is essential to improving diagnostic and therapeutic strategies. This study focuses on comparing clinicopathologic features of EOPC and LOPC to help identify distinguishing traits with potential clinical implications. Methods: This study was a single-center retrospective cohort study on patients with pancreatic cancer between 2002 and 2022 (n = 216). A study protocol was developed prior to analysis and approved by the institutional review board. Patients were classified as EOPC ( &lt; 50 years, n = 37) or LOPC (≥50 years, n = 179). Variables analyzed included sex, race/ethnicity, body mass index (BMI), smoking and alcohol status, tumor location, stage at diagnosis, tumor grade, diabetes, family history of pancreatic cancer, and history of pancreatitis. Missing data were handled by complete-case analysis for each variable. Statistical analysis was performed using chi-square tests, Fisher’s exact tests (including Fisher–Freeman–Halton exact testing for race), and Welch’s t-test. Statistical significance was set at p &lt; 0.05. Results: Patients with EOPC were more likely to be male compared with those with LOPC (73.0% vs 47.5%, p = 0.009 and also more frequently presented with advanced-stage disease (stage III–IV: 87.5% vs 69.6%, p = 0.041). Mean BMI was higher in EOPC than in LOPC (28.4 vs 26.5 kg/m²), and a history of pancreatitis was more common in EOPC (25.0% vs 11.2%); however, neither of these variables reached a statistically significant difference. No significant differences were observed between EOPC and LOPC in race distribution (White/Caucasian 73.0% vs 81.0%, Black/African American 18.9% vs 15.1%, Other 8.1% vs 3.9%), smoking (29.7% vs 22.3%), alcohol use (35.1% vs 41.3%), pancreatic head location (67.7% vs 66.5%), tumor grade (high grade 52.6% vs 54.1%), diabetes (41.7% vs 43.0%), or family history of pancreatic cancer (8.1% vs 5.0%) (all p &gt; 0.05). Conclusions: Based on this study, EOPC was associated with males and more advanced stage at presentation. Other clinicopathologic features were largely similar between age groups, with non-significant trends toward higher BMI and greater prevalence of personal history of pancreatitis in EOPC. These findings suggest EOPC patients may represent a clinically different subgroup compared to LOPC and support the need for further studies to investigate the biological drivers of EOPC and refine risk-based screening and management for younger populations.