Citations

TPS655 Background: Early (14-28 day) on-treatment suppression of tumor proliferation during neoadjuvant endocrine therapy (NET) is strongly associated with favorable long-term outcomes in estrogen receptor–positive (ER+) HER2– breast cancer. In premenopausal women, tamoxifen with or without ovarian function suppression (OFS) results in suboptimal Ki-67 suppression compared with aromatase inhibitor + OFS. (Z)-endoxifen (ENDX), the active metabolite of tamoxifen, dually inhibits ER signaling and PKCβ1-mediated AKT activation, supporting its evaluation as an alternative NET strategy in this population. Methods: EVANGELINE (NCT05607004) is an ongoing, multicenter, open-label Phase 2 study evaluating daily 40 mg ENDX plus goserelin administered every 28 days as neoadjuvant therapy in premenopausal women with ER+/HER2–, cT2–3, cN0–1 breast cancer. The primary objective is to determine the proportion of patients with baseline Ki-67 >10% who achieve Ki-67 ≤10% after 4 weeks of therapy. A Simon two-stage design is used to test whether the Week 4 Ki-67 ≤10% rate is at least 65%, with 20 patients enrolled into the first stage and, if promising, another 25 patients enrolled into the second stage (cohort A). A parallel cohort of 20 patients with baseline Ki-67 ≤10% (cohort B) is enrolled to assess objective response rate (ORR) at 24 weeks per RECIST v1.1. Secondary objectives include examining safety and tolerability, residual cancer burden, and PEPI score. Correlative analyses include examining effect of treatment on select tumor and plasma biomarkers. Clinical trial information: NCT05607004 .

TPS1679 Background: Cancer care in the United States remains highly centralized, imposing substantial time, caregiver, and financial burdens on patients, particularly those residing in rural and medically underserved regions. While international experience supports the feasibility of home-based cancer therapy delivery, prospective U.S. clinical trial data are limited. The Cancer CARE Beyond Walls (CCBW) program was developed to address these gaps through a decentralized cancer care model integrating virtual oversight, remote monitoring, mobile clinical services, and community-based nursing partners. The study evaluates the feasibility, safety, and patient-centered impact of delivering cancer-directed therapy in patients’ homes or near-home mobile units in the Florida Panhandle, a region characterized by long travel distances to tertiary centers and limited oncology infrastructure. Methods: This is a phase 2, single-arm clinical trial evaluating the delivery of standard-of-care cancer-directed therapy outside of traditional infusion centers. Eligible adult patients (ECOG 0–3) with histologically confirmed malignancies receiving guideline-supported or FDA-approved systemic cancer therapy must demonstrate tolerability of at least one prior in-clinic treatment cycle. Following registration, patients transition to home-based or near-home mobile unit administration for a minimum of 12 weeks, with an option to continue up to 24 weeks. Care delivery is coordinated through a virtual command center providing real-time virtual oversight, remote monitoring, and escalation pathways. Treatment administration is performed by trained local home health nurses, medication shipping, and digital interaction with the electronic health record. A fully equipped mobile unit extends access to rural areas not covered by home health agencies. The primary endpoint is patient preference for treatment location at week 12. Secondary endpoints include safety, avoidable acute care utilization, patient-reported function and global health/quality of life, patient-reported symptoms, and satisfaction with care. Exploratory endpoints assess travel burden, patient perceptions of caregiver experience, and patient perceptions of home versus mobile unit care. Enrollment of 27 patients will provide 80% power to reject a 50% null rate (2-sided exact test, α=0.10), assuming 75% prefer decentralized care or express no preference. This investigator-initiated trial is open to accrual and is supported by a grant from the Florida Cancer Innovation Fund. Clinical trial information: NCT07285044 .

e23223 Background: Early-stage lung cancer is potentially curable with surgery, yet emergency or nonelective presentation represents a care-delivery phenotype reflecting failures in early diagnosis or access to care rather than tumor biology alone. The national impact of emergency presentation among surgically treated, presumed early-stage lung cancer patients is poorly defined. This study evaluates emergency versus elective presentation as a care-delivery phenotype and its association with perioperative morbidity, failure-to-rescue, and inpatient outcomes. Methods: A survey-weighted analysis of the National Inpatient Sample (2016–2023) was conducted. Adult lung cancer hospitalizations were identified using ICD-10-CM C34* in any diagnosis position. A presumed early-stage surgical cohort was defined by curative-intent lung resection without metastatic disease, malignant pleural effusion, or palliative care coding. The primary exposure was nonelective versus elective admission. Outcomes included in-hospital mortality; ICU-level care, defined by invasive mechanical ventilation, shock, or respiratory failure; major complications; failure-to-rescue; length of stay; and hospitalization cost and charges. Multivariable survey-weighted models adjusted for patient demographics, payer, neighborhood income, hospital characteristics, and year. Results: In the weighted cohort of 422,925 hospitalizations, nonelective admission occurred in 27.3%. After multivariable adjustment, nonelective admission was independently associated with higher odds of in-hospital mortality (adjusted odds ratio [aOR] 2.59, 95% CI 2.22–3.03), ICU-level care (aOR 4.53, 95% CI 4.32–4.76), and major complications (aOR 5.00, 95% CI 4.78–5.23), as well as longer length of stay (+2.42 days). Notably, failure-to-rescue among patients with major complications did not differ by admission type (aOR 0.90, 95% CI 0.77–1.05), indicating that excess mortality associated with nonelective presentation is driven by presentation severity and care pathway rather than differences in rescue quality. In unadjusted analyses, nonelective presentation was associated with higher mortality (2.21% vs 0.68%), greater ICU-level care use (33.8% vs 8.9%), more frequent major complications (45.0% vs 12.4%), and longer length of stay (7.84 vs 4.99 days) compared with elective admissions. Conclusions: In a procedure-defined, presumed early-stage lung cancer surgical cohort, nonelective admission identifies a common care-delivery failure phenotype associated with higher perioperative morbidity, ICU-level care, in-hospital mortality, and longer hospitalization. Emergency presentation represents a systems-level vulnerability in curative-intent lung cancer care and serves as a scalable and actionable marker for quality improvement and disparity-focused analyses.

e23193 Background: Small cell lung cancer (SCLC) is typically treated with outpatient systemic therapy; inpatient chemotherapy during acute hospitalization represents a high-risk care-delivery phenotype driven by delayed diagnosis, access barriers, or acute clinical decompensation rather than tumor biology alone. National data describing this care pathway and its inpatient outcomes remain limited. Methods: The U.S. National Inpatient Sample (2016–2023) was analyzed using survey weights. Adult hospitalizations meeting an ICD-10–based proxy definition for small cell lung cancer, defined by lung cancer diagnoses combined with neuroendocrine malignancy codes and excluding palliative care admissions, were identified. Inpatient chemotherapy was defined using ICD-10-PCS administration codes with prespecified sensitivity definitions. Outcomes included in-hospital mortality (primary), ICU-level care, sepsis, acute kidney injury, length of stay, hospitalization costs, and routine discharge. Multivariable survey-weighted logistic regression adjusted for patient demographics, payer, admission characteristics, and hospital factors. Results: The analytic cohort included 2,507 unweighted hospitalizations, representing 12,535 nationally weighted admissions. In multivariable analyses adjusting for demographics, payer, admission characteristics, and hospital factors, inpatient chemotherapy was independently associated with higher in-hospital mortality (adjusted odds ratio [aOR] 2.31, 95% CI 1.48–3.60) and greater ICU-level care (aOR 2.80, 95% CI 1.86–4.23). These associations were consistent across prespecified sensitivity analyses. In unadjusted analyses, inpatient chemotherapy occurred in 12.3%–19.3% of admissions annually from 2016–2023 and was associated with higher mortality (8.7% vs 5.2%), greater ICU-level care (11.8% vs 4.9%), longer length of stay (11.6 vs 7.0 days), higher costs ($38,446 vs $23,746), and lower routine discharge rates (42.8% vs 48.4%). Among 400 admissions with procedure-day data, chemotherapy was administered a mean of 3–5 days after admission. Late inpatient chemotherapy (day ≥2) was associated with higher mortality (10.6% vs 5.6%), greater ICU-level care (14.8% vs 9.2%), longer hospitalization (14.1 vs 8.0 days), and higher costs ($46,203 vs $28,025) compared with early chemotherapy (day 0–1), supporting inpatient chemotherapy as a marker of late care escalation rather than planned inpatient treatment. Conclusions: Inpatient chemotherapy identifies a high-risk care-delivery phenotype in hospitalized small cell lung cancer, with higher mortality, greater ICU-level care, and increased resource use, supporting its role as a marker of late care escalation or system-level barriers and a scalable quality indicator.

e20700 Background: Leptomeningeal metastases (LM) are a particularly challenging complication of EGFR-mutant non–small cell lung cancer (NSCLC) and are often associated with rapid neurologic decline. Intrathecal (IT) chemotherapy is frequently used in this setting, but its efficacy and safety have not been well defined. We conducted a systematic review and meta-analysis to assess neurologic response and treatment-related toxicity associated with IT chemotherapy in EGFR-mutant NSCLC with LM. Methods: We performed a PRISMA-guided search of MEDLINE, EMBASE, Cochrane CENTRAL, and targeted grey literature to identify prospective and retrospective studies reporting outcomes of IT chemotherapy in EGFR-mutant NSCLC with LM. Quantitative analyses were restricted to studies with extractable endpoints. Neurologic response and grade ≥3 toxicity were pooled using random-effects generalized linear mixed models with logit transformation. Heterogeneity was assessed using I² and τ². Prespecified sensitivity analyses examined neurologic response by route of administration (lumbar puncture vs Ommaya reservoir), concomitant EGFR-TKI use, and study design or era. Results: Four studies comprising 76 patients reported extractable neurologic response data. The pooled neurologic response rate was 81.9% (95% CI, 64.0%–92.0%), with moderate heterogeneity (I² = 63.4%, p = 0.04). Grade ≥3 toxicity was reported in three studies (n = 59), with a pooled incidence of 11.8% (95% CI, 3.2%–34.9%) and substantial heterogeneity (I² = 71.3%, p = 0.03). Myelosuppression was the most frequently reported severe adverse event, and no consistent signal of severe neurologic toxicity was identified. Exploratory sensitivity analysis suggested higher neurologic response in LP-treated cohorts compared with mixed LP/Ommaya cohorts; however, this finding was driven by a single small study and is likely influenced by limited sample size and selection bias and should be considered hypothesis-generating only. Neurologic response was otherwise consistent across study designs and eras. Stratification by concomitant EGFR-TKI use was limited by incomplete reporting. Median overall survival was variably reported and ranged from approximately 7 to 12 months. Conclusions: In EGFR-mutant NSCLC with leptomeningeal metastases, IT chemotherapy is associated with a high pooled neurologic response and relatively uncommon severe toxicity, although heterogeneity across studies remains substantial. The observed neurologic benefit appears consistent across study designs and is more likely related to underlying EGFR-sensitive disease biology than to a definitive effect of route of administration. These findings support further prospective evaluation of IT chemotherapy as part of multimodal treatment strategies in this high-risk population.

e17134 Background: Despite being the most prevalent malignancy among men, prostate cancer (PC) lacks FDA-approved primary prevention therapies. Current options, such as 5-alpha reductase inhibitors (5-ARIs), offer only modest risk reduction—approximately 23–25%—as shown in the PCPT and REDUCE trials. Emerging preclinical data indicate that GLP-1 receptor agonists (GLP-1RAs) may offer a novel alternative by inhibiting oncogenic pathways and inducing apoptosis in PC cell lines. To investigate this potential, we conducted the first real-world comparative analysis of PC incidence among high-risk men receiving GLP-1RAs versus 5-ARIs. Methods: Using the TriNetX global collaborative network (150M patients), we identified men with elevated PC risk (genetic risk, family history, or high-risk demographics/comorbidities). GLP-1RA users (cohort A) were propensity-score-matched 1:1 with 5-ARI users (cohort B) on demographics, metabolic comorbidities, baseline PSA, BMI and HbA1c. A minimum of 2 month’s prescription was required. The primary endpoint was incident PC. The secondary endpoint was adverse events related to GLP-1RA and 5-ARI. Patients with outcomes before the study inclusion were excluded. Sensitivity and subgroup analyses were performed, adjusting for screening frequency and baseline BMI. Kaplan–Meier curves assessed cumulative incidence, Cox models estimated hazard ratios (HRs, 95% CI), and logistic regression analyzed binary outcomes. Results: After matching, 118,904 high-risk men were identified (59,452 patients per cohort). Cohorts had comparable demographics with a mean age of 48 years, 77% White, 9% Black, and 2% Asian. GLP-1RA users had higher mean A1C (6.3% vs 5.7%) and BMI (38 vs 31), while 5-ARI users had higher mean PSA (3.1 vs 1.3). Median follow-up was 7 years for both cohorts. PC incidence was 2.10% (1,245/59,189) in GLP-1RAs users versus 2.85% (1,689/59,164) in 5-ARI users (NNT 133). GLP-1RAs were associated with a 20% reduction in PC risk (HR: 0.803; CI: 0.746–0.864). Safety outcomes showed that GLP-1RAs were associated with an increased risk of erectile dysfunction and nausea/vomiting. In contrast, GLP-1RAs were associated with lower risks of abdominal pain and constipation. No significant associations were observed for gynecomastia or diarrhea. Conclusions: In this large-scale, head-to-head comparison, GLP-1RAs demonstrated superior efficacy over 5-ARIs, providing a 20% relative risk reduction in PC incidence among high-risk men. Given the global surge in GLP-1RA utilization, these findings suggest a profound public health opportunity: the ability to achieve systemic oncologic protection through existing metabolic therapies. If validated by prospective trials, GLP-1RAs could transition from metabolic blockbusters to a cornerstone of precision oncology and primary cancer prevention.

e16488 Background: Small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (ampullary AC) are rare gastrointestinal (GI) malignancies. Treatment strategies are largely extrapolated from colorectal cancer, where oxaliplatin-based regimens are the most common first-line therapy in advanced disease. Although bevacizumab is considered safe in metastatic SBA, its efficacy remains unproven, and evidence is limited to small retrospective studies. We assessed the association of adding bevacizumab to FOLFOX with survival and toxicity in a large real-world cohort. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network (January 2000-December 2025), including data from 105 healthcare organizations. Adults (≥18 years) with SBA or ampullary AC treated with FOLFOX with or without bevacizumab were identified. Cohorts were propensity score-matched on age, sex, race, comorbidities, and metastatic sites. Outcomes included overall mortality, GI perforation, bleeding, venous thromboembolism (VTE), hospital admission, and emergency department (ED) visits. Kaplan-Meier and Cox proportional hazards models were used for time-to-event analyses. Results: After matching, 818 patients were included in each cohort. In the FOLFOX + bevacizumab cohort, mean age was 66.1 ± 12.0 years and 53.8% were male; 63.7% were White, 13.8% Black, 5.6% Asian, 12.0% Unknown/Other, and 4.4% Hispanic/Latino. Over a median follow-up of 13 months, FOLFOX + bevacizumab was associated with higher overall mortality compared with FOLFOX alone (55.3% vs 45.2%; HR 1.24 [95% CI 1.1-1.4]; p = 0.002) and shorter median OS (15.1 vs 19.5 months). Rates of GI perforation (15.5% vs 16.7%; HR 0.90 [95% CI 0.71-1.15]; p = 0.39), GI bleeding (13.1% vs 13.6%; HR 0.96 [95% CI 0.73-1.25]; p = 0.74), and VTE (19.1% vs 21.4%; HR 0.88 [95% CI 0.71-1.09]; p = 0.23) were similar between groups. Hospital admissions were higher in the FOLFOX + bevacizumab cohort (2.8% vs 1.3%; HR 2.1 [95% CI 1.0-4.3]; p = 0.04). Findings were consistent at 5-year follow-up. Conclusions: In this real-world cohort, the addition of bevacizumab to FOLFOX was not associated with improved survival and was associated with higher healthcare utilization. Prospective, disease-specific studies are needed to define its role in this population. Outcomes at median 13-month follow-up after propensity matching (FOLFOX + bevacizumab vs FOLFOX). Outcome % vs % HR p Overall mortality 55.3 vs 45.2 1.24 0.002 Hospital admission 2.8 vs 1.3 2.1 0.04 ED visit 45.2 vs 42.4 1.02 0.75 GI perforation 15.5 vs 16.7 0.90 0.39 GI bleeding 13.1 vs 13.6 0.96 0.74 VTE 19.1 vs 21.4 0.88 0.23

e16449 Background: Pancreatic cancer (PC) carries a dismal 5-year survival of < 12%, and no FDA-approved agents exist for primary prevention. PC risk is strongly linked to obesity, diabetes, and chronic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) directly target obesity-driven inflammatory pathways, reduce metabolic stress, and modulate signaling pathways (PI3K/AKT/mTOR) that drive cancer apoptosis. Based on this biological rationale, we conducted the first large-scale real-world study to evaluate the safety and efficacy of GLP-1RA for primary prevention of PC in high-risk patients. Methods: Leveraging a large real-world database (TriNetX), we identified patients aged 18-90 years with ≥1 PC risk factor (tobacco use, obesity, type 2 diabetes, alcohol use disorder, chronic pancreatitis, first-degree relative with PC, genetic susceptibility to PC) based on ICD-10 codes. Patients were stratified by GLP-1RA exposure into two cohorts: Cohort A (GLP-1RA users with ≥ 2 months of prescriptions) and Cohort B (controls). The primary endpoint was incident PC, and the secondary endpoints were adverse events related to GLP-1RAs. Patients with outcomes before the study window were excluded. Propensity score matching adjusted for confounders. Multivariate logistic regression was used to estimate odds ratios for categorical outcomes, and the Cox proportional hazards model was used to estimate hazard ratios for time-to-event outcomes. Subgroup and sensitivity analyses were employed to validate the strength of our results. Results: Median follow-up was 3,397 days for GLP-1RA users and 2,531 days for controls. Demographics were balanced between cohorts (mean age 42 years; 74% White, 15% Black; 72% female). Among 572,330 high-risk patients (286,165 per cohort), PC incidence was significantly lower among GLP-1RA users (0.05%; 134/286,165) than among non-users (0.13%; 362/286,097), with a 2.6-fold reduction in the absolute incidence of PC among high-risk patients (NNT of 1,255). GLP-1RA use was associated with a 71% reduction in PC incidence (HR 0.289; 95% CI 0.237–0.352). GLP-1RA use was associated with an increased risk of gastrointestinal adverse events, including nausea/vomiting (HR 1.108; 95% CI 1.096–1.121), abdominal pain (HR 1.081; 95% CI 1.066–1.097), diarrhea (HR 1.199; 95% CI 1.182–1.217), and constipation (HR 1.159; 95% CI 1.143–1.176). Conclusions: GLP-1RA use significantly reduced PC incidence by 71% in high-risk patients, the strongest real-world signal yet for a pharmacologic prevention of this lethal malignancy. Although the absolute incidence remained low, the magnitude of the risk reduction underscores the transformative potential of GLP-1RA in preventive oncology. These findings address a critical unmet need in pancreatic oncology. Prospective mechanistic and randomized studies are warranted to validate these associations.

e16435 Background: Peritoneal metastasis in pancreatic ductal adenocarcinoma (PDAC) is historically associated with a dismal prognosis and limited response to systemic therapy alone. The role of locoregional therapy remains controversial. This study evaluated the survival impact and safety of HIPEC, with or without cytoreductive surgery (CRS), compared to standard-of-care systemic therapy in patients with peritoneal metastatic PDAC. Methods: We conducted a comparative analysis of 130 patients with peritoneal metastatic PDAC, comprising a study cohort treated with HIPEC (n = 33) and a control group treated with systemic chemotherapy alone (Non-HIPEC, n = 97). HIPEC patients received induction chemotherapy (predominantly FOLFIRINOX) followed by HIPEC ± CRS. Co-primary endpoints included 12 months survival, and 6 months progression free survival (PFS). Secondary endpoints evaluated Overall Survival (OS ), safety of CRS, and impact of germline mutation status on survival. Study was approved under IRB protocol 25-008762. Results: The 12-month OS rate was significantly higher in the HIPEC group compared to the chemotherapy-only control group (100% vs. 52.6%, P < 0.001). The 6-month PFS rate in the HIPEC group was 63.0% vs. 47.94 in-only control group (P < 0.001). For secondary endpoints, the HIPEC group demonstrated a significantly longer median OS of 33.0 months vs. 17.0 months for controls (P < 0.001). Within the HIPEC cohort, the addition of CRS (n = 25) significantly improved outcomes compared to HIPEC alone (n = 8): median OS improved from 21.5 to 36.0 months (P = 0.03). Germline testing was performed in 61% of HIPEC patients and 48% of controls, identifying pathogenic mutations in 25% and 17%, respectively. Identified pathogenic mutations in both groups included ATM (n = 4), MUTYH (n = 2), BRCA2 (n = 1), CHEK2 (n = 1), PALB2 (n = 1), and KIT (n = 1). In the control group, specific mutations drove divergent outcomes; ATM median OS: 23.5 months vs. MUTYH : 8.0 months (P = 0.04). Conversely, in the HIPEC+CRS cohort, survival was excellent regardless of genetic profile: mutation carriers achieved a median OS of 33.0 months compared to 31.0 months in wild-type patients (P = 0.85). Despite a 34.8% postoperative complication rate in the HIPEC group, there was no perioperative mortality. Conclusions: In selected patients with peritoneal metastatic PDAC, HIPEC provides a substantial survival advantage over systemic therapy alone, achieving a 100% 12-month survival rate and more than doubling the median overall survival. Importantly, germline mutation status did not preclude survival benefit, with mutation carriers deriving equal efficacy from the multimodal approach. These findings support HIPEC+CRS as a highly effective strategy that may overcome adverse biologic drivers.

e16018 Background: Intrahepatic cholangiocarcinoma (iCCA) exhibits marked heterogeneity in outcomes that is incompletely explained by stage or treatment timing. Although treatment delay is frequently cited as a modifiable risk factor, its prognostic significance in real-world practice remains unclear. We applied machine learning (ML) to model iCCA as a dynamic disease process and to evaluate whether longitudinal disease trajectories better explain outcomes than treatment timing alone. Methods: We conducted a population-based retrospective analysis of adults diagnosed with iCCA using the Surveillance, Epidemiology, and End Results (SEER) database (2000–2022). Time from diagnosis to first cancer-directed therapy was categorized as ≤30 days, 31–60 days, or > 60 days. Associations between treatment delay, disease characteristics, and overall survival (OS) were assessed using multivariable logistic and Cox regression models. To capture real-world disease evolution, each patient’s clinical course was encoded as an ordered longitudinal sequence of diagnosis, treatment states (surgery, chemotherapy, radiation), and outcome. Unsupervised ML was used to identify latent disease-course trajectories. A supervised ML model using variables available at diagnosis was developed to predict membership in high-risk trajectories. Results: The cohort included 18,312 patients with iCCA. Treatment initiation beyond 30 days occurred in more than half of patients and was more common in localized than advanced disease. In adjusted survival analyses, shorter time to treatment was paradoxically associated with worse OS, consistent with confounding by disease severity rather than a protective effect of delay. Unsupervised ML identified four distinct and reproducible disease trajectories with markedly different outcomes. Median OS ranged from approximately 2 months in early-failure trajectories to approximately 15 months in favorable multimodality trajectories. Trajectory membership was not fully explained by stage or treatment timing. A supervised ML model predicted high-risk trajectory membership with good discrimination (AUC 0.82). Key predictors included tumor grade, age, tumor burden, and incomplete staging, whereas treatment timing had minimal influence. Conclusions: In iCCA, treatment delay reflects underlying disease biology and care prioritization rather than independently determining survival. ML-based trajectory modeling reveals clinically meaningful disease courses that better explain outcome heterogeneity than treatment timing or stage alone and enables early identification of patients at highest risk for unfavorable real-world outcomes.