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Squamous cell lung cancer (SqCLC) accounts for 20–30% of non-small cell lung cancer (NSCLC) and remains associated with a poorer prognosis compared with adenocarcinoma. Despite advances in treatment, 5-year overall survival for advanced (stage IV) disease remains below 10–15%. Unlike non-squamous NSCLC, SqCLC is characterized by a high tumor mutational burden and complex genomic landscape dominated by alterations in tumor suppressor genes and lineage survival pathways including TP53, CDKN2A, PIK3CA, FGFR1, SOX2, and the NFE2L2/KEAP1 oxidative stress pathway, as well as dysregulation of the NOTCH signaling pathway, but it harbors relatively few actionable oncogenic drivers, resulting in limited treatments for targeted therapy. HER2 alterations can occur by multiple mechanisms, including activating mutations, gene amplifications, and protein overexpression. They comprise a very small percentage of NSCLC, with HER2 mutations reported in approximately 1–3% and HER2 amplifications observed roughly in 2–4%. While HER2 alterations are well characterized in lung adenocarcinoma, the prevalence, genomic context, and clinical significance of HER2 alterations in SqCLC remain incompletely defined. Advances in next-generation sequencing have led to improved ability to detect HER2 alterations and facilitated the development of HER2 targeted therapies. Available treatments for advanced/metastatic SqCLC have been historically limited to platinum-doublet chemotherapy, with immune checkpoint inhibitors such as anti-PD-1/PD-L1 newly emerging in the past decade. Selective HER2 tyrosine kinase inhibitors and HER2 antibody/drug conjugates have shown improved efficacy in HER2-altered NSCLC as shown in DESTINY-LUNG02 and BEAMION LUNG-1 trials; however, most of the enrolled patients had non-squamous histology, with minimal or no SqCLC-specific efficacy data reported. Future progress in HER2-altered SqCLC will require inclusion of SqCLC in HER2 basket trials, incorporation of comprehensive molecular profiling and standardized HER2 testing in squamous histology. This review summarizes the current state of knowledge of HER2 biology in SqCLC and highlights areas for future directions for precision oncology in SqCLC.

e20595 Background: Circadian regulation of immune function has been proposed as a modifier of immune checkpoint inhibitor (ICI) efficacy, with retrospective studies suggesting improved outcomes with earlier infusion timing. Whether these findings translate to routine oncology practice, where ICIs are administered across multiple lines, frequently combined with chemotherapy, and subject to treatment interruptions, remains uncertain. We evaluated the association between ICI infusion timing and overall survival (OS) in a real-world cohort of patients with non-small cell lung cancer (NSCLC). Methods: A retrospective cohort study included adults with NSCLC who received at least one line of ICI therapy at a community oncology center between January 2018 and December 2024. Infusion timing was defined at the patient level as morning-only ( < 1300 hours), evening-only (≥1300 hours), or mixed timing, reflecting receipt of infusions exclusively in different time-of-day categories across treatment lines. OS was measured from diagnosis to death or last follow-up. Kaplan-Meier and Cox proportional hazards models were used. Multivariable analyses adjusted for stage, ECOG performance status, body mass index, and premature ICI discontinuation. Line of therapy was excluded due to collinearity with mixed-timing classification and risk of immortal time bias. Results: A total of 127 patients were included (morning-only n = 77; mixed timing n = 36; evening-only n = 14). Staging data were available for 99.2%, and 94 deaths occurred. Median OS was 495 days for morning-only, 850 days for mixed timing, and 388 days for evening-only patients. Kaplan-Meier analysis showed no statistically significant OS differences across groups. In sensitivity analysis excluding patients with mixed infusion timing, morning-only and evening-only groups demonstrated overlapping survival curves, with no evidence of a time-of-day–specific survival advantage. In univariate analysis, mixed timing was associated with a borderline reduction in mortality compared with morning-only infusions (HR 0.63, 95% CI 0.39-1.00), while evening-only timing was not (HR 1.63, 95% CI 0.85-3.16). In multivariate analysis restricted to stage III-IV disease, infusion timing was not independently associated with OS. ECOG performance status, premature ICI discontinuation and advanced staging were the strongest predictors of mortality. Conclusions: In this real-world NSCLC cohort, ICI infusion timing was not independently associated with overall survival after adjustment for patient fitness and treatment continuity. These findings suggest that in pragmatic settings, clinical factors may outweigh subtle chronotherapy effects reported in more selected populations.

e17027 Background: Guidelines recommend active surveillance for low-risk prostate cancer and definitive therapy for high-risk disease. We evaluated national patterns of risk-misaligned care and the survival consequences of undertreatment. Methods: National Cancer Database prostate cancer cases diagnosed from 2010–2022 were analyzed. Low-risk disease was defined as clinical T1–T2, Grade Group 1, and PSA < 10; overtreatment was definitive treatment vs active surveillance or no treatment. High-risk disease was defined as Grade Group ≥4, PSA ≥20, or clinical T3–T4; undertreatment was no definitive local therapy or incomplete definitive therapy. Multivariable logistic regression evaluated factors associated with misalignment. Overall survival (OS) among high-risk patients was assessed using multivariable Cox regression. Results: Among low-risk patients (N = 124,562), overtreatment occurred in 40% of cases. Overtreatment was more common among young men (adjusted odds ratio [aOR] 0.982; p < 0.001) and less common at academic centers (aOR 0.414; p = 0.015). Compared with White men, odds of overtreatment were lower among Black men (aOR 0.946; p = 0.002) and Asian men (aOR 0.827; p < 0.001), with additional variation by education and region (all p < 0.001). Among high-risk patients (N = 318,532), undertreatment affected 27.3% of patients and was more common among older men (aOR 1.061; p < 0.001). Compared with White men, undertreatment was higher among Black men (aOR 1.479; p < 0.001) and lower among Asian patients (aOR 0.863; p < 0.001) (overall race p < 0.001). Compared with private insurance, undertreatment was higher in Medicaid (aOR 2.038; p < 0.001) and uninsured patients (aOR 2.649; p < 0.001), and slightly lower with Medicare (aOR 0.931; p < 0.001) (overall insurance p < 0.001). Multiple comorbidities were associated with higher undertreatment (≥2 vs 0: aOR 1.252; p < 0.001). Facility type was not independently associated (p = 0.490), while region remained significant (overall p < 0.001). In the survival cohort (high risk) (N = 338,919), undertreatment was associated with substantially worse OS (HR 2.745, 95% CI 2.706–2.784; p < 0.001), adjusted for age (HR 1.056; p < 0.001), race (p = 0.001), insurance (p < 0.001), comorbidity (p < 0.001), income (overall p < 0.001), education (overall p < 0.001), and facility region (overall p < 0.001). Conclusions: Low-risk overtreatment remains common nationwide and varies across patient and health-system factors. In high-risk disease, undertreatment affects over one-quarter of patients and disproportionately impacts Black men and those with Medicaid or no insurance. Undertreatment confers a nearly threefold mortality hazard (adjusted HR 2.75; p < 0.001), highlighting a major national quality gap and the urgent need for system-level interventions to ensure equitable, guideline-concordant delivery of definitive therapy.

e16586 Background: Guideline-discordant care disproportionately affects racial minorities, uninsured, and underinsured patients, yet prior studies lack quantification of absolute survival time lost. We evaluated equity-adjusted survival penalties from non-adherence to guideline-concordant therapy in muscle-invasive bladder cancer (MIBC). Methods: From the National Cancer Database, we identified patients with non metastatic muscle invasive bladder cancer (cT2 to T4a, N0 or N1, M0). Overall survival was defined from diagnosis to death or last contact. Guideline-concordant therapy was defined as radical cystectomy (± perioperative systemic therapy) or trimodality therapy (definitive bladder radiotherapy with chemotherapy); all other patterns were classified as discordant. Of 55,873 eligible patients, 28,025 received concordant therapy (27,401 cystectomy; 524 trimodality therapy) and 27,848 received discordant careInverse probability of treatment weighting (IPTW) was used to balance demographic, socioeconomic, facility, tumor, and temporal covariates. We analyzed survival using weighted Kaplan-Meier and Cox models censored at 36 and 60 months. Equity-adjusted survival penalties were calculated as the difference between observed survival and counterfactual survival predicted from concordant-only models. Restricted mean survival time losses were extrapolated to years lost per 1,000 patients. Results: Guideline concordance was associated with significantly improved survival (36-month HR 0.64; 60-month HR 0.68; both p < 0.01). Among concordant modalities, radical cystectomy conferred an early survival advantage over trimodality therapy at 36 months (HR 0.23; p < 0.05) which dissipated by 60 months (HR 0.53; p > 0.05). Survival penalties were most severe for vulnerable populations. At 36 months, uninsured patients incurred a 0.90-month survival penalty (75.0 life-years lost per 1,000 patients). By 60 months, penalties widened: uninsured patients lost 1.94 months (161.7 life-years/1,000), Filipino patients lost 1.53 months (127.0/1,000), Medicaid beneficiaries lost 0.97 months (80.8/1,000), and patients at community cancer programs lost 0.21 months (54.1/1,000). Conclusions: In this national cohort of 55,873 patients, guideline concordance reduced the propensity-weighted risk of death by 32% to 36% at 3 and 5 years. However, non-adherence results in substantial absolute survival losses for marginalized groups. By quantifying these "survival penalties," we demonstrate that targeting the factors underlying discordance offers a direct opportunity to reduce inequities and achieve measurable population-level survival gains in MIBC.

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

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.

9021 Background: An escape room is a team-based activity in which participants collaborate to solve puzzles within a fixed time limit and escape. Prior studies demonstrate high learner satisfaction and improved teamwork and communication with medical education escape rooms. To date, no published reports describe an escape room designed specifically for hematology/oncology (hem/onc) fellows. As part of Hem/Onc Curriculum, we designed and implemented a hem/onc-focused escape room and evaluated learner satisfaction and perceived learning impact. Methods: The escape room was designed using evidence-based learning science principles (Table 1). Teams worked to solve sequential puzzles, centered on a patient case, addressing key hem/onc concepts, including transfusion medicine, peripheral blood smears, lymphoma classification, and coagulation disorders. Each solved puzzle revealed additional patient laboratory and pathology data. Successful completion required teams to diagnose the patient and select appropriate treatment. Following the activity, teams participated in a facilitator-led debrief focused on team dynamics, communication, and problem solving. Teams observed each other and shared feedback. A larger group debrief co-led by chief fellows and faculty reviewed learning objectives and key takeaways. Learner outcomes were assessed using a post-activity survey evaluating satisfaction, engagement, and impact on learning. Results: Eighteen learners participated, including 14 hem/onc fellows, 1 APP hem/onc fellow, and 3 internal medicine residents. Three of four teams escaped within 1 hour (mean completion time, 52 minutes). All participants provided positive verbal feedback. Fifteen learners completed the post-activity survey, and all respondents reported satisfaction with the activity and would recommend it for future fellows. One-word descriptors included “engaging,” “fun,” and “challenging.” Most respondents (93.3%) agreed that the activity reinforced key hem/onc concepts and improved confidence in clinical problem-solving. All learners felt the activity supported learning, and 93.3% reported that collaboration enhanced the learning experience. Participants identified team-based problem solving, clinical application, and interactive puzzles as the most effective components. Conclusions: A hem/onc escape room resulted in high learner satisfaction and reinforced hem/onc knowledge and clinical problem-solving. This feasible, fun, and innovative activity complements traditional fellowship education by leveraging adult learning principles through gamified, team-based learning and should be incorporated into training programs’ curriculum. Learning science principles applied in a hem/onc escape room. Active Learning Belonging Contrasting Cases Debriefing Deliberate Practice Elaboration Generation Listening and Sharing Reward Worked Examples

590 Background: The landmark FAST-Forward trial demonstrated that ultra-hypofractionated whole-breast irradiation with 26 Gy in 5 fractions over 1 week was non-inferior to 40 Gy in 15 fractions for local control (HR 0.67, 95% CI 0.38–1.16), with similar normal tissue effects at 5 years. In response, major international guidelines incorporated 26 Gy in 5 fractions as a standard approach or recommended option for selected patients. Despite robust randomized evidence and guideline endorsement, U.S. real-world adoption patterns and equity of uptake across patient populations remain incompletely characterized. This study evaluated national trends in 5-fraction breast radiotherapy and sociodemographic differences from 2020 to 2023. Methods: The National Cancer Database radiotherapy fractionation fields were used to identify radiotherapy (RT) courses with evaluable fraction counts, and a binary indicator for 5-fraction RT (yes/no) was created. Temporal trends by diagnosis year (2020–2023) were assessed, and associations between 5-fraction RT and sociodemographic factors (primary insurance, urban or rural status, neighborhood income quartile, and race) were examined using chi-square testing. Results: Among 536,783 RT courses with complete data from 2020 to 2023, use of 5-fraction RT increased substantially over time: 4.3% in 2020, 8.1% in 2021, 12.7% in 2022, and 17.4% in 2023, resulting in an overall adoption rate of 10.7% (p < 0.001). In the subset eligible for fractionation (5, 15–16, 25–28 fractions; N = 31,448), 5-fraction RT accounted for 11.7% and differed significantly by insurance type (p < 0.001): Medicare 17.4%, Private 7.6%, Medicaid 5.9%, and Uninsured 6.9%. Geographic variation was notable (p < 0.001), ranging from 7.3% in mid-size metropolitan areas (250,000–1 million population) to 17.7%–18.1% in more remote or non-adjacent areas; large metropolitan areas (≥1 million) had 12.8% uptake. Neighborhood income showed a gradient (p < 0.001): 10.1% in the lowest quartile compared to 12.5% in the highest. Race was also associated with uptake (p < 0.001), with lower use among Black patients compared to White patients (9.4% vs 12.2%). Conclusions: In routine U.S. practice, adoption of 5-fraction breast RT increased rapidly from 2020 to 2023, with the most pronounced growth after 2021, reflecting the swift translation of trial evidence into clinical practice. However, uptake varies by insurance, geography, income, and race, indicating that diffusion is not uniform. Given the potential benefits of ultra-hypofractionation in reducing treatment burden and supporting timely completion, targeted implementation strategies, such as provider education, reimbursement alignment, and facility-level operational support, may be necessary to ensure equitable access as 5-fraction regimens become more widely adopted and potentially become the standard of care.

Background/Objectives: Locoregional anal squamous cell carcinoma (ASCC) is usually cured with chemoradiotherapy; however, some patients relapse, require salvage abdominoperineal resection or develop metastatic disease. Approximately 90% of cases are driven by high-risk human papillomavirus, most commonly HPV16. Conventional surveillance using clinical examination and imaging may have limited sensitivity and specificity and is not individualized by recurrence risk. Circulating biomarkers (CBs), particularly circulating tumor DNA (ctDNA), have emerged as promising methods for real-time disease monitoring. We systematically reviewed available evidence evaluating CBs across treatment timepoints in localized ASCC. Methods: A PROSPERO-registered review (ID: 1133987) was conducted according to PRISMA guidelines. PubMed, EMBASE, Cochrane CENTRAL, Web of Science, and major conference proceedings (ASCO, ESMO, ASTRO) were searched on 30 November 2025. We included prospective or retrospective studies (≥10 patients) with stage I–III disease treated with curative-intent chemoradiotherapy that reported CBs, assay characteristics, and at least one clinical outcome. Studies with predominantly localized cohorts were included even if small proportions of metastatic patients were present, provided results relevant to curative-intent populations could be interpreted. Data were synthesized narratively by timepoint (baseline, mid-treatment, end of treatment, post-treatment/surveillance) and assay type given methodological heterogeneity. Results: Fifteen studies were included. CB assays comprised four categories: viral HPV ctDNA assays, tumor-informed ctDNA assays, non-specific total cell-free DNA (cfDNA) quantification, and circulating tumor cell (CTC)-based assays. Baseline detection rates varied by assay type. Viral HPV ctDNA assays demonstrated detection rates of 59–100%, while tumor-informed ctDNA assays showed rates of 79–89%. Across studies, higher CB detection rates and levels were generally associated with greater tumor burden, including more advanced T and N stage disease. Mid-treatment ctDNA clearance identified patients with excellent locoregional control and progression-free survival, whereas persistent ctDNA was associated with treatment failure. End-of-treatment and surveillance ctDNA positivity predicted recurrence within individual cohorts, with reported sensitivities of 80–90%, specificities of 95–99%, and molecular lead times preceding clinical or radiographic detection. In contrast, non-tumor-specific cfDNA dynamics showed more variable prognostic associations and were less consistently linked to tumor burden. Conclusions: Across heterogeneous assays, CB dynamics provide clinically meaningful prognostic information in localized ASCC, particularly when measured during treatment and early surveillance. Viral HPV and tumor-informed ctDNA may have the potential to guide follow-up intensity and inform future escalation or de-escalation strategies; however, prospective, standardized trials are needed to define actionable thresholds and test ctDNA-guided management.