Ganatra, Nency

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.

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.

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.

Abstract Background: Early-onset gastrointestinal (GI) cancers are increasing globally, yet the genomic basis for age-related differences across multiple tumor types remains poorly defined. We leveraged AACR Project GENIE v18.0 (N≈34,000 GI tumors) to characterize molecular distinctions by age in colorectal, pancreatic, small bowel, and anal cancers with sufficient early-onset representation. Methods: Clinical and genomic data were extracted and tumors classified into early-onset (&lt;50 years) and late-onset (≥50 years). Mutation frequencies were compared by cancer type and age group, focusing on recurrent drivers, DNA repair, Wnt signaling, RAS/MAPK, chromatin remodeling genes, and targetable alterations. Results: Early-onset colorectal cancer (N=5,724) showed increased Wnt/β-catenin pathway alterations: APC (+4.9%), TCF7L2 (+4.1%), and TP53 (+5.0%), while late-onset tumors (N=15,807) were enriched for BRAF (−5.4%), RNF43 (−1.9%), and GNAS (−1.1%), indicating divergent tumorigenic pathways. Early-onset pancreatic cancer (N=890) exhibited significantly lower frequencies of canonical drivers—KRAS (−24.7%), TP53 (−15.6%), CDKN2A (−6.9%), SMAD4 (−6.0%)—with enrichment of MEN1 (+3.5%), TSC2 (+3.0%), ATRX (+2.0%), DAXX (+1.9%), and CTNNB1 (+2.4%), consistent with fusion-driven, hereditary, and chromatin remodeling biology. Small bowel cancer (N=99) in early-onset patients demonstrated enrichment in DNA damage response and MAPK/RAS genes including BRCA2 (+7.2%), NF1 (+7.4%), FBXW7 (+8.8%), FLT4 (+6.5%), ARAF (+6.4%), and ALK (+5.1%), whereas late-onset tumors (N=538) were enriched for KDR (−5.1%) and MGA (−5.2%). Early-onset anal cancer (N=62) showed elevated MGA (+7.8%), WHSC1/NSD2 (+6.9%), PBRM1 (+6.2%), FANCA (+5.2%), ERCC5 (+6.2%), and MSH6 (+5.9%), highlighting chromatin remodeling and DNA repair pathways potentially related to HPV biology; late-onset tumors (N=464) had enrichment in ATM (−5.6%), PTEN (−5.5%), STK11 (−5.2%), APC (−5.2%), and KMT2C (−5.0%), reflecting age-associated genomic instability. Conclusions: This pan-GI age-stratified analysis reveals distinctive oncogenic programs in early-onset GI cancers characterized by Wnt/TP53-driven colorectal, fusion- and chromatin remodeling-driven pancreatic, DNA damage response/MAPK-driven small bowel, and chromatin-immune DDR signatures in anal cancers. These findings underscore the need for age-tailored precision oncology and support routine genomic profiling in early-onset GI malignancies to identify targetable alterations enriched in younger patients. Citation: AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through an International Consortium. Cancer Discov. 2017;7(8):818-831. (Data: GENIE Release 18.0-public)Acknowledgement: AACR and Project GENIE registry Citation Format: Ahmed Abdelhakeem, Nency Ganatra, Dina Elantably, Tayo Adeoye, Nayef H. Abdel-Razeq, Mosalem M. Osama, Hani M. Babiker. Distinct age associated genomic landscapes in colorectal, pancreatic, small bowel, and anal cancers: A pan gastrointestinal analysis of 34,000 tumors from AACR Project GENIE v18.0 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4105.

Abstract Background: PARP inhibitors are restricted to a subset of BRCA-associated cancers, but homologous recombination repair (HRR) deficiency signifies a broader genomic vulnerability that may extend therapeutic opportunities across diverse malignancies. We utilized AACR Project GENIE v18.0-public to define the pan-cancer prevalence of HRR gene alterations. Methods: Somatic mutation and clinical sample data from GENIE v18.0-public were analyzed. HRR genes included BRCA1, BRCA2, ATM, CHEK2, PALB2, RAD51B/C/D, RAD51L1, BARD1, BRIP1, and core FANC genes. HRR alteration rates were calculated by tumor type using unique samples; only de-identified aggregate results are reported. Results: Among 101,240 tumors, HRR gene alterations were frequent in multiple non-BRCA-associated cancers. Highest rates were seen in sialoblastoma (100%), large cell medulloblastoma (50%), malignant glomus tumor (50%), lung cancer (46.0%), infantile fibrosarcoma (42.9%), liver (40%), kidney (40%), non-melanoma skin (36.9%), colorectal (36.6%), melanocytoma (34.2%), biliary tract (33.3%), bladder (31.5%), and ovarian/fallopian tube (30.2%). Notably, lung, bladder, hepatobiliary, renal, gastrointestinal, and some sarcoma subtypes showed HRR mutation prevalence equal or higher than current PARP indications, yet lack FDA approval. Conclusions: HRR alterations are widespread across solid tumors, often surpassing rates in cancers eligible for PARP treatment. These findings support expanding tumor-agnostic HRR genomic testing beyond BRCA-linked malignancies and warrant prospective trials of PARP inhibitors in HRR-enriched tumor types such as lung, bladder, hepatobiliary, renal, gastrointestinal, and pediatric/rare cancers. Impact: Large-scale genomic profiling from AACR Project GENIE demonstrates that HRR gene alterations are common across diverse solid tumors, with prevalence in multiple cancer types surpassing those currently eligible for PARP inhibitor therapy. These findings support broad implementation of HRR genomic testing in routine molecular diagnostics and provide a rationale for expanding PARP inhibitor use beyond BRCA-associated malignancies. The data justify prospective tumor-agnostic clinical trials of PARP inhibitors in HRR-enriched cancers such as lung, bladder, hepatobiliary, renal, gastrointestinal, and select pediatric and rare tumors; this could transform therapeutic decision-making and accelerate development of synthetic lethality-based targeted therapies Citation: AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831 Acknowledgement: AACR and Project GENIE Citation Format: Ahmed Abdelhakeem, Nency Ganatra, Dina Elantably, Tayo Adeoye, Nayef H. Abdel-Razeq, Osama M. Mosalem, Hani M. Babiker. Pan cancer enrichment of homologous recombination repair (HRR) gene alterations in 101,240 tumor samples from AACR Project GENIE: Implications for tumor-agnostic PARP inhibitor expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4106.