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Biomarker use in subgroup analysis versus enrichment trial design as a predictor of oncology trial success.
e23122 Background: Biomarkers are widely used in oncology clinical trials for patient stratification and endpoint definition, yet it remains unclear whether trials should i) use an “enrichment design” that treats only biomarker-positive patients or ii) use other designs that treat biomarker-negative patients and use biomarkers for subgroup analysis. We performed the first systematic analysis of biomarker placement across all interventional oncology clinical trials to assess whether enrichment designs are associated with higher trial success rates. Methods: We analyzed 105,203 interventional oncology trials from Trialtrove, a curated clinical trial database. After excluding trials with incomplete biomarker data or indeterminate outcomes, 22,277 trials with 3,711 unique biomarkers remained. For 161 frequently studied biomarkers, such as HER2, CYP3A4, EGFR, biomarker mentions were identified across eight trial documentation fields: Trial Title, Trial Objective, Patient Population, Inclusion Criteria (IC), Exclusion Criteria (EC), Primary Endpoints, Secondary Endpoints, and Trial Results. Biomarker use in IC or EC defined enrichment designs. Each biomarker mention was paired with its surrounding text to determine its semantic role. A subset of biomarker-context pairs was manually labeled as true, incidental, or false mentions, and used to train a BERT-based classifier (94.1% accuracy) to label remaining pairs at scale. For success analyses, user-defined field sets were constructed by grouping one or more documentation fields containing biomarker mentions, while non-field sets had all remaining documentation fields not in the field set. Trial success was defined as positive or early positive outcomes, and success rates were compared between field and non-field sets using chi-square tests with Bonferroni correction. Results: Comparisons between user-chosen field and not-chosen field sets (all other fields) revealed consistent differences in trial success rates. When biomarkers were used in field sets corresponding to patient selection—most notably Inclusion Criteria and Exclusion Criteria—trials consistently showed lower success rates than when the same biomarkers appeared in the other six fields. In contrast, field sets that included downstream trial components suggestive of post-hoc analysis, particularly Trial Results and Patient Population, were associated with significantly higher success rates (e.g. 0.692 vs 0.360 for Trial Results and all other fields, respectively). Overall, trials in which biomarkers were evaluated outside enrollment-focused fields demonstrated greater likelihood of success than trials using biomarkers for patient selection. Conclusions: Future trials may benefit from minimizing biomarker-based patient selection in favor of designs that have biomarker-positive and biomarker-negative subgroups that are compared after treatment.
Incidence, severity, and management of severe adverse events in first-line (1L) treatments for metastatic pancreatic ductal adenocarcinoma (mPDAC): A retrospective observational study.
e16377 Background: 1L systemic treatment of mPDAC can lead to severe adverse events (AEs). To contextualize the safety profile of irinotecan-based regimens, real-world data were used to characterize AEs and their management in patients receiving 1L mPDAC treatment with FOLFIRINOX (FFX) or gemcitabine+Nab-paclitaxel (Gem+NabP). Methods: De-identified data from Mayo Clinic electronic health records (all sites; records collected 2010–2023) were used. Natural language processing was leveraged to confirm staging and metastatic classification and to extract treatment data. Adults with mPDAC with stage IV and/or TNM staging of M1 who received ≥ 1 dose of FFX or Gem+NabP were included. Primary endpoint: proportion of patients with AEs of interest (diarrhea, nausea, vomiting, neuropathy, and neutropenia) following initiation of 1L treatment. Secondary endpoints: proportion of patients who received treatment for each AE of interest, median time to resolution and treatment of each AE of interest, and proportion of patients who switched mPDAC treatment or had dose reductions due to AEs. Results: In total, 405 patients (FFX, 197; Gem+NabP, 208) were identified. The proportions of patients who experienced and were treated for any-grade AEs of interest are reported in the Table. Of the AEs of interest, neutropenia resolved most quickly (median time from onset to resolution, FFX: 9.5 days; Gem+NabP: 12.5 days); neuropathy took the longest time to resolve (FFX: 44.0 days; Gem+NabP: 74.0 days). Median time to AE treatment was shortest for nausea and vomiting (both 0.0 days for FFX and for Gem+NabP). Time to treatment was longest for neuropathy (FFX: 158.5 days; Gem+NabP: 70.0 days). Only 5.1% of patients on FFX and 13.4% on Gem+NabP received treatment for neuropathy. Of patients in the FFX group who switched/reduced treatment (n=140), 58.6% received a dose reduction and 7.1% switched to Gem+NabP due to AEs. Conclusions: At the Mayo Clinic sites, incidence of any-grade AEs associated with 1L mPDAC treatment were similar or higher than rates of any-grade or ≥ 2/3–4 grade AEs reported in the literature. Nausea, vomiting and diarrhea were the most commonly treated AEs for both irinotecan-based (FFX) and non-irinotecan-based (Gem+NabP) 1L regimens; neutropenia and neuropathy were less commonly treated. FFX dose reductions were commonly attempted before switching regimens. Proportion experiencing any-grade AE (AE incidence in the literature) Proportion experiencing AE treated for an AE FFX Gem+NabP FFX Gem+NabP Diarrhea 74.6% (50–80%, any grade) 43.8% (< 5%, any grade) 92.5% 56.0% Nausea 81.7% (45%, any grade) 72.1% (20%, grade ≥ 2) 98.8% 96.7% Vomiting 54.8% (10%, any grade) 42.8% (20%, grade ≥ 2) 98.1% 98.9% Neutropenia 58.9% (45%, grade 3–4) 48.1% (12–21%, grade 3–4) 62.1% 46.0% Neuropathy 59.9% (25%, grade 3–4) 32.2% (30%, grade 3–4) 5.1% 13.4%
A phase 1/2 study of ubamatamab (REGN4018), a MUC16×CD3 bispecific antibody, administered alone or in combination with cemiplimab in a low-grade serous ovarian cancer cohort: Trial in progress.
TPS5638 Background: Low grade serous ovarian cancer (LGSOC) typically has a poor response to chemotherapy, presenting an unmet need for efficacious novel therapies that remain tolerable. Mucin 16 (MUC16) is a cell surface glycoprotein that is highly expressed in ovarian cancers, including LGSOC, and has been identified as a potential therapeutic target. Ubamatamab, a MUC16 × cluster of differentiation 3 bispecific antibody, bridges MUC16+ tumor cells and T cells through a major histocompatibility complex-independent mechanism, promoting cytotoxicity. In a first-in-human study (NCT03564340), ubamatamab demonstrated an acceptable safety profile and durable clinical activity in recurrent ovarian cancer, including LGSOC, which has particularly high MUC16 expression on tumor cells. Here, we describe an LGSOC-specific expansion cohort. Methods: In the LGSOC-specific cohort, patients who have received prior platinum-containing therapy (no maximum number of prior therapies) and whose disease has relapsed or progressed after the most recent line of therapy will receive ubamatamab 800 mg intravenously (IV) once every 3 weeks (Q3W). Prior to Q3W dosing of ubamatamab, patients will receive once-weekly step-up dosing to mitigate the risk of cytokine release syndrome, as well as sarilumab 350 mg IV prophylaxis on Day 1. Utilizing a Simon two-stage design, 20 patients will initially be enrolled in this cohort, expanding to 50 if there are ≥3 objective responses. The cohort may be further expanded to 100 patients if ≥14 objective responses (28%) are observed in the first 50 patients. The primary endpoint is objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints include safety, pharmacokinetics, patient-reported outcomes and further efficacy assessments. As of January 5, 2026, 6 patients with LGSOC have initiated ubamatamab treatment. Findings from this study will clarify the therapeutic potential of targeting MUC16 in LGSOC. Clinical trial information: NCT03564340 .
Clinical pharmacokinetics and neutropenia-related pharmacodynamics of BAL0891 in patients with solid tumors.
e15161 Background: BAL0891 is a dual TTK and PLK1 inhibitor, and its pharmacokinetic (PK) and neutropenia-related pharmacodynamic (PD) characteristics were evaluated using data from a Phase I study. Regimen A of Substudy 1, which involved monotherapy administration in patients with solid tumors using a 3-week cycle with consecutive weekly dosing during the first two weeks, has been completed. Plasma concentration and absolute neutrophil count (ANC) data were collected through Cycle 4. Methods: Full PK sampling was performed on Day 1 and Day 8 of Cycles 1 and 2, with sparse sampling in subsequent Cycles. Blood samples for plasma concentration measurements were generally collected pre-dose and at multiple time points up to 167 hours after the end of the 1-hour infusion. ANC data were collected at protocol-specified time points, with additional measurements obtained at the discretion of the treating physician in patients with suspected or confirmed neutropenia. Cycle 1 data, least affected by patient-related factors such as G-CSF use, were used for mixed-effects modeling. The final dataset comprised 1,000 plasma concentration records and 340 ANC records from 41 patients. Data were analyzed using NONMEM (Version 7.5, ICON plc, Gaithersburg, MA, USA), applying the FOCE-I method where applicable. Models were compared by visual diagnostics and numerical criteria, including the objective function value and the Akaike Information Criterion. Results: BAL0891 exhibited linear PK that was well described by a two-compartment model. Systemic clearance and central volume were estimated at 22.7 L/h and 252 L, respectively, with a model-predicted terminal half-life of approximately 34.3 hours. Dose level was not identified as a significant covariate, and PK parameters were consistent across Cycles and Days. ANC PD were described using a semi-mechanistic turnover model in which plasma concentration inhibited neutrophil production via an E max function. Using this model, the exposure levels associated with an approximately 25% incidence of Grade 3 and Grade 4 neutropenia during Cycle 1 were estimated, corresponding to increasing dose levels. Conclusions: In patients with solid tumors, BAL0891 demonstrated linear and dose-proportional pharmacokinetics. Model-based simulations predict that repeated dosing will result in consistent plasma exposure, with no evidence of clinically relevant inter-occasional variability. Model-based simulations did not predict substantial accumulation with weekly administration. Neutropenia risk was quantitatively described in a dose-dependent manner, enabling characterization of the exposure–toxicity relationship. Clinical trial information: NCT05768932 .
Efficacy and toxicity of the antitumor agent SPESN38-8.
e15528 Background: SN38 as TOP1 inhibitor is a potent anticancer agent; however, poor water solubility prohibited its direct clinical applications. Only prodrug approach on SN38 has resulted in 2 types of drugs, irinotecan and sacituzumab govitecan. Furthermore, poor enzymatic conversion (2–8%) of irinotecan into active metabolite SN38 severely limits its efficacy. Numerous attempts on drug delivery systems have failed. Therefore, novel approaches are urgently needed for effectively delivering SN38. Methods: Our patented single protein encapsulation (SPE) platform, allowing encapsulation of small-molecule drugs by a single protein (albumins or globulins) without artificial nanoparticles and chemical modifications to drugs and proteins, has made SPEDOX-6 into human phase IB/IIA clinical trial (NCT0764018). Great success of SPEDOX-6 prompted us to utilize same SPE technology for encapsulation of SN38 by HSA to create SPESN38-5/8 complexes, which were well characterized by membrane dialysis, HPLC, UV & dynamic light scattering. We conducted different evaluations with respect to MTD, PK, in vitro and in vivo efficacy against various cancers. Results: SPESN38-5/8 complexes can be dissolved in water to form clear and stable solutions. PK of SPESN38-5 by IV at 55 mg/kg yielded much higher mouse plasma AUC for SN38 and SN38G, producing a molar ratio of SN38G:SN38 = 1.5:1. We tested in vitro growth-inhibitory effect of SPESN38-8 against SK-ES-1, SK-LMS-1, A204 and HT1080 with IC50 at 0.1079, 0.1526, 1.023, 1.087 uM, respectively, which is 7 to 60-fold lower than irinotecan. In vivo antitumor efficacy against 5 cancer models was evaluated: (1) SK-ES-1, SPESN38-8 at 35 mg/kg vs DOX at 3.0 mg/kg and doxorubicin at 4.0 mg/kg; led to 8/8 mice tumor free on Day 21, which were monitored for total 230 days, tumor relapse wasn’t found for > 209 days, indicative of cancer eradication; (2) A204, SPESN38-8 at 35 mg/kg vs doxorubicin at 4.0 mg/kg, led to all 4 females free of tumor & 4 males almost tumor free, (3) SK-LMS-1, SPESN38-8 at 35 mg/kg vs DOX at 5.0 mg/kg, led to 6/7 mice free of tumor, indicative of SPESN38-8’s superior anticancer efficacy; (4) HCT-116 (colorectal cancer) model, SPESN38-5 at 55 mg/kg vs irinotecan at 50 mg/kg, SPESN38-5 was much effective to suppress HCT-116 than irinotecan; (5) A549, SPESN38-8 at 35 mg/kg vs irinotecan at 50 mg/kg, SPESN38-8 was extremely effective to inhibit A549 than irinotecan. Conclusions: SPESN38 complexes provide a novel water soluble SN38 formulation. SPESN38-5 & SPESN38-8 demonstrate better PK values, lower toxicity and superior antitumor efficacy in mouse models, compared with irinotecan, DOX & doxorubicin. FDA has green-lighted SPESN38-8 (IND #: 164346) for clinical development.
Quality-adjusted survival comparison for tislelizumab (TIS) + chemotherapy (CT) versus placebo (PBO) + CT as first-line (1L) treatment in gastric/gastroesophageal junction adenocarcinoma (GC/GEJC) patients with peritoneal metastasis (PM): Long-term follow-up from RATIONALE-305.
4034 Background: There is an unmet need for better treatment among patients (pts) with PM. A post hoc analysis of the phase 3 RATIONALE-305 (NCT03777657) trial showed that TIS + CT as 1L treatment for GC/GEJC pts with PM improved survival compared to PBO + CT (Qiu et al, 2025). The current study evaluated whether this survival benefit translated into quality of life (QoL) adjusted survival gains. Methods: This post hoc analysis used long-term follow-up data from the RATIONALE-305 trial (minimum follow-up 3 years; data cutoff February 28, 2024). The analysis focused on the intent-to-treat (ITT) population and subgroups defined by programmed death ligand-1 (PD-L1) ≥1% as well as ≥5% by Tumor Area Positivity (TAP) score. The well-established Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) methodology was used. QoL adjusted survival was calculated as the average time spent in three distinct health states during the trial follow-up: survival time with grade 3/4 toxicity, survival without progression/toxicity, and survival post progression, each weighted by QoL utility parameters specific to that state. A sensitivity analysis (SA) using trial-derived, treatment-specific EQ-5D utility values was also conducted. QoL adjusted relative survival gains ≥15% were considered “clearly clinically important,” in line with commonly accepted Q-TWiST benchmarks (DOI 10.1007/s11136-005-1579-7). Results: At the maximum follow-up of 57 months in all randomized pts in RATIONALE-305, TIS + CT (n=501) pts experienced greater mean QoL adjusted survival than PBO + CT (n=496) (16.3 vs 13.1 months). Among pts with PM, TIS + CT (n=220) showed higher mean QoL adjusted overall survival than PBO + CT (n=214) (13.4 vs 10.8 months; 17.7% relative Q-TWiST gain) that was clearly clinically important. QoL adjusted survival benefit was also clearly clinically important in TIS + CT pts with PM with PD-L1 TAP score ≥1% (16.8% gain) and PD-L1 score ≥5% (33.0% gain) compared with PBO + CT. SA results further favored TIS + CT (Table). Conclusions: Treatment with TIS + CT resulted in clinically meaningful improvement in long-term quality-adjusted survival for GC/GEJC pts with PM versus those receiving CT alone. Clinical trial information: NCT03777657 . TIS + CT vs PBO + CT treatment difference. Mean Q-TWiST, months (95% CI) Relative Q-TWiST Gain Pts with PM a ITT pts (n=434) 2.6 (0.1 to 5.0), P =0.04 17.7% PD-L1 TAP ≥1% (n=386) 2.5 (0.1 to 5.1), P <0.05 16.8% PD-L1 TAP ≥5% (n=217) 4.7 (1.1 to 8.6), P =0.02 33.0% Pts with PM (SA using EQ-5D scores) b ITT pts (n=434) 3.1 (0.8 to 5.5), P <0.01 21.3% PD-L1 TAP ≥1% (n=386) 3.1 (0.5 to 5.6), P =0.02 20.8% PD-L1 TAP ≥5% (n=217) 4.8 (1.3 to 8.2), P <0.01 33.9% a Using standardized base case Q-TWiST utility weights. b Using US mapping algorithm weights.
Assessing loneliness in glioblastoma patients and caregivers using a nationwide survey.
12097 Background: Loneliness is associated with poorer health outcomes and quality of life in cancer patients, yet its prevalence in the glioblastoma (GBM) population remains understudied. GBM’s rapid progression and intensive treatment demands affect both patients and caregivers, but the burden of loneliness in these groups is unknown. We conducted a nationwide survey that assessed loneliness prevalence within the GBM community. Methods: OurBrainBank, a patient-led GBM nonprofit, distributed a HIPAA-compliant survey from February to September 2024 to GBM patients, current caregivers, and caregivers bereaved within 12 months. Loneliness was measured using the validated 3-item UCLA Loneliness Scale (range 3–9), with scores ≥6 indicating loneliness. Multivariable linear and logistic regression examined associations between caregiver status, race (white vs non-white), and financial difficulties in the past year and loneliness, adjusting for age, gender, and urban vs rural residence. Results: Among 525 respondents (404 caregivers, 121 patients), median age at diagnosis was 59 years. Overall, 52.0% (273/525) met criteria for loneliness, and the median UCLA score of the sample was 6.0. Caregivers reported higher loneliness than patients: 57.4% (232/404) vs 33.9% (41/121) were lonely, with mean UCLA scores of 5.88 (SD 1.90) versus 4.78 (SD 1.81). In adjusted models, caregivers had nearly threefold higher odds of loneliness (OR 2.97, 95% CI 1.91–4.67) and UCLA scores 1.22 points higher on average compared to GBM patients (95% CI 0.83–1.61; both p < 0.001). Financial difficulty in the last year (29% of sample) was similarly associated with greater loneliness (OR = 1.85 for loneliness, p = 0.002; 0.68-point higher average UCLA scores, 95% CI 0.32-1.05, p < 0.001). Finally, non-white respondents (12% of the sample) had higher odds of high loneliness compared to white respondents (OR = 4.00, p = 0.01) and had a 0.59 point higher UCLA score on average (p = 0.03). Conclusions: In this nationwide survey, GBM caregivers experienced substantially greater loneliness than patients themselves, and loneliness was also concentrated among those facing financial hardship and among non-white respondents. These findings highlight an underrecognized psychosocial burden and support integrating caregiver-focused and equity-oriented interventions into GBM care.
Targeted Modulation of <i>d</i> ‐Band Center in MoS <sub>2</sub> Interlayer With n‐Type Co/Fe Dopants Accelerating Sulfur Reaction Kinetics in Lithium‐Sulfur Batteries
ABSTRACT Although chalcogenide‐based catalysts offer significant potential for enhancing lithium‐sulfur (Li‐S) battery performance, the absence of reliable descriptors linking the d ‐band center to sulfur conversion kinetics hinders the rational design of electrochemical systems. Herein, we address this limitation by engineering a catalytic interlayer through modification of 2H‐MoS 2 electronic structure, achieved via substitutional doping of n‐type Co/Fe transition metals (TM) at Mo sites. Comprehensive findings elucidate that such doping initiates a distinct S‐mediated d ‐ p hybridization involving Mo 4 d— S 3 p— TM 3 d orbitals, thereby modulating electronic density of states near the Fermi level. Specifically, in the CoFe‐MoS 2 @carbon paper (CP) interlayer, synergistic effect of co‐doping with two different TM drives optimized downshift of the Mo 4 d ‐band center to intermediate energy states, fostering moderate catalyst‐reactant interaction. Furthermore, the simultaneously lowered S 3 p ‐band center enhances the degree of d ‐ p orbital overlap. These electronic redistributions enhance both electrical and ionic conductivity, thereby facilitating accelerated redox kinetics with reduced activation energy, while mitigating the shuttle effect and promoting uniform Li 2 S deposition. Consequently, the assembled cell delivers outstanding stability with a low decay rate of 0.024% for 2000 cycles even at 10C. This work emphasizes that a balanced d ‐band center is key to achieving highly active chalcogenide‐based materials for advanced Li‐S batteries.
Writable and Recyclable Cellulose‐Stabilized Ga Ink for Deformable Negative Electrode of Flexible Aluminum Battery
ABSTRACT Wearable and deformable electronics must be driven by safe and flexible batteries. Aluminum battery is an intrinsically safe energy storage device, but can not meet flexible requirements due to the rigid Al foil negative electrode. This work proposed a writable and recyclable cellulose nanofiber‐stabilized liquid gallium (CNF‐Ga) ink to prepare a deformable and self‐healing negative electrode for the construction of a flexible and wearable aluminum battery. CNF‐Ga ink was designed, and Ga nanoparticles (∼441 nm) were well dispersed. Flexible polyethylene terephthalate (PET) substrate was patterned by writing and rolling to obtain a CNF‐Ga/PET electrode. Resistance changes of CNF‐Ga/PET electrode under bending and twisting were negligible, and the electrode maintained structural integrity with nearly unchanged resistivity even after 1000 bending and twisting cycles. CNF‐Ga/PET negative electrode exhibited excellent cycling stability for 1200 h. CNF‐Ga‖carbon paper full aluminum battery possessed excellent charge/discharge properties and can be wrapped around the wrist. CNF‐Ga can be recycled by NaOH to recover liquid Ga and regenerate CNF‐Ga ink. This work provides a promising strategy to construct flexible aluminum batteries and wearable electronics.
Bevacizumab plus encorafenib-cetuximab in BRAF V600E mutated metastatic colorectal cancer (mCRC): A phase II study with a safety lead-in cohort (the BRAVE trial).
TPS3681 Background: Encorafenib plus cetuximab is the standard of care for patients with BRAF V600E mutant, microsatellite-stable (MSS) mCRC, BRAF inhibitor-naïve, whose disease has progressed after 1-2 prior lines of chemotherapy. However, all patients eventually experience disease progression, and progression-free survival (PFS) remains modest. Therefore, there is an unmet need to enhance the efficacy of encorafenib-based combinations in BRAF -mutant mCRC. Preclinical data from rodent models treated with BRAF inhibitors have demonstrated upregulation of hypoxia-related genes (VEGFA, ADM, and CXCR4), and alterations in tumor vessel architecture. Based on these observations, rodent models treated with BRAF inhibitors in combination with anti-VEGF therapy achieved a meaningful improvement in PFS. In this trial, we hypothesize that encorafenib–cetuximab with bevacizumab will result in synergistic activity leading to durable responses in patients with refractory BRAF -mutant mCRC. Methods: The BRAVE trial (NCT06411600) is a multicenter, single-arm, phase Ib/II study evaluating the safety and efficacy of encorafenib–cetuximab–bevacizumab. Patients must have progressed to 1-2 previous lines and have a BRAF V600E-mutant, MSS tumor. Previous treatment with BRAF inhibitors or antiEGFR was not allowed. All patients receive encorafenib 300 mg vo QD, cetuximab 500 mg iv Q2W, and bevacizumab 5 mg/kg iv Q2W, administered in 28-day cycles. The primary endpoints are dose-limiting toxicities (DLTs) and 6-month PFS (6mPFS). The study follows a Simon two-stage design. A sample size of 89 evaluable patients is required to detect an increase in 6mPFS to 49% in the study population, compared with a 36% 6mPFS achieved with encorafenib plus cetuximab in the BEACON trial, using a one-sided type I error of 0.05 and 80% statistical power. As there was no prior evidence on the safety of this combination, a safety lead-in (SLI) phase (n=9) was included to evaluate potential DLTs. An Independent Data Safety Monitoring Board (IDSMB) reviewed the toxicity profile and DLTs granted continuation of the study on April 1, 2025. Following completion of the SLI phase and IDSMB evaluation, the study proceeded to two subsequent stages. Stage I enrolled 41 additional patients (completed on December 12, 2025). A preplanned interim analysis (IA) is being performed before proceeding to Stage II. If fewer than 19 of the first 50 patients achieve 6mPFS, the study will be discontinued due to lack of efficacy. If 19 or more of the first 50 patients achieve 6mPFS, Stage II will enroll an additional 39 patients. Recruitment is currently on hold pending the planned IA. Biomarker analyses include plasma sample collection at screening, on C1D15, and at end of treatment, as well as tumor biopsies (optional) at baseline and at disease progression to study mechanism of sensitivity and resistance. Clinical trial information: NCT06411600 .
Clinical and epidemiological profile and overall survival by age-adjusted Charlson Comorbidity Index in patients aged 80 years or older receiving cancer care in São Paulo, Brazil.
e13766 Background: In daily oncology practice, caring for people aged ≥ 80 years often means balancing tumor control with comorbidity, functional reserve, and supportive needs. Because treatment decisions are frequently made under time pressure and with incomplete geriatric information, simple bedside tools can be helpful. We assessed whether the age-adjusted Charlson Comorbidity Index (ACCI) helps identify patients with different overall survival (OS). Methods: Retrospective cohort at a tertiary cancer center in São Bernardo do Campo (São Paulo, Brazil). We included patients diagnosed with cancer at age ≥ 80 years from Jan 2022 to Jan 2024. Data included demographics, tumor site, clinical stage and metastatic status at diagnosis, ECOG performance status, polypharmacy (≥ 5 chronic medications), palliative care follow-up, and ACCI. Patients were grouped as ACCI < 11 versus ≥ 11. OS was estimated by Kaplan–Meier, compared with log-rank, and assessed with Cox proportional hazards regression. Results: We analyzed 203 patients (mean age 84.2±3.2 years; 53.7% male). The most frequent tumors were prostate (17.7%), breast (16.3%), colon (12.8%), rectum (11.3%), and lung (5.9%). Stage distribution was I 10.3%, II 42.9%, III 23.2%, and IV 23.6%; metastases at diagnosis were present in 19.7%. Polypharmacy occurred in 38.4% and palliative care follow-up in 26.1%. ACCI ≥ 11 was present in 47 patients (23.2%). Male sex was more frequent in ACCI ≥ 11 (63.8% vs 50.6%), while tumor-site distribution was similar across ACCI groups (p > 0.05). Compared with ACCI < 11 (n = 156), ACCI ≥ 11 was associated with ECOG 3–4 (27.7% vs 11.5%; p = 0.011), stage IV disease (78.7% vs 7.1%; p < 0.001), metastatic presentation (68.1% vs 5.1%; p < 0.001), and palliative care follow-up (44.7% vs 20.5%; p = 0.002). Polypharmacy was higher in ACCI ≥ 11 (48.9% vs 35.3%) without statistical significance (p = 0.129). During follow-up, 80 deaths occurred (39.4%). Median OS was 94.8 months for ACCI < 11 and 18.0 months for ACCI ≥ 11 (log-rank p < 0.001). In Cox models, ACCI ≥11 increased mortality (HR 2.81, 95%CI 1.80–4.40), and each 1-point increase in ACCI increased mortality risk (HR 1.28, 95%CI 1.16–1.41). Conclusions: Among patients aged ≥ 80 years, higher ACCI marked a clinically vulnerable subgroup with worse performance status, more advanced disease, and substantially shorter OS. Beyond prognosis, this profile can guide conversations about goals of care, intensity of anticancer therapy, and follow-up planning. As a quick score derived from routine history, ACCI may complement geriatric assessment and support earlier supportive and palliative care when appropriate.
Differentiating donor age on AML patient outcomes in the post-transplant cyclophosphamide contemporary era.
6564 Background: alloHCT provides curative potential for patients with AML. PTCy GVHD prophylaxis has changed this paradigm. Impact of donor age is unknown in the PTCy era. Methods: Utilizing the publicly available CIBMTR dataset, de-identified AML patients receiving alloHCT between 2017-2021 with PTCy-based GVHD prophylaxis were identified. Patients with primary induction failure or relapsed disease status at time of transplant were excluded. The main effect of donor age was examined across outcomes at 24-months. Univariate and multivariate analyses were performed. Results: 5,702 patients were included in the analysis. The median age at alloHCT was 59 years (IQR, 46-66). Median donor age was 33 years (IQR, 22-42). CI of relapse at 24 months was 36.4% (95% CI, 33.1%-39.8%) for donors aged ≥45 years (yrs), 32.9% (95% CI, 24.6%-41.2%) for donors aged 0-19 yrs, 30.5% (95% CI, 28.6%-32.4%) for donors aged 20-34 yrs, and 30.1% (95% CI, 27.3%-32.9%) for donors aged 35-44 yrs; p=0.003 (Gray's test). Overall survival (OS) at 24 months was 45.9% (95% CI, 42.6%-49.6%) for donors aged ≥45 yrs, 55.4% (95% CI, 47.1%-65.2%) for donors aged 0-19 yrs, 58.5% (95% CI, 56.5%-60.6%) for donors aged 20-34 yrs, and 53.3% (95% CI, 50.3%-56.5%) for donors aged 35-44 yrs; p<0.001. Leukemia-free survival at 24 months was 39.4% (95% CI, 36.2%-43.0%) for donors aged ≥45 yrs, 48.2% (95% CI, 40.1%-57.9%) for donors aged 0-19 yrs, 51.4% (95% CI, 49.4%-53.5%) for donors aged 20-34 yrs, and 49.2% (95% CI, 46.2%-52.4%) for donors aged 35-44 yrs; p<0.001. In multivariable analysis, as compared to donor age >45, the 2 younger age groups, age 20-34 years (HR 0.41, 95%CI, 0.69-0.87; p=.004) and 35-44 years (HR 0.78, 95%CI, 0.66-0.92; p=.004) were independently associated with reduced relapse and superior LFS (HR 0.77, 95% CI, 0.69-0.87;p<.001) and (HR 0.77, 95% CI, 0.68-0.87; p<.001) respectively, and OS (HR 0.76, 95%CI, 0.67-0.86; p<.001) and (HR 0.80, 95% CI, 0.70-0.91; p<.001) respectively. In contrast, there was no significant difference between outcomes when the donor belonged to the age group 0-19 for relapse (HR 0.87, 95%CI, 0.61-1.22;p=.410, LFS (HR 0.84,95% CI, 0.65-1.09);p=.188), and OS (HR 0.79, 95%CI, 0.60-1.05;p=.108) (Table 1). Conclusions: In this homogeneous analysis, patients with AML undergoing PTCy-based GVHD prophylaxis in the contemporary era, younger donor between age groups 20-44 years conferred a significantly reduced relapse risk and superior LFS and OS. The findings inform optimal donor selection. Multivariate analyses (ref: donor age ≥45). Donor age 0-19 P 20-34 P 35-44 P OS 0.79 (0.60-1.05) 0.108 0.76 (0.67-0.86) <0.001 0.80 (0.70-0.91) <0.001 LFS 0.84 (0.65-1.09) 0.188 0.77 (0.69-0.87) <0.001 0.77 (0.68-0.87) <0.001 Relapse 0.87 (0.61-1.22) 0.410 0.81 (0.69-0.93) 0.004 0.78 (0.66-0.92) 0.004 Adjusted for donor age, year of transplant, DRI, year of HCT, donor type, graft type, conditioning intensity, and ethnicity.
A triage-aware neuro-symbolic approach for clinical trial matching in oncology: Real-world validation in lung and genitourinary cancer.
8536 Background: Low clinical trial accrual remains a critical barrier in oncology, driven by fragmented electronic health records (EHRs), limited trial awareness, and the substantial time required for manual eligibility screening. While large language models (LLMs) can extract clinical information from unstructured data, their probabilistic nature limits direct use for eligibility decisions that require protocol-level determinism and auditability. We developed a neuro-symbolic clinical trial matching platform that combines LLM-based information extraction with explicit rule-based eligibility reasoning, augmented by an uncertainty-aware triage strategy to safely integrate automation into real-world workflows. Methods: Unstructured EHRs were processed using a large language model (Llama 3.1–70B) to extract key clinical variables, which were normalized to a domain ontology. Trial eligibility was evaluated using deterministic inclusion and exclusion criteria encoded directly from full trial protocols, producing per-criterion explanations and an overall classification (eligible, not eligible, or indeterminate). A triage module quantified evidentiary completeness and logical consistency, categorizing cases into low-uncertainty confidence results suitable for automated screening, moderate and high-uncertainty cases requiring clinician review. Performance was assessed against clinician-validated ground truth in a real-world cohort of 107 patients, including advanced lung cancer patients and an independent genitourinary cancer validation cohort. Results: Among matchable patients (n = 79), the system achieved perfect Top-1 accuracy and Recall@3 of 1.00, with all eligible patients correctly identified within the top three trial recommendations. Thirty-nine patients (49%) were triaged as low-uncertainty and suitable for automated screening, while the remainder were appropriately flagged for clinician review. Among non-matchable patients (n = 28), no false-positive eligibility assignments were observed (false-positive rate 0.0). Triage correctly identified high-uncertainty cases, minimizing unsafe automation. In indeterminate cases (ground truth unknown, n = 6), the system deferred to manual review in two-thirds of cases, with zero unsafe automated classifications. Median end-to-end processing time was under one minute per patient. Conclusions: This neuro-symbolic, triage-aware approach enables transparent and deterministic clinical trial matching in oncology. By combining automated eligibility assessment with uncertainty-based triage, the system reduces manual screening burden while preserving clinician oversight, supporting scalable and trustworthy trial enrollment in real-world practice.
Phase Ib randomized open-label trial of sacituzumab govitecan plus nivolumab or sacituzumab govitecan plus nivolumab and relatlimab as second-line therapy metastatic triple negative breast cancer: SIMONE trial.
TPS1164 Background: The use of immunotherapy beyond first-line setting is not yet routine in the treatment arsenal of patients with metastatic triple-negative breast cancer (TNBC), and this opens an opportunity for clinical trials examining whether adding novel immunotherapy agents to standard of care therapies would benefit patients. Prior studies have combined immunotherapy with standard chemotherapy (Cortes J, NEJM 2022), but combining immunotherapies with antibody-drug conjugates (ADCs) is a strategy worth pursuing given improvement of outcomes of ADCs when compared to standard chemotherapy (Bardia A et al, NEJM 2021). Sacituzumab govitecan (SG), a TROP2-ADC, is currently the standard second-line therapy for patients with metastatic TNBC, and in this study it is being combined with either nivolumab (programmed cell death [PD-1] inhibitor) or nivolumab plus relatlimab (lymphocyte activation gene-3 [LAG3]-inhibitor) due to preliminary data showing that simultaneous PD-1 and LAG3 inhibition enhances the anti-tumor immune response and restores the effector function of exhausted T-cells (Woo S-R et al, Cancer Res 2012; Tawbi HA et al, NEJM 2022). Methods: This is an ongoing investigator-initiated randomized, open-label, phase Ib study to assess safety and efficacy of SG plus nivolumab (n= 30 patients) or SG plus a fixed dose combination (FDC) of nivolumab and relatlimab (n = 30 patients) in patients with metastatic TNBC; NCT06963905. The study is accruing patients whose tumors are PD-L1 positive (combined positive score >10) and an amendment in under review to also include patients whose tumors are PD-L1 negative on routine testing, with 1 prior line of cytotoxic chemotherapy with or without prior immunotherapy use in the metastatic setting or within 6 months from completion of curative intent treatment. Study treatment will be continued until progression of disease, unacceptable toxicity, death, or withdrawal of consent. Safety will be monitored, and tumor response will be regularly evaluated by RECIST 1.1 criteria every 9 weeks. The primary endpoint includes safety as the incidence of dose-limiting toxicities (DLT) in 3 weeks after C1D1. Secondary endpoints include objective response rate (defined as either complete response or partial response), duration of response, clinical benefit rate (objective response plus stable disease), progression-free survival, and safety with SG plus nivolumab or SG plus nivolumab + relatlimab FDC. Exploratory endpoints include overall survival, and biomarkers of prediction of response and resistance. There will be a follow-up visit after the last study treatment administration or before starting a new anticancer treatment, whichever occurs first, followed by long-term/survival chart review follow-up every three months for 2 years. Clinical trial information: NCT06963905 .
Machine learning–based projections of cancer and depression mortality in the United States through 2035.
e22577 Background: Clinical depression is a relatively common yet frequently overlooked source of suffering among patients with cancer. Recent research has highlighted a strong association between cancer and depression, where patients often develop depressive symptoms due to profound emotional stress, fear of the future, and the psychological burden of the disease . It is crucial to understand this association to establish integrated therapeutic strategies and for patient well-being, as depression has a substantial influence on treatment compliance, quality of life and survival rates. Furthermore, identifying sociodemographic disparities is vital to addressing health inequities and targeting high-risk populations. Methods: We analyzed U.S. national mortality data from 1999–2024 using the CDC WONDER database, identifying cancer as the underlying cause of death with depression as an associated cause . Data were stratified by sex, race, census region, and urbanization to identify specific population-level trends . Age-adjusted mortality rates (AAMR) were log-transformed and modeled using ARIMA-based machine learning forecasting . Machine learning–driven 10-fold time-series cross-validation was implemented to optimize model performance and generalizability, with residual autocorrelation assessed using the Ljung–Box test . Forecasted trends through 2035 were quantified using annual percentage change (APC) and average annual percent change (AAPC). Results: Between 1999 and 2024, there were 40,000 deaths with a marked rise of 10,000 such deaths occurring during the 2021–2024 period . Overall AAMR remained steady initially, followed by increasing mortality trends in females (APC: 5.06%) from 2016 to 2024, contributing to an overall significant rise (AAPC: +1.64%; P < 0.001) while males showed no net significant change (AAPC: +1.03; P=0.12) . However, forecast modeling projected a continued increase through 2035, with an estimated rise of 16.3% among females and a decline of 12.3% among males . Regional and racial disparities were significant, particularly for Black African/American, who showed a rise between 2017 and 2024 (APC: 5.51%) and a projected change of 147.4% by 2035 . Urban-rural differences also persisted, with medium metropolitan areas experiencing a sharp increase from 2015 to 2020 (APC: +8.71%) while the burden in rural areas rose from 2011 to 2020 (APC: +3.88%), followed by a projected change of 19.4% by 2035 . Regionally, the South had an increase from 0.63% APC (1999–2016) to 21.3% through 2035 . Conclusions: Cancer mortality among patients with comorbid depression varies significantly by populations. Projections through 2035 predict a rising burden, particularly among females, Black African/American and rural and south areas. These findings highlight the urgent need for targeted, integrated interventions that prioritize these high-risk groups to mitigate future mortality .
Safety and efficacy of atezolizumab with bevacizumab (A+B) for hepatocellular carcinoma (HCC) in patients with Child-Pugh (CP) class B cirrhosis.
e16219 Background: A+B is a first-line treatment with demonstrated safety and efficacy for patients with advanced HCC and CP class A (CPA) cirrhosis. Less is known about the tolerance and outcomes of this treatment for patients with CP class B (CPB) cirrhosis, a population with a more limited prognosis. Methods: We performed a retrospective cohort study using EHR records at the University of California, San Francisco from 2015 to 2025. Using drug administration data and ICD-10 codes, we identified 39 patients with a diagnosis of advanced HCC who received first-line treatment with A+B. CP class was defined at the start of treatment using averaged data in the 30 days prior to treatment start. A validated large-language-model (LLM) pipeline was used to grade and extract treatment-emergent adverse events (TEAEs) from unstructured clinical notes, and additional lab abnormalities were extracted and graded from lab values. Adverse events related to worsening liver function tests (LFTs) were counted separately. Median overall survival (OS) was estimated with Kaplan-Meier methods, and hazard ratios were estimated with Cox-proportional hazard models with CP class as a single covariate. Results: The distribution of CP classes was 46.2% CPA (18 patients), 51.3% CPB (20 patients), and 2.6% CPC (1 patient), who was excluded from this analysis. The majority of patients experienced at least one grade ≥3 (≥G3) TEAE regardless of CP class (CPA 72.2% vs. CPB 75.0%), with similar average numbers of unique TEAEs per patient (CPA 2.3 [95% CI, 1.6 – 3.0] vs. CPB 2.2 [95% CI, 1.6 – 2.9]). However, patients with CPB cirrhosis tended to experience more episodes of ≥G3 TEAEs per 100 days on treatment (4.7 [95% CI, 3.8 – 5.7] vs. 3.6 [95% CI, 2.7 – 4.4]). The most common ≥G3 TEAEs in the CPB group were lymphopenia (30%), hypoalbuminemia (20%), anemia (20%), diarrhea (15%), and hepatic failure (15%), and in the CPA group abdominal pain (17%) and lymphopenia (17%). TEAEs ≥G3 related to hemorrhage/thromboembolism were only observed in the CPB group, for 3 of 20 patients. Worsening ≥G3 LFTs after treatment start occurred more frequently in the CPB group (55.0% vs. 38.9%), and there was a trend towards higher rates of ED visits and hospitalizations on treatment for CPB patients (1.5 [95% CI, 0.9 – 2.0] vs. 0.8 [95% CI, 0.4 – 1.3]). Median OS from time of treatment initiation was higher for CPA patients (22.1 months [95% CI, 5.3 months to not estimable] vs. 7.9 months [95% CI, 4.8 months to 15.7 months]; HR 2.5 [95% CI, 0.1 – 1.8], p = 0.03). Conclusions: Compared to CPA patients receiving A+B, CPB patients experienced a comparable number of unique TEAEs, but experienced episodes more frequently. This study augments knowledge of A+B TEAEs and outcomes in CPB patients, an understudied but important population, and demonstrates the utility of an LLM pipeline in facilitating retrospective real-world outcomes analysis in this population.
A risk prediction model for severe, life-threatening, and fatal treatment-related toxicity.
12143 Background: Adverse events are major contributors to morbidity and mortality in patients receiving systemic cancer therapy. Accurate prediction of high-grade toxicity could inform risk-adapted treatment strategies. Methods: This cohort study included data from 18 SWOG adult phase 2 and 3 treatment trials conducted from 1990 to 2022. Baseline patient-reported symptoms (fatigue, pain, and anxiety, classified as clinically meaningful yes vs. no), baseline sociodemographic (age, sex, race, ethnicity), and performance status (PS) variables were used. The aim was to develop a unified risk score applicable across multiple toxicity severity thresholds; adverse events were classified using the Common Terminology Criteria for Adverse Events. The primary outcomes were severe (Grade >3), life-threatening (Grade >4), and fatal toxic events. A training set was derived using a random 60% sample, balanced by study and arm; validation will occur in the remaining 40%. Best-subsets logistic regression was used for variable selection; final models were stratified by cancer type (hematologic, hormone-driven solid tumor, or other solid tumor) and treatment status (untreated vs refractory). Model discrimination was assessed using the concordance (c) statistic. Patients were divided into tertiles according to their total risk score. Toxicity rates and odds ratios were evaluated across tertiles (Ts). Results: Of 7,936 patients, 4,776 (60.2%; median age 64.9 (range, 18-95.3); female 28.0%; Black 10.8%) formed the training cohort. Increased toxicity was associated with age ≥60 years, fatigue, female sex, and PS ≥1. The multivariable risk models demonstrated good discrimination for grade ≥3 (c=0.76), grade ≥4 (c=0.77), and grade 5 toxicity (c=0.77). Severe toxicity increased from 15.8% in the lowest risk tertile (T1) to 64.6% in T3; life-threatening toxicity increased from 2.7% in T1 to 26.2% in T3 (Table). Compared with the lowest tertile, the highest risk tertile had markedly higher odds of grade ≥3 (OR 9.76), grade ≥4 (OR 12.96), and grade 5 toxicity (OR 7.15; all p<.001). Model validation results will be presented. Conclusions: This risk model accurately identified patients with substantially elevated risk for severe, life-threatening, and fatal toxicities. Risk stratification may support individualized treatment counseling, risk-guided monitoring, and proactive toxicity management. Observed toxicity rates and odds ratios by predicted-risk tertile. Observed Toxicity Odds Ratios by Model(95% CI, p-value) T1(n=1536) T2(n=1646) T3(n=1594) Increase per risk level T2 vs. T1 T3 vs. T1 Grade >3 15.8 37.7 64.6 3.11(2.86-3.39, p<.0001) 3.23(2.73-3.83, p<.0001) 9.76(8.23-11.59, p<.0001) Grade >4 2.7 9.1 26.2 3.58(3.12-4.11, p<.0001) 3.66(2.57-5.20, p<.0001) 12.96(9.32-18.02, p<.0001) Grade >5 0.2 0.6 1.4 2.54(1.54-4.18, p<.0001) 3.12(0.86-11.37, p=.08) 7.15(2.14-23.94, p=.001)
Do the characteristics of the immune microenvironment of patients with 11q13 gene amplification reveal that it is an important factor for immune hyperprogression?
e16069 Background: Amplification of the 11q13 chromosomal region, encompassing genes such as CCND1 and FGF3/4/19, is frequently observed in esophageal cancer and has been implicated in tumor progression. However, the prevalence of 11q13 amplification far exceeds the incidence of hyperprogressive disease (HPD), raising uncertainty about its predictive value. This study aimed to characterize the immune microenvironment associated with 11q13 alterations in esophageal cancer and to explore their potential relevance to HPD. Methods: A total of 114 Chinese patients with esophageal cancer were enrolled. Genomic alterations were identified using next-generation sequencing (NGS). The immune landscape of both tumor parenchyma and stroma was profiled using multiplex immunohistochemistry (mIHC) and APTime pathology analysis software, quantifying multiple immune cell populations. Results: Patients were stratified based on 11q13 alteration status into a variant group (n = 36) and a non-variant group (n = 78). The variant group was predominantly characterized by copy number amplifications (94.4%), with only two cases harboring single-nucleotide variants. Consistent with previous reports, the non-variant group exhibited a high prevalence of TP53 mutations (63/78, 80.8%). Comparative immune profiling revealed significantly higher infiltration of M2 macrophages in the tumor parenchyma of the variant group compared with the non-variant group (P = 0.0301). In addition, both parenchymal and stromal levels of CD56 + dim NK cells (P = 0.0047 and P = 0.0416, respectively) and CD56 + bright NK cells (P = 0.0238 and P = 0.0406, respectively) were significantly increased in tumors harboring 11q13 alterations. No significant differences were observed between groups in adaptive immune components, including T cells, B cells, and PD-L1 expression. Conclusions: 11q13 alterations are associated with distinct innate immune microenvironment features in esophageal cancer, including M2 macrophage enrichment and increased NK cell infiltration, but not with adaptive immune markers. These findings suggest that 11q13 alterations may influence tumor biology through modulation of innate immunity rather than serving as direct drivers of HPD. Further studies incorporating treatment response and clinical outcome data are warranted to clarify the prognostic and predictive significance of 11q13 alterations.
Chemotherapy use and survival by demographic and socioeconomic factors in primary central nervous system lymphoma: A population-based SEER analysis.
7057 Background: Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin lymphoma confined to the brain and spinal cord. Despite the introduction of rituximab to modern systemic therapy, previous population-based studies suggest that survival disparities by race and socioeconomic status persist. This study uses chemotherapy utilization modeling and contemporary 2000–2022 data to quantify the real-world survival impact of chemotherapy underuse across ethnic and neighborhood income strata in adults with PCNSL. Methods: Adults (≥20 years) with histologically confirmed PCNSL diagnosed from 2000–2022 were identified from SEER 21 registries. Patients with concurrent systemic lymphoma were excluded. Chemotherapy receipt was coded as yes vs no/unknown; with blank fields excluded. Binary logistic regression estimated odds of receiving chemotherapy by demographics. Multivariable Cox proportional hazards models evaluated associations of age, sex, race, neighborhood median household income (MHI), rural–urban residence, and chemotherapy with cause-specific survival. MHI was categorized into quintiles derived from the cohort distribution (approximately equal case counts per band). Kaplan–Meier methods estimated cause-specific survival and median survival times. Results: A total of 9,533 adults met the inclusion criteria. Compared with Whites, Black (OR 0.42, 95% CI 0.35–0.49) and Hispanic patients (OR 0.75, 95% CI 0.66–0.84) were less likely to receive chemotherapy; patients from neighborhoods with MHI < $65k also had reduced chemotherapy use versus ≥$100k (OR 0.53, 95% CI 0.45–0.62). Median survival was 64 months for patients receiving chemotherapy versus 3 months for those with no/unknown chemotherapy. Median survival by race was 17 months in Black patients, 25 months in Whites, and 38 months in Hispanics. Median survival was 14 months in the lowest MHI band (<$65k) and 46 months in the highest (≥$100k). In Cox models, lack of chemotherapy was associated with more than twice the hazard of lymphoma-specific death (HR 2.29, 95% CI 2.17–2.44). After adjustment for age, sex, race, MHI, residence, and chemotherapy; Black patients had higher mortality than Whites (HR 1.22, 95% CI 1.10–1.36), female gender had improved survival than males (HR 0.88, 95% CI 0.833-0.929), and MHI < $65k was associated with worse survival versus ≥$100k (HR 1.20, 95% CI 1.09–1.32). Conclusions: In this cohort of adults with PCNSL, chemotherapy use, race, neighborhood income, and age were powerful independent determinants of cause-specific survival. Chemotherapy underuse was concentrated among Black, Hispanic, and lower-income patients and was associated with a dramatic survival penalty, indicating that inequities in access to systemic therapy are likely major drivers of persistent racial and socioeconomic survival gaps in PCNSL.
Ethno-religious inequities in clinical presentation and survivorship outcomes in breast cancer: A prospective cohort study.
e13633 Background: Breast cancer disparities related to ethnicity and religion are well described in U.S.-based populations, but prospective data from other healthcare systems are scarce. No national studies have previously examined ethno-religious inequities in breast cancer presentation and survivorship in Israel. By providing the first prospective national data outside the U.S. context, this study addresses a critical gap in understanding how social and cultural determinants shape both stage at diagnosis and early survivorship outcomes. Methods: This ethics board–approved prospective cohort enrolled 219 consecutively diagnosed breast cancer patients during the 2025 calendar year. Participants included Arab Muslim women (N = 38), Jewish ultra-orthodox women (N = 51), and other Jewish women (N = 128). Clinical variables included age, menopausal status, mode of diagnosis, stage, tumor size, biologic subtype, and treatment patterns. Survivorship outcomes were assessed using validated instruments evaluating quality of life (FACT-G, FACT-BC), endocrine symptoms (FACT-ES), anxiety and depression (PROMIS), and spirituality (FACIT-Sp, Systems of Belief Inventory). Between-group comparisons were performed. By the time of presentation, correlative analyses between clinical characteristics and patient-reported outcomes will be completed. Results: Significant ethno-religious inequities were observed at diagnosis. Arab Muslim and ultra-orthodox Jewish women were younger and more often pre-menopausal (p = 0.016). Screening detection was less frequent among Arab Muslim women, who more commonly presented via self-palpation. Stage at diagnosis differed significantly by group (p = 0.011), with higher rates of metastatic disease among Arab Muslim (15.8%) and ultra-orthodox Jewish women (12.5%) compared with other Jewish women (2.4%; p = 0.012). Larger tumors (T3–4) were also more prevalent among minority groups (p = 0.015). Time from diagnosis to first treatment did not differ. Arab Muslim women reported significantly lower overall, physical, emotional, and functional quality of life and higher anxiety (all p < 0.05), despite significantly stronger spiritual wellbeing (p≤0.002). Ultra-orthodox Jewish women demonstrated higher overall and social quality of life and lower depression compared with other Jewish women (p≤0.034). Conclusions: Ethno-religious inequities in breast cancer are driven primarily by differences in early detection and stage at diagnosis, with distinct survivorship trajectories shaped by cultural and spiritual contexts. Equity-focused strategies should integrate early detection with culturally adapted survivorship care.