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AI-enabled clinical trial framework for end-to-end site recommendation and enrollment projection.
11022 Background: Reliable accrual forecasting is essential in oncology trials because delayed enrollment reduces statistical power, increases costs, and prolongs timelines. We developed an AI-enabled framework integrating site recommendations with probabilistic enrollment modeling to support data-driven trial planning. Methods: Site-level attributes (Site360) and curated real-world patient datasets (Patient360) were integrated as inputs. Trial objectives including enrollment targets, timelines, sponsor and diversity requirements, and screen failure rates (SFR) were user specified. Candidate sites were ranked using a multi- criteria TOPSIS engine optimized with simulated annealing to identify portfolios meeting protocol requirements. Recommended site attributes informed Monte Carlo enrollment simulations incorporating site activation, patient arrival, and capacity constraints. Each underwent 1000 simulations, generating accrual distributions. Fifty-four CRC, NSCLC, and Breast trials from ClinicalTrials.gov were evaluated. Planned site counts and enrollment intensity (patients per month per planned site; ppmpps) from the same trials served as benchmarks. Enrollment intensity was calculated as enrolled patients divided by (trial duration in months × planned sites), with duration estimated from trial start to primary completion. Scenarios tested SFR 20%, 40%, and 60%. Model outputs were compared with planned benchmarks using Spearman correlation and summarized with medians and IQR. Results: Trials showed heterogeneous planned site counts: CRC median 76 (IQR: 43-119), Breast 204 (114-279), NSCLC 178 (101-227). Model recommended site counts showed moderate to strong rank agreement with planned sites across indications. CRC correlations increased from 0.67 to 0.73 as SFR rose from 20% to 60% (all p < 0.05). Breast correlations ranged 0.49-0.54 and NSCLC 0.61-0.63 across SFRs all with p < 0.05. Higher SFR required more recommended sites, compensating for screen failures. Predicted ppmpps aligned strongly with benchmarks. For Breast, predicted ppmpps decreased from 0.15 (0.10-0.31) at 20% SFR to 0.07 (0.04-0.16) at 60% SFR versus planned 0.08 (0.03-0.17), with ppmpps correlations 0.82, 0.77, 0.66 respectively (all p < 0.01). CRC predicted rates were 0.13 (0.08-0.29), 0.10 (0.07-0.24), 0.07 (0.05-0.18) across SFRs versus planned 0.09 (0.06-0.13), correlations 0.47 (p = 0.076), 0.54, 0.59 (both p < 0.05). NSCLC showed 0.23 (0.15-0.27), 0.18 (0.13-0.22), 0.12 (0.08-0.18) versus planned 0.12 (0.07-0.19) with correlations 0.54-0.64 (p < 0.02). Conclusions: This AI-enabled framework integrates optimization and probabilistic modeling to recommend sites and project enrollment behavior. Rank agreement with benchmarks supports improved site feasibility assessment by identifying trials with higher site requirements and enrollment risk and enabling risk-adjusted planning.
Renal function eligibility in multiple myeloma CAR T and bispecific antibody clinical trials.
e19528 Background: Chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAbs) have transformed the treatment of relapsed or refractory multiple myeloma (MM). Kidney impairment affects 20–50% of patients with MM and may limit access to these therapies, yet renal eligibility criteria in CAR-T and BsAb trials remain inconsistently defined. We systematically reviewed renal eligibility criteria in MM CAR-T and BsAb clinical trials. Methods: We systematically reviewed 202 MM CAR-T and BsAb clinical trials registered on ClinicalTrials.gov. Renal eligibility criteria were extracted when available and defined using either creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR), depending on trial reporting. Thresholds were categorized as permissive (0–39), moderate (40–59), or restrictive (≥60). Results: Of 202 trials, 28% (n = 57) reported a renal eligibility criterion. Among these, the most common threshold was CrCl or eGFR ≥30 mL/min, used in 51% (n = 29) of studies. More restrictive thresholds were frequently applied, with 23% (n = 13) requiring CrCl or eGFR ≥40–45 mL/min and 5% (n = 3) requiring ≥60 mL/min. Only 5% (n = 3) of trials permitted enrollment of patients with advanced renal impairment (CrCl or eGFR ≤20 mL/min). Fourteen percent (n = 8) of studies used nonspecific language such as “adequate renal function” without defining a numeric cutoff, and 2% (n = 1) explicitly excluded dialysis patients without specifying a renal function threshold. Renal thresholds did not differ significantly between CAR-T and BsAb trials. Most trials reporting renal criteria were conducted in the United States (67%), followed by international multicenter studies (19%), Europe (7%), and China (4%). Academic-sponsored studies accounted for 74% (n = 42/57) of trials reporting renal thresholds, compared with 26% industry-sponsored trials. Conclusions: Despite FDA labeling indicating no clinically meaningful pharmacokinetic differences for CAR-T cells and BsAbs in patients with mild to moderate renal impairment, over one-quarter of trials applied unnecessarily restrictive renal eligibility criteria. Exclusion of patients with CrCl 30-59 mL/min may not be pharmacokinetically justified and contributes to limited access and evidence gaps. Standardized, evidence-based renal eligibility criteria are needed to improve trial inclusivity and equity in MM.
Barriers to radiotherapy access and workflow efficiency in a resource-limited tertiary center: A real-world analysis from Bangladesh.
e13638 Background: Bangladesh faces a rapidly increasing cancer burden, with GLOBOCAN 2022 estimating nearly 167,000 new cases annually. Despite high demand, radiotherapy (RT) infrastructure is critically inadequate; current capacity serves only ~13% of the population. National RT services are highly centralized, and many major public medical colleges lack functional linear accelerators (LINACs), relying on aging or non-operational Cobalt-60 units. This shortage forces a disproportionate patient load onto a few high-volume tertiary centers like Ahsania Mission Cancer and General Hospital (AMCGH). This study evaluates the impact of these infrastructure constraints on clinical workflow and waiting times. Methods: We conducted a retrospective observational study of 80 consecutive patients receiving external beam radiotherapy (EBRT) at AMCGH between March and June 2025. Data were extracted from electronic and manual logs to measure key workflow intervals: Referral-to-Consultation, Consultation-to-CT Simulation, and Simulation-to-First Fraction. Descriptive statistics compared outcomes between inpatients (n = 40) and outpatients (n = 40). Results: Of the 80 patients, 90% (n = 72) received curative-intent RT. Inpatients were significantly more likely to initiate radiotherapy within one month of prior treatment compared with outpatients (60% vs 22.5%, p < 0.01)). The median interval from CT simulation to treatment initiation was 1.0–1.5 months for 62.5% of outpatients (p < 0.01). Treatment interruptions occurred in 35% (n = 28) of cases, primarily attributed to mechanical machine downtime and treatment-related toxicities. However, a dedicated prioritization protocol for emergency palliative cases (10%) ensured timely initiation via reserved treatment slots. Conclusions: While integrated inpatient scheduling and emergency prioritization protocols mitigate some delays, substantial systemic gaps remain for outpatients in AMCGH. The high rate of interruptions due to machine downtime underscores the need for proactive maintenance and expanded infrastructure. Strengthening national referral pathways and decentralizing RT services are critical to reducing waiting times and improving survival outcomes in resource-constrained settings of Bangladesh.
Phase 3 trial of trastuzumab rezetecan vs standard of care (SOC) for chemotherapy-refractory, HER2-positive, advanced colorectal cancer (CRC).
3505 Background: Antibody-drug conjugate (ADC) targeting HER2 represents standard therapy for HER2-positive gastric cancer and breast cancer. This study aimed to assess trastuzumab rezetecan (an HER2-targeted ADC) vs SOC in patients (pts) with chemotherapy-refractory, HER2-positive, RAS and RAF wild-type advanced CRC. Methods: In this randomized, open-label, multicenter, phase 3 trial, pts with HER2-positive, RAS and RAF wild-type, advanced CRC who have progressed after standard 2nd-line therapy were randomized 2:1 to receive trastuzumab rezetecan (4.8 mg/kg, d1, iv, q3w) or SOC (TAS-102 [35 mg/m 2 , bid, d1-5 and d8-12], fruquintinib [5 mg, qd, d1-21], or regorafenib [160 mg, qd, d1-21]; po, q4w). Randomization was stratified by HER2 status (IHC 3+ vs IHC 2+/ISH+) and ECOG PS (0 vs 1). Primary endpoint was PFS per RECIST v1.1 by independent review committee (IRC). Key secondary endpoint was OS. Results: As of data cutoff (Oct 31, 2025), 130 pts were randomly assigned to trastuzumab rezetecan (N=86) or SOC (N=44). 70.8% of pts had HER2 IHC 3+, and 57.7% had an ECOG PS of 1. Median follow-up was 9.6 mo (95% CI 7.4-10.7). PFS per IRC was significantly increased with trastuzumab rezetecan vs SOC (median 5.5 mo [95% CI 4.8-6.7] vs 2.8 mo [95% CI 2.2-4.2]; HR 0.33 [95% CI 0.21-0.53]; 1-sided p<0.0001). Although median OS were immature, risk of death with trastuzumab rezetecan was reduced by 23% compared with SOC (HR 0.77 [95% CI 0.35-1.73]). PFS per investigator, ORR and DoR were also better with trastuzumab rezetecan vs SOC (Table 1). Grade ≥3 TRAEs occurred in 48.8% with trastuzumab rezetecan and 50.0% with SOC. No patients discontinued treatment due to TRAEs. Treatment-related death was reported in two pts (2.3%) with trastuzumab rezetecan (septic shock and myelosuppression). Conclusions: Compared with SOC, trastuzumab rezetecan achieved prolonged PFS and improved ORR in chemotherapy-refractory HER2-positive advanced CRC, with a tolerable safety profile. Clinical trial information: NCT06199973 . Efficacy. Trastuzumab rezetecan (N=86) SOC (N=44) Treatment effect (95% CI) 1-sided p value IRC-assessed PFS, mo 5.5 (4.8-6.7) 2.8 (2.2-4.2) HR, 0.33 (0.21 0.53) <0.0001 * Investigator-assessed PFS, mo 5.6 (5.0-6.8) 2.8 (1.5-4.1) HR, 0.31 (0.20-0.50) <0.0001 * OS, mo NR (14.6-NR) NR (12.5-NR) HR, 0.77 (0.35-1.73) 0.2651 * IRC-assessed ORR 35 (40.7; 30.2-51.8) 2 (4.5; 0.6-15.5) RD, 36.2 (24.1-48.2) <0.0001 † Investigator-assessed ORR 28 (32.6; 22.8-43.5) 2 (4.5; 0.6-15.5) RD, 28.0 (16.4-39.7) 0.0002 † IRC-assessed DoR, mo 4.4 (3.3-NR) 3.4 (2.7-NR) - - Investigator-assessed DoR, mo 5.8 (4.2-NR) 1.4 (NR-NR) - - Data are median (95% CI), or n (%; 95% CI), unless otherwise stated. * Stratified log-rank test. † Stratified Cochran-Mantel-Haenszel test. NR, not reached; RD, rate difference.
Volrustomig monotherapy for recurrent/metastatic HNSCC: Substudy 2 of the eVOLVE-02 phase 2 study.
6025 Background: Inhibition of PD-1 is an important part of standard of care treatment options for patients (pts) with recurrent/metastatic (R/M) HNSCC, but prognosis remains poor and there is a need for novel regimens to improve outcomes. Dual PD-(L)1 and CTLA-4 inhibition has shown a trend towards improved survival vs the EXTREME regimen as first-line (1L) therapy in PD-L1-expressing R/M HNSCC. Volrustomig, a monovalent, bispecific, humanized IgG1 monoclonal antibody, inhibits PD-1 and CTLA-4, with increased CTLA-4 blockade on PD-1-positive activated T cells compared to PD-1-negative resting peripheral T cells. We report safety and efficacy from the planned interim analysis of substudy 2 of the phase 2 eVOLVE-02 (NCT06535607) study, investigating volrustomig monotherapy in pts with R/M HNSCC. Methods: Eligible pts had histologically or cytologically confirmed R/M HNSCC of the hypopharynx, oral cavity, larynx, or oropharynx (HP, OC, LX, OP), had ECOG performance status (PS) 0/1, and were either treatment-naïve in the 1L setting with confirmed PD-L1 positivity or had disease progression (PD) on/after a 1L platinum-containing regimen. Pts received IV volrustomig until PD (RECIST v1.1)/discontinuation criteria were met. Primary endpoints: safety and confirmed objective response rate (cORR). Secondary endpoints include progression-free survival (PFS) and overall survival. Data cutoff (DCO): August 15, 2025. Results: 23 pts with recurrent (n=12) or metastatic (n=11) HNSCC (7 HP, 8 OC, 4 LX, 4 OP) received volrustomig as 1L (n=12) or 2L (n=11) treatment. Median age was 61 years; 16 pts (69.6%) had PS 1; 19 (82.6%) had a PD-L1 combined positive score (CPS) ≥1. Median duration of exposure was 2.1 months (range 0.7–6.4). Treatment-emergent adverse events (TEAEs) were reported in 91.3% of pts (30.4% grade 3/4, 34.8% serious TEAEs); treatment-related AEs per investigator were reported in 82.6% (8.7% grade 3/4, 4.3% serious AEs). No pts discontinued treatment due to AEs. Grade 5 AEs were reported in 13.0% of pts (none considered related to treatment). At DCO, median follow-up was 5.4 months. In pts with CPS ≥1: 5 had partial responses (3 LX, 1 HP, 1 OC); cORR was 26.3%; disease control rate was 52.6%. Median time to response was 2.6 months (IQR 1.4–2.8); responses were ongoing in 60% of responders at DCO. Blood RNA seq showed increased CTLA-4-associated immune proliferation/activation (Ki67/ICOS gene expression) with volrustomig on cycle 1, day 8 vs at baseline. Conclusions: Volrustomig monotherapy showed an acceptable safety profile and encouraging activity in pts with R/M HNSCC, warranting further clinical development. Volrustomig is under investigation in combination with chemotherapy as 1L treatment for R/M HNSCC in the phase 2 eVOLVE-02 substudy 3, and as consolidation monotherapy in locally advanced HNSCC after concurrent chemoradiotherapy in the phase 3 eVOLVE-HNSCC (NCT06129864) study. Clinical trial information: NCT06535607 .
Outcome of adjuvant BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600K– compared to V600E-mutated melanoma.
9576 Background: Patients with resected stage III BRAF V600 mutated melanoma can be treated with combined dabrafenib and trametinib (D/T) with significant improvement of recurrence-free survival (RFS). The results of the pivotal Combi-AD study showed overall survival (OS) improvement only for patients with BRAF V600E mutations, while for V600K there was even an OS impairment as compared to placebo, although not statistically significant. Methods: We analysed EUMelaReg data for patients with adjuvant D/T therapy for resected stage III melanoma. Only patients with V600E and V600K mutations were selected, where n=93 from a total of 1,033 patients (9.0 %) harboured V600K. Results: Demographics of patients with V600K mutations differed significantly for age (67 vs. 58 years, p <0.001) and a higher proportion of males (67.0% vs. 54.6%, p=0.03) at baseline. Other baseline variables, including substage, were not significantly different. One year of treatment was completed in 51.6% for V600K, and 62.8% for V600E, respectively, while with V600K mutations 22.6% of the patients stopped for toxicity (vs. 18.8% with V600E), and 10.8% for disease recurrence (vs. 6.9%), which was not statistically significant. After a median follow-up of 41.7 (V600K) and 41.2 (V600E) months, Kaplan-Meier analysis estimated 4-year overall survival of 75.7% for V600K compared to 77.8% for V600E. The 4-y-RFS estimates were 48.3% for V600K and 47.0% for V600E. These differences were not statistically significant. Cox regression analysis revealed no different results when adjusted for demographic co-variates, including age and sex, for RFS and OS, respectively. Conclusions: It appears that V600E and V600K mutations are not associated with a different outcome from adjuvant treatment with combined D/T. The findings offer no explanation for differences found in the Combi-AD trial, although part of these differences also resulted from a different natural course of V600K mutated melanomas the placebo group. A longer follow-up will help to further confirm these results and also analyse the possible role of further treatments in the metastatic setting. Baseline characteristics and outcome. V600E(N=940) V600K(N=93) P-value SEX 0.035 Female 426 (45.3%) 31 (33.3%) Male 514 (54.7%) 62 (66.7%) AGE <0.001 Mean (SD) 57.4 (13.8) 65.6 (11.9) Median [Min, Max] 58.0 [17.0, 90.0] 67.0 [28.0, 87.0] ECOG 0.1 0 846 (90.0%) 82 (88.2%) 1 51 (5.4%) 8 (8.6%) 2 5 (0.5%) 2 (2.2%) Baseline Stage 0.34 III 8 (0.9%) 1 (1.1%) IIIA 126 (13.4%) 7 (7.5%) IIIB 293 (31.2%) 29 (31.2%) IIIC 470 (50.0%) 54 (58.1%) IIID 43 (4.6%) 2 (2.2%) STAGE III DIAGNOSIS TYPE 0.96 Primary Diagnosis 679 (72.2%) 68 (73.1%) Relapse 260 (27.7%) 25 (26.9%) SUBTYPE 0.06 SSM 358 (38.1%) 26 (28.0%) NMM 315 (33.5%) 44 (47.3%) NOS 207 (22.0%) 18 (19.4%) MUP 49 (5.2%) 4 (4.3%) OUTCOME 4-Year RFS (95%-CI) 0.47 (0.43; 0.51) 0.48 (0.38; 0.61) 0.94 4-Year OS (95%-CI) 0.78 (0.75; 0.81) 0.76 (0.65; 0.88) 0.94
Real-world outcomes of doxorubicin plus trabectedin (D+T) in leiomyosarcoma (LMS).
e23536 Background: LMS-04 trial shows improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) with D+T followed by trabectedin (T) alone compared with doxorubicin alone in advanced LMS. Real-world outcomes with this regimen remain limited. This single-center retrospective study reports on the standard-of-care use of D+T in localized and advanced uterine LMS (ULMS) and soft-tissue LMS (STLMS). Methods: We included patients with confirmed histologic diagnosis of LMS treated with D+T at any point in routine clinical practice at MD Anderson Cancer Center (MDACC). The objective was to assess recurrence-free survival (RFS)/PFS, OS, ORR, and toxicity for both advanced and localized LMS patients treated with D+T in a real-world setting. Kaplan Meier method and log rank tests were used to assess survival outcomes and compare outcomes in subgroups. Data collection is ongoing with over 100 patients to date. Results: Fifty patients were included in this primary analysis (26 with ULMS, 24 with STLMS, cf. Table). In STLMS, primary tumor location was retroperitoneum in 20% (n=10), visceral in 10% (n=5), limb in 10% (n=5), abdominal wall in 4% (n=2), and scalp in 4% (n=2). In those with advanced LMS (n=40), median PFS was 10.5mo, PFS at 1 year was 37%. Overall, the ORR was 42% (21/50), and 40% (16/40) in patients with advanced disease. Median PFS for patients with advanced ULMS and STLMS was 9.6mo and 11mo months, respectively (p=0.73). Among 10 patients with localized disease, 5 underwent surgery before D+T (1 STLMS, 4 ULMS), and 6 received post-induction local therapy, including surgery alone (2 STLMS, 1 ULMS) or surgery and radiotherapy (3 STLMS). Nine patients with advanced disease received post-induction local therapy with surgery alone (1 ULMS, 4 STLMS), surgery plus radiotherapy (1 ULMS, 1 STLMS), surgery plus ablation (1 STLMS), or ablation alone (1 ULMS), with median PFS not reached (NR) versus 8.6 months in those without local therapy (p=0.011). Median OS for patients with advanced disease was 32.6mo. Grade ≥3 toxicity occurred in 92% (46/50), with 46% (23/50) requiring dose reductions; common toxicities were anemia, fatigue, and thrombocytopenia. Conclusions: In a real-world setting, outcomes with D+T are consistent with LMS-04 for ORR though slightly inferior in PFS for ULMS. We observe improved PFS in patients receiving local treatments after induction. ORR, toxicity, and dose-reduction rates were also comparable. Updated results with larger cohorts will be presented. Localized ULMS (N=5) Advanced ULMS (N=21) Localized STLMS (N=5) Advanced STLMS (N=19) Median age, yrs 45 48 49 54 Gender - - 60% F40% M 53% F47% M Size≥10 cm 4 (80%) 13 (62%) 3 (60%) 4 (21%) ORR 40% 42.9% 60.0% 36.8% RFS/PFS, mo (95% CI) 9.7 (5.1 – NR) 9.6 (4.5 – 14.7) NR 11 (8.6 – 16.6) RFS/PFS at 12 mo 40% 40.4% 100% 34.2% OS, mo NR 22.5 NR 32.6 Dose reduction, N (%) 2 (40%) 10 (48%) 2 (40%) 9 (48%) % of grade ≥3 toxicity 100% 90.5% 80.0% 89.5%
Clonal hematopoiesis and cardiovascular outcomes after hematopoietic cell transplantation: A systematic review and meta-analysis.
e18578 Background: Clonal hematopoiesis (CH) is a known risk factor for cardiovascular disease, but its impact in cancer patients undergoing hematopoietic cell transplantation (HCT) is not well defined. We conducted a systematic review and meta-analysis to assess the association between CH and post-HCT cardiovascular outcomes. Methods: PubMed, Embase, Web of Science, and Cochrane were searched from inception to December 2025 for randomized control trials and observational studies evaluating cardiovascular outcomes after HCT. Eligible studies included adult patients undergoing HCT with sequence-defined CH, using gene panels and variant allele fraction (VAF) thresholds, that reported extractable post-transplant cardiovascular, cerebrovascular, or thromboembolic outcomes. We excluded case reports/series, reviews/abstracts without extractable data, animal or pediatric studies, non-oncologic transplant populations, studies without sequencing-confirmed CH or relevant outcomes, and overlapping cohorts. Adjusted and subdistribution hazard ratios were extracted and pooled using random effects meta-analysis using inverse weighting. Results: Of 2,187 studies, 5 studies, including both autologous and allogenic HCT recipients, were extracted from. The most frequently mutated genes were DNMT3A, TET2, ASXL1,TP53. In a pooled analysis of two independent autologous HCT cohorts, including multiple myeloma and lymphoma populations, CH was associated with increased risk of post-transplant heart failure (HR 3.24, 95% CI 2.02–5.19; I²=21%). In an autologous HCT survivorship cohort analyzed using competing-risk models, CH was associated with higher risks of coronary artery disease (sHR 2.22, 95% CI 1.06–4.64) and stroke (sHR 3.02, 95% CI 1.07–8.52). In an allogeneic HCT cohort with post-transplant deep sequencing, a higher CH mutation burden, defined as two or more CHIP mutations a variant allele fraction of 2% or more, was linked to an increased risk of incident atrial fibrillation (adjusted HR 4.05, 95% CI 1.17-14.04). Venous thromboembolism risk was higher, though not statistically significant after multivariable competing-risk adjustment (sHR 2.01, 95% CI 0.88–4.60). Conclusions: This meta-analysis demonstrates CH is associated with increased risk of adverse cardiovascular outcomes after HCT, supporting its potential cardiac biomarker, prior to HCT, and underscores the need for further prospective studies to further characterize cardiovascular surveillance in CH patients undergoing HCT to mitigate morbidity and mortality.
A multicenter randomized phase III study for newly diagnosed, maximally resected glioblastoma comparing carmustine wafer implantation followed by chemoradiotherapy with temozolomide versus chemoradiotherapy alone: Japan Clinical Oncology Group study JCOG1703 (MACS study).
2001 Background: Three randomized phase III trials evaluated carmustine wafers (CWs) before temozolomide (TMZ) became standard therapy. To date, no randomized study has assessed CWs with standard TMZ chemoradiotherapy in newly diagnosed glioblastoma (GB). A post hoc analysis of Westphal’s phase III trial, which evaluated CWs versus placebo, suggested a survival benefit with CWs in GB patients with ≥90% resection. We conducted a randomized phase III trial to determine whether adding CWs to standard chemoradiotherapy improves overall survival (OS) in newly diagnosed GB with ≥ 90% resection. Methods: This multicenter trial (38 institutions; JCOG1703) enrolled patients with newly diagnosed GB considered resectable at ≥90%. After intraoperative pathological confirmation of malignant glioma and ≥90% removal, patients were randomized (1:1) to CW implantation (Arm B) or no implantation (Arm A). Arm B received intraoperative placement of up to 8 CWs. All patients received 60 Gy radiotherapy with concomitant daily TMZ followed by 12 cycles of maintenance TMZ. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), loco-regional PFS (LPFS), and adverse events. DNA methylation array analysis and molecular testing included MGMT promoter methylation and copy number profiling. Results: Among 234 registered patients, 221 (Arm A, n=110; Arm B, n=111) were randomized between June 2019 and November 2022. Baseline characteristics were well balanced. Median OS for all randomized patients was 26.5 months (1-year 86.4%, 2-year 54.3%, 5-year 16.6%), with no significant difference between Arm A and B (21.7 vs 27.7 months; hazard ratios (HR) 0.907, 91.5% confidence interval (CI) 0.691–1.192; one-sided p=0.269 by the stratified log-rank test). Median PFS was 9.8 months (1-year 43.4%, 2-year 16.3%), also without significant difference (9.5 vs 10.4 months; HR 0.867, 95% CI 0.658–1.141). Median LPFS was 11.6 months (1-year 48.4%, 2-year 25.1%), with no difference between arms (10.6 vs 12.7 months; HR 0.886, 95% CI 0.669–1.173). MGMT promoter methylation was a significant favorable factor for OS, PFS, and LPFS. Early postoperative complications and adverse events were comparable between groups, and no treatment-related deaths occurred. Conclusions: CW implantation added to standard TMZ chemoradiotherapy did not significantly improve OS in newly diagnosed GB after ≥90% resection. Based on these findings, CW implantation does not provide significant therapeutic or survival benefit when standard TMZ chemoradiotherapy is feasible in this population. Clinical trial information: jRCT1031190035.
Differential impact of venous thromboembolism and metastatic disease on in-hospital mortality and 30-day readmission in pancreatic cancer: A Nationwide Readmissions Database analysis.
e16445 Background: Pancreatic cancer is associated with a high incidence of venous thromboembolism (VTE), early mortality, and frequent unplanned readmissions. While VTE is a known adverse prognostic factor and metastatic disease drives healthcare utilization, their relative contributions to short-term mortality versus rehospitalization in real-world practice remain incompletely defined. Methods: We conducted a retrospective cohort study using the Nationwide Readmissions Database 2022. Adult index admissions for pancreatic cancer were classified by VTE phenotype and metastatic status. Outcomes were in-hospital mortality (index and readmission hospitalizations) and 30-day all-cause readmission. Multivariable logistic regression and Cox proportional hazards models were used, adjusting for demographic, socioeconomic, hospital, and clinical severity variables. Results: Among 58,340 survey-weighted index admissions, 52,199 patients survived to discharge and were included in the readmission analysis. VTE was present in 12.0% of admissions and occurred more frequently in metastatic disease. Patients with VTE and/or metastatic cancer had substantially higher acuity, with increased rates of sepsis, shock, acute kidney injury, ICU admission, and mechanical ventilation, and were more often treated at large, urban teaching hospitals. Metastatic cases accounted for 57.8% of 30-day readmissions and the majority of in-hospital deaths. In time-to-event analyses, metastatic disease independently increased the hazard of 30-day readmission (adjusted HR 1.11, 95% CI 1.05–1.18; p < 0.001). In contrast, VTE phenotype was not associated with time to readmission, and no significant interaction between VTE subtype and metastatic status was observed. In-hospital mortality demonstrated a different pattern. Pulmonary embolism was independently associated with increased odds of death (adjusted OR 1.56, 95% CI 1.09–2.23; p = 0.016), and metastatic disease was the strongest predictor of mortality (adjusted OR 1.83, 95% CI 1.67–2.00; p < 0.001). The absence of a significant VTE–metastasis interaction indicated that the adverse prognostic impact of VTE on survival was consistent across disease stages. Mortality was further driven by sepsis, acute kidney injury, ventilation, while treatment at teaching and large-bed hospitals was associated with lower adjusted mortality. Conclusions: In pancreatic cancer, VTE—particularly pulmonary embolism—primarily magnifies in-hospital mortality, whereas metastatic burden is the dominant determinant of early readmission. These findings highlight the need for intensified inpatient thromboembolic management to reduce early deaths and for enhanced postdischarge care pathways for patients with metastatic disease to mitigate rehospitalization.
Drivers of clinician engagement in oncology trial accrual within an IMC in Shanghai: A mixed-methods study.
e23034 Background: Recruitment shortfalls frequently delay oncology clinical trials. Integrated medical consortia (IMCs) may enhance accrual by strengthening cross-institution collaboration and aligning incentives across core hospitals and community health centers, but real-world evidence on the key IMC-related drivers of recruitment engagement remains limited. Methods: We conducted an anonymous cross-sectional online survey of healthcare professionals within an IMC led by Fudan University Pudong Medical Center (Shanghai, China). Using 5-point Likert items, we measured IMC-related constructs—Inter-organizational Collaboration Strength (ICS), Incentive Performance Perception Scale (IPS), Non-Performance Incentive Scale (NPIS), Subject Protection Index (SPI), and Capability Support (CS)—as well as Proactiveness in Screening/Recruitment (PS). Participants also reported accrual indicators from the prior 12 months (enrollment, informed-consent time, and loss-to-follow-up rate) and provided open-ended responses. Internal consistency was assessed using Cronbach’s α. Associations with PS were examined using Pearson correlations and multivariable linear regression with HC3 robust standard errors; mediation by CS was evaluated using a regression-based path model. Results: We analyzed 187 valid questionnaires; 22 (11.76%) respondents were from the core hospital and 165 (88.24%) from community health centers. Most were physicians (140, 74.87%), and 128 (68.45%) reported contact with cancer patients in the past 12 months. Mean years in practice was 16.07 (SD 10.32; n = 186). Recruitment indicators were right-skewed: median annual enrollments were 3 (IQR 0–10; n = 167), median informed-consent time was 15 minutes (IQR 0–30; n = 167), and median loss-to-follow-up rate was 10% (IQR 0–30; n = 168). Mean construct scores ranged from 2.91±0.60 (CS) to 3.60±1.04 (SPI), with excellent reliability (Cronbach’s α = 0.93–0.98). All constructs were positively correlated (r = 0.60–0.89; all p < 0.01), and PS correlated most strongly with NPIS (r = 0.89) and SPI (r = 0.84). In multivariable regression, the model explained substantial variance in PS (R² = 0.83; adjusted R² = 0.82; overall p < 0.001). After mutual adjustment, NPIS remained the strongest independent correlate of PS (β = 0.60, p < 0.001), and SPI also remained significant (β = 0.26, p = 0.020); ICS, IPS, and CS were not significant. In the path model, CS was predicted by SPI (β = 0.60, p < 0.001) and IPS (β = 0.24, p = 0.030), while the CS→PS path was not significant (β = 0.03, p = 0.591), indicating no evidence of mediation. Conclusions: In this IMC, NPIS and SPI showed the most robust associations with healthcare professionals’ PS. Implementation strategies that pair transparent recognition and career-aligned incentives with strengthened participant-protection workflows may enhance recruitment performance in consortium-based oncology trials.
Latent transitions of distress risk during cancer treatment and their concordance with anxiety, depression, and quality of life in a large multicenter cohort.
11106 Background: Distress is prevalent in patients with cancer and may change throughout treatment. However, longitudinal transitions between distress-risk states and their relationship with psychosocial outcomes in real-world oncology settings remain poorly characterized. We sought to identify latent distress-risk states, describe transitions during cancer treatment, and evaluate their clinical determinants and concordance with anxiety/depression and health-related quality of life (HRQOL). Methods: This longitudinal multicenter cohort study included adult patients with cancer treated across all Brazilian states. Distress was assessed at baseline (prior to treatment initiation), mid-treatment, and end of treatment using the Distress Thermometer (DT). Symptoms of anxiety/depression and HRQOL were assessed using the Hospital Anxiety and Depression Scale (HADS) and FACT-G. Latent Transition Analysis (LTA) identified distress-risk states and transition probabilities over time; model selection was based on Bayesian Information Criterion, entropy, and clinical interpretability. Multinomial logistic regression evaluated clinical predictors of baseline distress-risk states. Directional concordance between changes in DT and changes in HADS and FACT-G was assessed using concordance matrices and chi-square tests. Results: A total of 2197 patients were included. Median age was 58 years, 72.3% were female, and most were diagnosed with breast (40.1%) or gastrointestinal (18.8%) cancer, with 40.0% presenting with advanced-stage disease (III-IV). A four-state LTA model with optimal fit identified high critical, moderate persistent, low vulnerable, and low stable distress-risk profiles. The low stable state was the most prevalent and highly stable, with 94.5% remaining in the same state across assessments, whereas the high critical and low vulnerable states were more dynamic. Among high critical patients, 22.8% transitioned to moderate risk and 19.6% to low risk, while 28.6% of moderate persistent patients transitioned to the low stable state. Worsening occurred in up to 12.6% of patients. Male sex (OR = 1.8, 95% CI 1.08-3.09) and stage IV disease (OR = 1.8, 95% CI 1.09-2.97) were independently associated with higher-risk distress states (Ps = 0.02). Changes in distress states showed high directional concordance with psychosocial outcomes (HADS 82.9%; FACT-G 77.0%; χ² p < 0.001). Conclusions: Distinct and clinically meaningful distress-risk states and dynamic transitions were observed during cancer treatment. While most patients remained stable or improved, a relevant subgroup experienced worsening distress. These findings support repeated distress screening and adaptive, risk-based psychosocial interventions integrated into routine oncology care.
Neoadjuvant cemiplimab plus cetuximab prior to salvage surgery for recurrent oral cavity squamous cell carcinoma.
TPS6136 Background: Locoregional recurrence of oral cavity squamous cell carcinoma (OCSCC) after curative-intent therapy remains a major cause of morbidity and mortality. Salvage surgery is the standard of care when feasible but is associated with substantial functional impairment. The combination of PD-1 blockade and EGFR inhibition has demonstrated promising activity in the recurrent/metastatic setting. We hypothesize that the combination of cemiplimab and cetuximab will elicit a robust antitumor response in patients with resectable recurrent OCSCC that will lead to improved clinical outcomes. Methods: This is an open-label, single-center, phase II trial designed to assess the efficacy and safety of cemiplimab plus cetuximab in patients with recurrent, resectable OCSCC irrespective of PD-L1 status (NCT06448026). Key eligibility criteria include histologically confirmed locoregional recurrence at least 3 months after prior curative-intent therapy, including surgery and postoperative radiation, ECOG performance status 0–1, measurable disease per RECIST v1.1, and adequate organ function. Eligible participants receive neoadjuvant cemiplimab 350 mg intravenously every 3 weeks for two cycles combined with weekly cetuximab (loading dose 400 mg/m² followed by 250 mg/m² for up to 6 weeks), followed by salvage surgery. Patients achieving ≥50% pathologic tumor response are eligible to receive adjuvant cemiplimab for up to one year. Blood and tumor tissue for correlative analyses are collected at baseline, during treatment, and at the time of surgery. The primary endpoint is the rate of pathologic tumor response ≥50% (pTR-2) assessed in the surgical specimens local and/or regional. Secondary endpoints include objective response rate per RECIST v1.1, pathologic response rate, disease-free survival, overall survival, and safety. The planned sample size is 17 patients based on a Simon two-stage design. The study is active and accruing; to date, 9 of 17 planned patients have been enrolled. Clinical trial information: NCT06448026 .
Time-dependent recurrence risk stratification after neoadjuvant chemotherapy for risk-adapted surveillance in breast cancer.
e12672 Background: Post-treatment surveillance after neoadjuvant chemotherapy (NAC) is largely uniform and does not account for time-dependent recurrence risk. Although pathologic complete response (pCR) is associated with a favorable prognosis, recurrence still occurs in a subset of patients, with substantial heterogeneity in timing. We aimed to characterize dynamic recurrence risk after NAC to inform risk-adapted surveillance strategies. Methods: We retrospectively analyzed 2,331 patients with stage I–III breast cancer treated with NAC followed by surgery between 2005 and 2023. Disease-free survival (DFS) was the primary outcome. Conventional Cox proportional hazards models and flexible parametric survival models were used to evaluate time-dependent effects of clinicopathologic factors. Separate analyses were performed for patients who achieved pCR and for those with residual disease to identify clinically relevant risk windows. Results: Overall, 947 patients (40.6%) achieved pCR. Across all molecular subtypes, pCR was associated with significantly improved DFS; however, recurrence events occurred even among pCR responders. Among patients achieving pCR, baseline nodal positivity was associated with a delayed but progressively increasing risk of recurrence, with clinical significance beyond 3 years of follow-up. In contrast, patients who were node-negative at baseline and achieved pCR exhibited consistently low recurrence risk over time. Among patients with residual disease, high tumor proliferative activity (Ki67) conferred a pronounced early recurrence risk within the first two years after surgery, with diminishing impact thereafter. Conclusions: Recurrence risk after NAC is heterogeneous and evolves over time, even among patients who achieve pCR. Identification of distinct early- and late-high-risk windows challenges the adequacy of uniform post-treatment surveillance strategies. Aligning surveillance intensity with time-specific recurrence risk—rather than binary response status alone—may enable more precise and clinically meaningful survivorship care after NAC.
Association of angiogenic, fibrotic, and immunosuppressive tumor microenvironment with immunotherapy outcomes in metabolic disease–associated biliary tract cancers.
e16004 Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasing risk factor for biliary tract cancers (BTC), including cholangiocarcinoma (CCA). Although MASLD is characterized by chronic hepatic inflammation, its impact on the efficacy of immune checkpoint inhibitors (ICI) remains poorly defined. We evaluated clinical outcomes of ICI-treated MASLD-associated BTC and explored underlying genomic and transcriptomic features. Methods: We retrospectively analyzed BTC patients treated with durvalumab, cisplatin, and gemcitabine between June 2015 and December 2024 using an institutional database. MASLD was defined as metabolic dysfunction and hepatic steatosis visible on imaging or biopsy, based on American Association for the Study of Liver Diseases (AASLD) criteria. Hepatic steatosis was quantified on pre-treatment non-contrast CT scans using liver proton density fat fraction (PDFF), with PDFF ≥5% classified as steatosis. Overall survival (OS) following ICI therapy was compared between MASLD and non-MASLD groups using multivariable analyses. A molecularly characterized subset underwent whole-exome sequencing and bulk RNA sequencing (RNA-seq). Tumor microenvironment (TME) features were investigated using established transcriptomic classifiers (BostonGene) and cell deconvolution methods. Results: Among 151 BTC patients, 74 (49%) received ICI, and 53 (35.1%) met AASLD criteria for MASLD. Median OS for the overall cohort was 18.4 months. Non-MASLD patients had a longer median OS compared with MASLD patients (23.0 vs 16.7 months; p = 0.056). Transcriptomic profiling (n = 93) revealed that MASLD tumors exhibit a distinct TME relative to non-MASLD controls. Key features: (i) enhanced angiogenesis with upregulation of the angiogenic gene signature (p = 0.01), increased endothelial cell fraction (p = 0.04) (ii) an immunosuppressive infiltrate marked by regulatory T cells (p = 0.06), with increased B cells (p = 0.03) (iii) a fibrotic TME with upregulated matrix remodeling (p = 0.15) and cancer-associated fibroblast signatures (p = 0.16). Genomic analyses revealed no significant differences in tumor mutational burden or copy number variation between MASLD and non-MASLD, suggesting TME remodeling, rather than genomic alterations, as the main driver of the clinical differences observed. Conclusions: MASLD-associated BTC is characterized by a distinct TME marked by angiogenesis, fibrotic remodeling, and immunosuppressive cell infiltration, features that may contribute to diminished responses to ICI. These observations provide a rationale for comprehensive molecular profiling incorporating both DNA and RNA analysis, as well as combination approaches that pair ICIs with anti-angiogenic or anti-fibrotic agents to enhance therapeutic outcomes in this expanding patient population.
Comparison of real-world overall survival between atezolizumab- and durvalumab-containing first-line induction and maintenance regimens in extensive-stage small cell lung cancer.
8093 Background: Both atezolizumab (atezo) and durvalumab (durva) are preferred first-line (1L) systemic treatment options for extensive-stage small cell lung cancer (ES-SCLC) with similar efficacy in the IMpower133 and CASPIAN phase 3 trials. There is limited evidence comparing their survival outcomes in the real-world (rw) setting. This study described rw overall survival (rwOS) in patients (pts) with ES-SCLC treated in 1L and 1L maintenance (1Lm) settings and also compared rwOS stratified by cohort and treatment with 1L atezo vs durva in combination with platinum-based chemotherapy (chemo) followed by atezo vs durva as 1Lm immunotherapy (IO). Methods: Using the US Flatiron Health Research Database, this retrospective noninferiority study included adults with ES-SCLC across 2 cohorts. The 1L cohort included pts treated with atezo or durva + chemo between Apr 1, 2020, and Sept 30, 2025. The 1Lm cohort included a subset of pts from the 1L cohort who were subsequently treated with atezo or durva monotherapy. The index date was the initiation of atezo or durva in the 1L or 1Lm setting in each cohort. rwOS hazard ratios (HRs) and 95% CIs comparing durva with atezo as reference in the 1L and 1Lm settings were calculated using Cox proportional hazard models, adjusting for prognostic covariates. Based on prior literature, the noninferiority margin was set at HR = 1.25. Results: A total of 2063 and 1122 pts were included in the overall 1L and 1Lm cohorts, respectively. In both cohorts, median age was 68 years, ≥20% of pts had an ECOG PS ≥2, and ≥19% had brain metastases at baseline. The 1L cohort had 1614 (78%) pts on atezo + chemo and 449 (22%) on durva + chemo. The 1Lm cohort had 865 (77%) pts on atezo and 257 (23%) on durva. Pt characteristics were generally similar between those treated with atezo vs durva in 1L or 1Lm settings. In the 1L cohort, median OS (95% CI) from the index date was 8.7 (8.2, 9.3) months for atezo and 8.5 (7.9, 9.5) months for durva. In the 1Lm cohort, median OS (95% CI) from index date (start of maintenance) was 9.3 (8.2, 10.2) and 9.2 (7.5, 10.8) months for atezo and durva. In the 1L cohort, the adjusted HR for OS for durva vs atezo was 0.98 (95% CI: 0.86, 1.10; P = 0.7), indicating no statistically significant difference between the 2 treatments. In the 1Lm cohort, the adjusted HR for OS for durva vs atezo was 1.04 (95% CI: 0.88, 1.22; P = 0.7). In both cohorts, the upper 95% CI was < 1.25, supporting the noninferiority of durva vs atezo. Conclusions: In this rw population, atezo and durva offered comparable rwOS, which was shorter than those reported in phase 3 clinical trials, for pts with ES-SCLC when used with chemo in 1L or as monotherapy in 1Lm.
Cognitive impairment during anti-EGFR targeted therapy in metastatic colorectal cancer patients.
12085 Background: Cognitive function is a critical determinant of psychosocial adaptation and quality of life in patients with cancer. Even mild cognitive impairment may negatively affect daily functioning, communication, compliance, and social participation. The psychosocial consequences of cognitive changes during medical treatment are insufficiently studied in metastatic colorectal cancer (mCRC) patients. Anti-EGFR-targeted therapy affects downstream MAPK signaling, a pathway involved in synaptic plasticity and cognitive processes. This provides a biological rationale for investigating cognitive outcomes and their psychosocial relevance. Methods: This study included patients with mCRC who received FOLFOX6-based first-line treatment. The main group (n = 50) received FOLFOX6 combined with an anti-EGFR monoclonal antibody (cetuximab or panitumumab), while the control group (n = 50) received FOLFOX6 +/-bevacizumab. Cognitive function was assessed at baseline and after eight cycles of therapy using the Addenbrooke’s Cognitive Examination–Revised (ACE-R) and the Frontal Assessment Battery (FAB). Changes in cognitive performance were analyzed in relation to patients’ functional vulnerability during ongoing treatment. Cognitive side effects were also evaluated according to CTCAE V.5.0. Results: Baseline cognitive performance was comparable between groups. After eight cycles of therapy, patients receiving anti-EGFR-targeted treatment demonstrated a significant decline in cognitive performance, including ACE-R total scores (from 93 [90; 94.5] to 87 [85; 90.5], p < 0.001), memory domain scores (from 22 [22; 23.5] to 20 [19; 20], p < 0.001), and attention/orientation scores (from 18 [16; 18] to 17 [15; 18], p = 0.005). In contrast, cognitive measures in the control group showed only minimal changes or remained stable over the same observation period. Evaluation according to CTCAE V.5.0. showed cognitive disturbance, memory and concentration impairments of mild and moderate grades, which were significantly more frequent in the anti-EGFR targeted group than in the control group (p<0,005). Conclusions: Anti-EGFR-targeted therapy in metastatic colorectal cancer patients may cause significant cognitive impairment, which undoubtedly contributes to psychosocial maladaptation and reduced quality of life. This pattern of selective cognitive decline may compromise functional independence, communication, and psychosocial adaptation during active anticancer treatment. Routine cognitive assessment during treatment may facilitate early identification of patients at risk and support multidisciplinary management strategies. In addition, the role of the MAPK signaling pathway in memory formation should be studied.
Self‐Assembly of Stimuli‐Responsive Peptide Enhances Therapeutics by Specifically Disrupting Hepatocellular Carcinoma Lysosomes In Vivo
ABSTRACT Lysosome sequestration or drug‐triggered autophagic flux curtails antitumor drug potency in hepatocellular carcinoma (HCC) and can potentially be reversed with tumor cell‐specific lysosomal disruption. Here, we demonstrate that a chimeric peptide (RS‐FS), consisting of HCC‐targeting RS and nanostructure‐forming motifs (FS), self‐assembles into nanospheres at neutral pH and transforms into nanofibers under acidic and reductive conditions. These nanofibers specifically localize to tumors and disrupt tumor cell lysosomes, thus enhancing doxorubicin's activity in human HCC cells in vitro and orthotopic HCC mice in vivo after RS‐FS‐doxorubicin treatment. Importantly, intravenous RS‐FS potentiated oral Lenvatinib's antitumor activity up to 61‐fold, and eradicated tumors in orthotopic HCC mice via HCC cell‐specific lysosome disruption. Potent antitumor effects were also achieved with intravenous RS‐FS and oral Epimedium brevicornu Maxim. ‐derived extracellular vesicles in orthotopic HCC mice, with markedly reduced tumor growth and increased cytotoxic T infiltration, in which RS‐FS‐mediated lysosome disruption promoted drug release and autophagic flux blockade. Our study demonstrates that RS‐FS self‐assembles into nanospheres or nanofibers in response to stimuli and enables tumor cell‐specific lysosome disruption, resulting in enhanced drug release, autophagic flux blockade, and antitumor activities of diverse therapeutics in HCC mice, and thus provides a generalizable peptide adjuvant for sensitizing HCC‐targeted therapeutics.
A Nano‐Interception Strategy for Chronic Heart Failure: Prussian Blue Nanoparticles Disrupt Fibroblast‐Immune Communication via CCL2 Sequestration
ABSTRACT Chronic heart failure (HF) remains a global health challenge due to the lack of therapies that effectively disrupt the pathological fibro‐inflammatory networks driving disease progression. While current nanomedicine strategies often target intracellular pathways in isolated cell types, they overlook the multicellular crosstalk central to HF. Here, we develop scalably synthesized Prussian blue (PB) nanoparticles that selectively intercept the CCL2‐CCR2 chemokine axis, a key pathway in fibroblast‐macrophage communication. Single‐nucleus RNA sequencing of murine and human failing hearts identifies a conserved pro‐fibroinflammatory cardiac fibroblast subpopulation (POSTN hi CCL2 hi ) that recruits CCR2 + macrophages via CCL2 secretion. PB nanoparticles exhibit ultrahigh affinity (K D = 1.11 × 10 −10 m ) for free CCL2, inducing conformational distortion in its N‐terminal domain via specific C≡N interface interactions with CRS1 residues, thereby blocking CCR2 engagement, a mechanism distinct from conventional nanomaterials. Although ineffective in monocultures, PB nanoparticles robustly improve cardiac function and remodeling in murine and translational porcine pressure‐overload HF models, reducing left ventricular end‐diastolic volume by 56.2% and fibrosis by 40.5%, while selectively depleting CCR2 + macrophages without systemic immunosuppression. Supported by scalable production (> 100 g/batch), long‐term stability, and biosafety, this work establishes a cell communication‐targeting nanomedicine strategy for network‐driven diseases like HF.
Oncological outcomes in post-menopausal women with Kallmann syndrome: A propensity-matched study from the Global Federated Health Network.
e23061 Background: Kallmann syndrome, a rare form of hypogonadotropic hypogonadism with anosmia, is a condition primarily seen and understood in males. Little information is available regarding the smaller subset of females with the condition. The current standard of care for management of Kallmann syndrome includes hormone-replacement therapy (HRT) that includes estrogen and progesterone, to mimic hormonal profiles of females without the condition. Though estrogen and its metabolites have been implicated in multiple malignancies, little is known about the impact of HRT on post-menopausal women with Kallmann syndrome. Methods: To investigate rates of estrogen-associated malignancies in post-menopausal females with Kallmann syndrome, TriNetX’s US Collaborative Network was used to query deidentified health information. Females with Kallmann syndrome at or over 50 years old were stratified into those prescribed and not prescribed HRT. Those on HRT were compared with women at or over 50 years old without Kallmann syndrome on HRT. Those with Kallmann syndrome not on HRT were compared with women at or over 50 years old without Kallmann syndrome not on HRT. Kallmann syndrome cohorts were then compared with each other. Rates of development of breast, endometrial, ovarian, and colorectal cancer were studied, as well as non-small cell lung cancer (NSCLC). Results: Propensity-score matching identified 10,506 patients per cohort with Kallmann syndrome both with and without HRT. Between cohorts, there were no significant differences in rates of breast, endometrial, ovarian, colorectal cancers, or NSCLC. Propensity-score matching between females with Kallmann syndrome on HRT at or over 50 years old and females at or over 50 years old without Kallmann syndrome and with HRT identified 10,065 patients per cohort. There was a significantly higher rate in the Kallmann cohort of endometrial cancer (HR 1.236, 95% CI 0.832-1.837, p=0.009). Propensity-score matching between females with Kallmann syndrome without HRT at or over 50 years old and females at or over 50 years old without Kallmann syndrome and without HRT found 45,736 patients per cohort. In the cohort without Kallmann syndrome, there was a significantly higher risk of endometrial cancer (HR 2.876, 95% CI 2.465-3.355, p=0.000), NSCLC (HR 1.08, 95% CI 0.816-1.429, p=0.046), and colorectal cancer (HR 1.02, 95% CI 0.865-1.202, p=0.008). Conclusions: Our findings indicate that HRT does not appear to affect estrogen-associated cancer risk among post-menopausal women with Kallmann syndrome. There may be differences between cancer rates that are related to the syndrome itself, as evidenced by differences between Kallmann cohorts and non-Kallmann cohorts. Further research should focus on exploring these differences.