Browse Articles
Discover research articles across all indexed journals
Actinic keratosis as a premalignant lesion: Systematic review and meta-analysis of topical field–directed therapy versus vehicle/placebo.
e21568 Background: Actinic keratosis represents a premalignant lesion within the field cancerization pathway and isassociated with an increased risk of keratinocyte carcinoma. Topical field-directed therapies arecommonly used to treat photodamaged skin; however, comparative vehicle-controlled randomizedevidence on complete clearance outcomes has not been consistently synthesized. A meta-analysis wasconducted to evaluate the efficacy of topical field-directed therapies (5-fluorouracil) versusvehicle/placebo in achieving complete lesion clearance. Methods: A systematic search was conducted in PubMed, Embase, and the Cochrane Central Register ofControlled Trials from inception to January 2026 to identify randomized vehicle- orplacebo-controlled trials evaluating topical field-directed therapies (5-fluorouracil) for actinickeratosis. Eligible studies enrolled adults with clinically diagnosed actinic keratoses and reporteddichotomous efficacy outcomes or adverse events. Three independent randomized trials comprising atotal of 1,422 participants were included. Pooled analyses were performed using random-effectsmodels, and results were expressed as risk ratios (RRs) with 95% confidence intervals (CIs). Results: Three randomized vehicle-controlled trial datasets were included. For complete clinical clearance,topical field-directed therapy was associated with a significantly higher likelihood of complete lesionclearance compared with vehicle/placebo (RR 2.90; 95% CI 1.76–4.77; P < 0.0001; I² = 58%), with atotal of 276 complete clearance events among 631 patients receiving active topical therapy versus 88events among 539 patients in the vehicle/placebo group. The direction of effect was consistent acrossthe two largest trials, which contributed the majority of the pooled weight. Conclusions: Topical field-directed therapy significantly increases the probability of complete clinical clearance ofactinic keratosis compared with vehicle/placebo. Given that actinic keratosis represents apremalignant manifestation of field cancerization within the keratinocyte carcinoma pathway, theseresults support topical field therapy as an effective strategy for controlling the premalignant field inhigh-risk populations. However, the available evidence is limited by the number of randomized trialsand clinical heterogeneity, underscoring the need for additional well-designed studies to further defineoptimal treatment strategies and long-term oncologic relevance. Complete clearance emerges as aclinically meaningful dichotomous endpoint for evaluating interventions targeting field cancerizationin skin oncology.
A multi-agent AI system integrating real-world data and competitive intelligence to generate automated trial eligibility recommendations.
e23008 Background: Designing eligibility criteria is central to clinical trial feasibility but requires laborious manual review across multiple dimensions, including competitive intelligence (CI), standard-of-care real-world data (SoC-RWD), and therapeutic evolving trends (ET). We developed a multi-agent AI framework to automate this process and generate evidence-based recommendations for optimizing trial design. Methods: The framework integrates Precision360 RWD and a vectorized ClinicalTrials.gov database accessed through internal APIs and uses proprietary LLMs as the reasoning engine. Draft eligibility criteria are evaluated by three agents: (1) a CI agent applying embedding-based similarity with a 30% biomarker/indication weighting to prioritize trials within the same disease context; (2) a SoC agent benchmarking criteria against real-world treatment pathways; and (3) an ET agent detecting recently approved therapies. Each agent issues criterion-level recommendations with rationale, which are consolidated into a unified output. Validation included 30 oncology trials (NSCLC, breast, colorectal), with two clinical scientists ( > 5yr experience) independently rating outputs on a 1–5 scale. Weighted F1-scores measured concordance (predefined threshold ≥0.80). Results: Overall agent–scientist concordance was 95% (range 93–98%). The CI agent performed best with 5–10 competitor trials and correctly identified biomarker and indication alignment for 87% of evaluations (26/30). Across trials, the agents identified opportunities to broaden eligibility that were consistent with competitive trial standards and clinical scientist assessment. Example recommendations included alignment of eligibility thresholds with ranges observed in competitor trials within the same disease and treatment setting, such as hematologic criteria (e.g., ANC ≥1500 to ≥1200/µL), renal function cutoffs (creatinine clearance ≥45 to ≥40 mL/min), and functional status requirements (ECOG ≤1 to ≤2). These suggestions were derived from competitive trial patterns and were intended to flag potential opportunities for protocol adjustment. The SoC and ET agents each achieved F1 ≥0.92. In an EGFR exon19del example, the SoC agent found osimertinib representing ~60% of first-line RWD use, while the ET agent identified rising adoption of amivantamab with marked growth in 2024 and ~40% year-over-year increase, supporting inclusion of this regimen as an acceptable prior therapy. Conclusions: This multi-agent AI framework enables automated, transparent evaluation of eligibility criteria with expert-level concordance and identifies optimization opportunities informed by competitive and RWD evidence. It helps identify overly restrictive criteria that limit enrollment feasibility and contribute to protocol amendments and is extensible across therapeutic areas.
Feasibility of expansion of home phlebotomy with type and screen testing for hematologic monitoring: A single-institution pilot study.
e13577 Background: Patients with hematologic malignancies require intensive supportive care, including frequent lab monitoring and transfusion support. Home phlebotomy has been shown to improve patient satisfaction and reduce healthcare utilization; however, current standards of care typically exclude type-and-screen (T&S) testing from home collection. As a result, patients require additional testing at transfusion visits, leading to delays in transfusion administration. This study aims to evaluate the feasibility, safety, and operational efficiency of incorporating home type-and-screen testing to streamline hematologic care. Methods: We performed a retrospective, single-institution audit of patients who had T&S collected at home 2x weekly with routine lab monitoring. Inclusion criteria included adult; transfusion-dependent hematologic malignancy diagnosis; enrolled in T&S pilot during period. Exclusion criteria included expired during period; absence of at least 1 home T&S. Data was collected via EMR and analyzed using descriptive statistics. Primary endpoints were feasibility ( > 80% same-day T&S processed) and acceptable redundancy ( < 20 % repeated T&S collection). Secondary endpoints were safety (transfusion-related adverse events) and efficiency (estimated transfusion waiting times as defined by time from patient arrival to transfusion start). Results: From 5/1 – 8/1/2025, a total of 212 home T&Ss were collected among 14 patients (n = 212; N = 14). The cohort was 36% male (5) and 64% female (9), age ranged from 28 – 86 years (median age = 68) and had 4 primary hematologic diseases: AML (10), ALL (2), MDS (1), and aplastic anemia (1). 201 of 212 (94.8%) T&Ss were processed same-day. 26 of 212 (12.3%) home T&Ss were repeated prior to transfusion visits. Of 212 total T&Ss, there were 163 subsequent transfusion visits, with 308 total transfusions (115 RBC, 193 platelets). Based on subset estimates, transfusion visit waiting times differed between standard-of-care and home T&S patients with a mean difference of 82.1 minutes (95% CI 39.1–125.2; p = 0.001). Regarding adverse events, there were 7 total transfusion reactions, of which none were serologic. 4 reactions occurred in patients who had home T&Ss. Conclusions: This retrospective pilot study demonstrates the feasibility of integrating T&S testing into home phlebotomy. Collection of T&S at home was associated with shorter transfusion visit wait times, demonstrating increased care efficiency, which may positively impact patient quality of life. Interdisciplinary care coordination is needed for patient selection, handling/delivery of lab supplies, and visit scheduling. Future research should explore patients’ experiences with home T&S testing.
Diagnostic accuracy of blood-based cfDNA fragmentomic assays for lung cancer detection: A meta-analysis of clinically validated cohorts.
10577 Background: Early detection of lung cancer remains limited by suboptimal sensitivity and specificity of current screening and diagnostic strategies. Blood-based cell-free DNA (cfDNA) fragmentomic assays that leverage genome-wide fragmentation patterns have emerged as a promising noninvasive approach for lung cancer detection. However, reported diagnostic performance varies across studies and clinical settings. A meta-analysis was conducted to evaluate the pooled diagnostic accuracy of cfDNA fragmentomic assays in clinically validated cohorts. Methods: We systematically searched PubMed, Cochrane Library, and Scopus for studies evaluating blood-based cfDNA fragmentomic assays for lung cancer detection. Eligible studies were required to be lung cancer-specific, use fragmentomics-based features derived from plasma cfDNA, include an independent validation or test cohort, and report extractable binary diagnostic accuracy data. Training-only studies, multi-omic assays, and studies lacking sensitivity and specificity at a prespecified threshold were excluded. Sensitivity and specificity were jointly pooled using a bivariate random-effects model based on 2×2 contingency tables, accounting for threshold effects and between-study heterogeneity. Results: Five studies with independent validation cohorts comprising 725 lung cancer cases and 435 non-cancer controls were included, spanning screening-eligible populations, LDCT-positive pulmonary nodules, early-stage disease, and mixed-risk cohorts. Using a bivariate random-effects model, pooled sensitivity was 87.5% (95% CI, 77.4%–93.4%) and pooled specificity was 85.7% (95% CI, 63.6%–95.4%), corresponding to a pooled positive likelihood ratio of 6.14 (95% CI, 2.34–19.26) and negative likelihood ratio of 0.146 (95% CI, 0.074–0.295), and diagnostic odds ratio of approximately 42. Moderate inter-study heterogeneity was observed (I²=62%), largely attributable to differences in clinical setting, disease spectrum, and control composition; however, diagnostic performance remained directionally consistent across cohorts. The summary receiver operating characteristic curve demonstrated excellent overall discrimination (AUC 0.92). Conclusions: Across clinically validated cohorts, blood-based cfDNA fragmentomic assays demonstrated strong discriminative performance for lung cancer detection. Despite heterogeneity across study populations and clinical use cases, pooled sensitivity and specificity were robust, supporting the potential role of cfDNA fragmentomics as a noninvasive adjunct to existing screening and diagnostic strategies. Diagnostic performance of cfDNA fragmentomic assays for lung cancer detection. Measure Estimate 95% CI Sensitivity 87.5% 77.4–93.4 Specificity 85.7% 63.6–95.4 LR+ 6.14 2.34–19.26 LR– 0.15 0.07–0.30 AUC 0.92 —
Clinicopathologic characteristics of somatic <i>TP53</i> mutations in Philadelphia chromosome–negative myeloproliferative neoplasms: A systematic review and pooled analysis.
e18597 Background: TP53 mutations ( TP53 m) are uncommon in chronic-phase (CP) Philadelphia (Ph) chromosome–negative myeloproliferative neoplasms (MPN) but are increasingly reported in myelofibrosis (MF) and accelerated/blast phase (AP/BP). Their distribution, allelic configuration, and associated clinical outcomes have not been systematically synthesized. Methods: A PRISMA-guided search of EMBASE and PubMed (1974-July 1, 2025) identified cohort studies reporting adult Ph–negative MPNs with molecularly confirmed TP53 m. Case reports were excluded; Conference abstracts were included if cohort-level data were available. Extracted variables included demographics, MPN subtype, disease phase, TP53 allelic status (per International Consensus Classification), variant allele frequency (VAF), allogeneic hematopoietic cell transplantation (allo-HCT), median overall survival (mOS), and leukemic transformation. Given heterogeneity and lack of comparators, pooled proportions with (95% CI) were generated for descriptive variables; outcomes were summarized descriptively. Results: 10 retrospective studies met inclusion criteria. Pooled mean age was 61 years (95% CI 57.18–65.17) with male predominance (58%, 95 CI 53–63). TP53 m were uncommon in patients with Ph-negative MPN (3%, 95% CI 0–15%) but were higher in MF/AP/BP (10%, 95% CI 4–24%). Among patients with TP53 m, disease distribution included MF (35%, 95% CI 13–65%), AP/BP (33%, 95% CI 26–41%), essential thrombocythemia (ET) (10%, 95% CI 3–28%), and polycythemia vera (PV) (8%, 95% CI 4–14%). Multi-hit TP53 m accounted for 52% (95% CI 40–64%), while single-hit comprised 47% (95% CI 34–60%). The pooled mean TP53 VAF was 37.48% (95% CI 30.73–44.24%). Allo-HCT was used in 16% (95% CI 13–20%). One cohort reported leukemic transformation in 47% with a median follow-up of 9.6 months (m). Reported mOS in TP53 m CP-MF ranged from 11.6–18 m and was not reached in PV/ET, whereas AP/BP mOS ranged from 4.5–6 months. Conclusions: TP53 m Ph–negative MPNs are enriched in MF and AP/BP and frequently demonstrate multi-hit TP53 m with high VAF and associated with high leukemic transformation. Standardized molecular reporting and prospective studies are needed to refine prognostication and treatment strategies in TP53m MPN. Characteristics of patients with TP53 m MPN. Variable Pooled variables (95% CI) Age 61.18 years (57.18–65.17) Male/Female 58% (53–63)/42% (53–63) TP53 mutation in the cohort 3% (0–15) TP53 in MF/AP/BP 10% (CI 4–24) Primary myelofibrosis 35% (13–65) MPN in AP/BP 33% (26–41) Essential thrombocythemia 10% (CI 3–28) Polycythemia vera 8% (CI 4–14) Multi-hit/single-hit TP53 52% (CI 40–64) 47% (CI 34–60) TP53 VAF 37.48% (30.73–44.24) Abbreviations: MF: Myelofibrosis, AP: accelerated phase, BP: Blast phase, MPN: myeloproliferative neoplasm, VAF: Variant Allele Frequency.
Association of socioeconomic and clinical factors with overall survival in immunotherapy-eligible stage III non-small cell lung cancer following definitive chemoradiation.
1522 Background: Use of consolidative immunotherapy (IO) for stage III non-small cell lung cancer (NSCLC) has increased since FDA approval in 2018, yet disparities in access persist. Few studies have examined survival in the IO era accounting for both socioeconomic and clinical factors. We evaluated determinants of overall survival (OS) in IO-eligible patients (pts) after definitive chemoradiation (CRT). Methods: Retrospective National Cancer Database analysis was performed, of adults ≥18 years with stage III NSCLC (2018-2020) receiving ≥60 Gray in ≥30 fractions of RT with known IO status, defined as receipt 50-150 days from CRT start. Surgical cases were excluded. Variables included race/ethnicity (R/E), insurance, facility type, Charlson-Deyo comorbidity index (CCI), high school graduation rate (HSGR), household income, sex, age, NSCLC primary site, and histology. OS was assessed using the Kaplan-Meier method, followed by multivariable Cox regression models adjusting for aforementioned variables, including IO receipt. Results: Among 19,418 pts, 54.4% received IO. Median age was 68 years; 44% were female; 85% White, 12.5% Black, 2% Asian, and 2% Hispanic. Median OS was higher with IO (42.1 vs 22.3 months [mo], P <.001) and in females (38.8 vs 28.1 mo, P <.001). OS differed by R/E: Asian (52 mo), Black (40.3 mo), Hispanic (37.2 mo), American Indian/Alaska Native (24 mo) vs White pts (31.1 mo), P <.001. Privately insured pts (41.7 mo) and those treated at academic/research (A/R) centers (36.5 mo) had higher OS ( P <.001). On multivariable analysis, IO receipt was associated with lower all-cause mortality (HR 0.53; 95% CI, 0.51-0.56). Reduced mortality was seen in Asian (HR 0.82; 95% CI, 0.68-0.99) and Black pts (HR 0.83; 95% CI, 0.77-0.89) vs White pts. Higher mortality was associated with male sex (HR 1.28; 95% CI, 1.22-1.34), urban (non-metropolitan) vs metropolitan residence (HR 1.14; 95% CI, 1.07-1.22), Medicare (HR 1.10; 95% CI, 1.03-1.18) or no insurance (HR 1.36; 95% CI, 1.14-1.63) vs private insurance, nonacademic facilities (comprehensive: HR 1.09; 95% CI, 1.03-1.16; integrated network: HR 1.15; 95% CI, 1.07-1.23), and CCI of 2 (HR 1.13; 95% CI, 1.04-1.21) or ≥3 (HR 1.29; 95% CI, 1.19-1.40). Income and HSGR showed marginal association with OS. Upper-lobe vs main bronchus sites were associated with better OS ( P <.02), while squamous histology was associated with worse OS ( P <.001). Conclusions: Approximately half of IO-eligible stage III NSCLC pts received IO, which was independently associated with improved OS, adjusting for socioeconomic and clinical factors. Asian and Black race, and treatment at A/R centers, were associated with lower mortality. Insurance and facility type significantly influenced OS, highlighting persistent access-related disparities and the need for targeted interventions to promote equitable care.
Clinical implications and diagnostic utility of <sup>68</sup> Gallium FAPI PET CT in patients with testicular germ cell tumors: The prospective phase Ib FAPI-TEST study.
5127 Background: The fibroblast activation protein (FAP) is overexpressed in tumor tissue by cancer associated fibroblasts and radiopharmaceuticals can bind to this target. Recently, the 68 Ga-FAPI PET has emerged as a novel imaging modality for optimized differentiation between benign and malignant lesions. However, data on patients with testicular germ cell tumors (TGCT) are rare. This prospective study aims to investigate the expression, uptake and sensitivity of the 68 Ga-FAPI PET in TGCT patients. Methods: In this prospective observational phase Ib study, patients with TGCT up to clinical stage III and unfavorable TGCT histology in the testis such as teratomas were included. A 68 Ga-FAPI PET was performed in all included patients and analyzed with static (SUVmax/mean). Histology from the testis and whenever available from the metastasis were also stained for FAP and manually categorized into negative, medium and high expression. This study was approved by the local ethics committee (no 2024-17844). Results: We included 12 patients with a mean age of 34.5 (SD 8.81). Clinical stage at time of inclusion were CS II (n = 9), CS1 (n = 1) and CS III (n = 1) as well as one extragonadal TGCT. In eight and four cases the 68 Ga-FAPI PET was performed before and after completion of curative chemotherapy, respectively. Histology was available in six cases (5 = LNs, 1 = mediastinal tumor). FAP expression in the tumor of the testis was high in 50%, and in metastasis 60%. Stratification for high and low FAP lesions was performed according to mean SUVmax of 7.81 (SD 7,9) for all radiographic and histopathologic true positive metastasis. Sensitivity for 68 Ga-FAPI PET was 57% with a specificity 100%. Conclusions: This is the first prospective study that evaluates 68 Ga-FAPI PET in TGCT patients with the largest cohort so far. Stratification for SUVmax lesions above 7.81 showed excellent specificity, and the 68Ga-FAPI PET might potentially serve as a useful novel imaging modality for primary staging in clinical stages IIA and IIB, as well as post-chemotherapy with residual mass.
CAR-Mix cell therapies to treat solid tumors by providing synergistic interaction between engineered macrophages and polyclonal T cells.
e14543 Background: Chimeric antigen receptor (CAR) T cells have shown remarkable success against hematologic cancers and are now being adapted for solid tumors. However, MSLN-targeting CAR-T cells demonstrated limited efficacy in chemotherapy-refractory metastatic pancreatic ductal adenocarcinoma patients (NCT03323944). Besides, initial clinical trial data for the HER2-targeting CAR-macrophage (CAR-M) showed suboptimal clinical outcomes (NCT04660929). Current CAR-T or CAR-M therapies typically involve either engineered T cells or macrophages alone. Recent studies revealed that T cells cluster with tumor cells and/or antigen-presenting cells (APCs) in tumors, enhancing their tumor-killing ability. A trispecific antibody engaging T cells with both tumor and myeloid cells also improved antitumor immunity, highlighting the potential of T cell–APC cooperation in combating solid tumors. Based on this, we designed a novel adoptive cell therapy leveraging the synergy between T cells and macrophages to activate both adaptive and innate immunity, aiming to improve solid tumor treatment. Methods: We developed a novel MSLN-targeting CAR-Mix or CAR-cluster cell product using a one-step process optimized from CAR-M production. CAR-Mix mainly consists of CAR-M and T cells. After co-culture with tumor cells, clusters of T cell–tumor cell and T cell–macrophage could be detected by flow cytometry. Results: In vitro tumor-killing assays and in vivo studies with the SKOV3 ovarian cancer xenograft model in NSG mice showed that CAR-Mix had significantly enhanced antitumor efficacy compared to CAR-M or T cells alone. CD69 expression on T cells in CAR-Mix was markedly upregulated following co-culture with MSLN-expressing SKOV3 cells. NY-ESO tetramer-positive T cells also appeared after co-culturing CAR-Mix with SKOV3 cells expressing MSLN and NY-ESO, indicating antigen cross-presentation and efficient T cell activation. Bulk TCR sequencing revealed that the diversity of both TRA and TRB genes significantly decreased after CAR-Mix was co-cultured with tumor cells. This result indicates that specific T cell clones were selectively expanded within the CAR-Mix population upon encountering tumor cells. The enhanced anti-solid tumor activity of CAR-Mix is driven by its antigen cross-presentation capability combined with robust polyclonal T cell activation. Toxicity studies in immunodeficient NSG mice showed no damage to major tissues or organs, and serum biochemical indices remained comparable to controls. Conclusions: In summary, this study shows that CAR-Mix achieves significantly greater anti-solid tumor efficacy than CAR-M or T cells alone, primarily through synergistic interactions between CAR-M and T cells. These results strongly support further clinical evaluation of CAR-Mix as a promising therapy for patients with MSLN-positive solid tumors.
Validation of prognostic scores in Hispanic patients with advanced solid tumors enrolled in a single-center phase I clinical trial program.
1541 Background: Prognostic scores are commonly used to guide enrollment in early-phase oncology trials. Despite their widespread use, these models have not been specifically evaluated in Hispanic patients, to the best of our knowledge — a population historically underrepresented in clinical trials. We evaluated the predictive performance of the Royal Marsden Hospital (RMH) score, the Princess Margaret Hospital Index (PMHI), and the MD Anderson Cancer Center (MDACC) score in a cohort of Hispanic patients with advanced solid tumors enrolled in phase I clinical trials. Methods: We performed a retrospective chart review of Hispanic patients with advanced solid tumors enrolled in phase I clinical trials at USC Norris Comprehensive Cancer Center and its affiliated safety-net institution, Los Angeles General Medical Center, between 2015 and 2022. Prognostic scores were calculated using the established criteria: RMH score (albumin <3.5 g/dL, LDH > ULN, >2 metastatic sites), PMHI (albumin <3.5 g/dL, ECOG >0, >2 metastatic sites), and MDACC score (albumin <3.5 g/dL, LDH > ULN, ECOG >0, >2 metastatic sites, gastrointestinal tumor type). RMH and PMHI risk groups were categorized as low (0–1 points) or high (2–3 points), while MDACC risk groups were defined as low (0–1 points), intermediate (2–3 points), or high (4–5 points). Overall survival (OS) was analyzed using Kaplan–Meier methods. Results: A total of 191 Hispanic patients were included (109 gastrointestinal, 36 lung/head and neck, 20 other, 16 gynecologic, 6 genitourinary, 4 breast). Median age was 59 years (25–86). The median OS for this cohort was 13.1 months (95% CI, 8.8-18.3). Significant differences in OS were observed across prognostic risk groups for all three prognostic scores. Median OS for RMH high- versus low-risk patients was 5.1 versus 18.3 months (p=0.004); for PMHI high- versus low-risk patients, 6.5 versus 20.0 months (p=0.002); and for MDACC high-, intermediate-, and low-risk patients, 4.1, 15.7, and 32.7 months, respectively (p=0.007). Conclusions: In this Hispanic solid tumor phase I trial population, higher RMH, PMHI, and MDACC scores were associated with poorer overall survival. These findings support the use of established prognostic scores in Hispanic patients for identifying candidates with poor prognosis and informing early-phase trial enrollment. Prospective studies are warranted to further validate prognostic scores in the Hispanic population. RMH Median OS (Months) PMH Median OS (Months) MDACC Median OS (Months) Low (0-1) 5.1 Low (0-1) 6.5 Low (0-1) 4.1 High (2-3) 18.3 High (2-3) 20.0 Intermediate (2-3) 15.7 High (4-5) 32.7 p=0.004 p=0.002 p=0.007
Invasive-field radiotherapy plus rituximab versus rituximab alone after response to immunochemotherapy in stage III follicular lymphoma: An open-label, multicenter, randomized clinical study.
7054 Background: Stage III follicular lymphoma (FL) remains incurable with immunochemotherapy followed by rituximab maintenance. Radiotherapy plays a critical role in the curative treatment of early-stage FL; however, its role in the management of stage III disease remains undefined. Methods: In this open-label, multicenter, randomized clinical trial, patients with stage III FL, who demonstrated complete or partial response without bulky after induction immunochemotherapy were enrolled. Eligible patients randomly assigned (1:1) to receive invasive field consolidation radiotherapy (IFRT) combined rituximab maintenance (IFRT+R arm) or rituximab maintenance alone (R arm). The dose of IFRT was 30Gy. The primary endpoint was 5-year progression-free survival (PFS), and the secondary endpoint was 5-year overall survival (OS). This study is registered with Chinese ClinicalTrials.gov, number ChiCTR2000032550. Results: Between January 2015 to January 2021, 152 eligible patients were randomly assigned to receive IFRT+R (n=74) or R alone (n=78). Baseline characteristics showed no significant differences between the two arms. After a median follow-up of 82 months, the 5-year PFS was 88.9% in IFRT+R group and 66.7% in R alone group (HR, 0.32; 95% CI, 0.16-0.66, P = 0.002). The 5-year OS was 97.3% in IFRT+R group versus 84.4% in R group (HR, 0.23; 95% CI, 0.07-0.81, P = 0.02). Treatment-related adverse events were more frequent in the IFRT+R arm than in the R arm (58% vs 38%), predominantly consisting of acute hematologic toxicities, including neutropenia (33% vs 26%) and leukopenia (34% vs 28%). Grade 3-4 toxicities were more common in the IFRT+R arm (27% vs 18%), and no treatment-related deaths were observed. Conclusions: Involved-field radiotherapy after effective systemic therapy significantly improved PFS and OS with manageable toxicity, highlighting its potential role in the management of stage III FL. Clinical trial information: ChiCTR2000032550.
Longitudinal evaluation of a multidisciplinary lung cancer early detection program.
e20707 Background: Lung cancer remains the leading cause of cancer-related mortality in the United States and globally. Multiple clinical trials have demonstrated reduced mortality and stage shift among participants of low-dose CT lung screening (CTLS). Although real-world studies suggest similar trends following screening adoption, longitudinal evaluations that integrate CTLS, incidental pulmonary nodule (IPN) management, and symptomatic presentation across diagnostic pathways remain limited. In 2015, our community-based teaching hospital established a multidisciplinary lung cancer early detection program, which integrates CTLS, IPN, and symptomatic presentation of lung cancers. Methods: We conducted a retrospective analysis of lung cancers diagnosed through this quality improvement program from 2015 to 2024. Cancers were classified by CTLS-, IPN-, or symptomatic-detection. Changes in the diagnostic pathway distribution were assessed using chi-squared testing. Among CTLS-eligible patients, multivariable logistic regression estimated the odds of symptomatic diagnosis in 2024 versus 2015, adjusting for age, sex, and race. Results: Over the study period, 825 lung cancers were diagnosed through the integrated program. Comparison of cancers diagnosed in 2015 (n = 90) and 2024 (n = 85) demonstrated a significant redistribution of diagnostic pathways (χ² p < 0.001), with symptomatic presentation declining from 54.4% to 21.2% alongside increases in IPN-detected and CTLS- detected cancers. Twice as many cancers were detected via the IPN pathway as compared to CTLS. Among screening-eligible patients, the adjusted odds of symptomatic diagnosis in 2024 were markedly lower than in 2015 (OR 0.063, 95% CI 0.014-0.291; p < 0.001). Notably, there was a significantly higher proportion of patients who reported never using tobacco as the program matured (8.9% in 2015 compared with 23.5% in 2024, p=0.039). Conclusions: Over a decade, implementation of a multidisciplinary integrated lung cancer early detection program was associated with a substantial reduction in symptomatic presentation among screen-eligible patients and a significant stage shift to earlier stage disease, and a significantly higher percent of patients with no tobacco use history. These data support the role of organized and integrated lung screening and structured follow-up of pulmonary nodules in improving early detection of lung cancer. Program characteristics by year of diagnosis. Variable 2015 (n=90) 2024 (n=85) p-value / OR (95% CI) Age, mean (SD) 69.5 (8.8) 71.3 (9.7) - Male sex, n (%) 42 (46.7) 36 (42.4) p=0.67 No prior cigarette use, n (%) 8 (8.9) 20 (23.5) p=0.039 Screening-eligible, n (%) 30 (33.3) 32 (37.6) - Screening-detected, n (%) 13 (14.4) 24 (28.2) p<0.001 Incidental, n (%) 28 (31.1) 43 (50.6) p<0.001 Symptomatic, n (%) 49 (54.4) 18 (21.2) p<0.001 Symptomatic upon diagnosis (screen eligible) 18 (60.0) 4 (12.5) OR 0.063 (0.014-0.291)
HER2-targeted tyrosine kinase inhibitors in breast cancer: Real-world analysis of gastrointestinal and musculoskeletal toxicities using the FAERS database.
1058 Background: Human Epidermal Growth Factor Receptor 2 (HER2)-targeted tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib are approved for HER2-positive breast cancer but have distinct adverse event (AE) profiles. We analyzed the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to characterize gastrointestinal (GI) and musculoskeletal (MSK) toxicities associated with these agents. Methods: We conducted a retrospective FAERS data review to assess GI and MSK AEs associated with the three TKIs from 2020-2025. The chi-square test was used to compare categorical variables across drugs and age groups (<65 vs ≥65 years). Results: Among 9,045 total cases (lapatinib n=1,897; neratinib n=1,113; tucatinib n=6,035), neratinib demonstrated the highest GI toxicity rate at 64.2%, compared to 40.4% for tucatinib and 31.3% for lapatinib (χ²=319.3, p<0.001). Diarrhea was the predominant GI AE across all agents, affecting 82.1% of neratinib-treated patients, 64.8% of tucatinib-treated patients, and 55.6% of lapatinib-treated patients. Other common GI AEs included nausea (33.2 neratinib, 34.6 tucatinib, 23.1 lapatinib) and vomiting (21.1% neratinib, 19.5% tucatinib, 23.9 lapatinib). MSK AE rates were comparable across all three agents (lapatinib 10.5%, neratinib 11.3%, tucatinib 10.5%; χ²=0.72, p=0.70). The most frequent MSK AEs were pain in extremities (23% overall), arthralgia (18% overall), back pain (17.8% overall), and muscle spasms (17.6% overall). Age-stratified analysis revealed significant differences in GI toxicity. In patients <65 years, neratinib showed the highest GI AE rate at 63.1%, versus 34.8% for tucatinib and 28.1% for lapatinib (χ²=74.0, p<0.001). In patients ≥65 years, this pattern persisted with neratinib at 73.7%, tucatinib at 36.9%, and lapatinib at 40.1% (χ²=49.4, p<0.001). Moreover, older patients (≥65 years) experienced significantly higher rates of both GI and MSK AEs with lapatinib (GI: 40.1% vs 28.1%, p<0.001; MSK: 19.3% vs 9.6%, p<0.001) and neratinib (MSK: 25.3% vs 6.3%, p<0.001). Tucatinib showed no significant age-related differences in AE rates. Conclusions: The findings in this study highlight trends for selected AEs with various TKIs in order to help guide shared decision-making and tailored management strategies for patients with HER2-positive breast cancer.
Refusal of chemotherapy, surgery, and radiation in non-metastatic triple-negative breast cancer.
e12712 Background: Refusal of oncologist-recommended therapy is uncommon but clinically consequential. In triple-negative breast cancer (TNBC), understanding which patients decline treatments and the resulting survival impacts may inform oncologist discussions and interventions. Using real-world data, we examined factors associated with refusal of chemotherapy, surgery, and radiation among patients with stage I–III TNBC. Methods: Using the National Cancer Database, we identified women younger than 60 diagnosed with stage I–III TNBC from 2010–2019 who received or refused oncologist-recommended treatment. Multivariate logistic regression evaluated factors associated with treatment refusal. Multivariate Cox regression assessed three-year overall survival (OS). Analyses adjusted for stage, age, diagnosis year, comorbidity burden, insurance status, urban-rural residence, zip-code income quartile, and race/ethnicity. Results: The final cohort included 96,633 patients (39.1% stage I, 43.7% stage II, 17.2% stage III) with complete data for covariates. Refusal rates among treatment-recommended patients were 3.1% for chemotherapy, 0.3% for surgery, and 4.3% for radiation. Refusal of chemotherapy (adjusted hazard ratio [aHR] 2.18, 95% CI 1.96–2.43, p < 0.001), surgery (aHR 3.21, 95% CI 2.66–3.89, p < 0.001), and radiation (aHR 1.67, 95% CI 1.49–1.87, p < 0.001) were each associated with worse three-year OS. Higher comorbidity burden was associated with higher odds of refusal across all treatment modalities, whereas urban-rural residence, diagnosis year, and zip-code income quartile did not reach significance. For chemotherapy, refusal was less likely with increasing stage (stage III vs. stage I: adjusted odds ratio [aOR] 0.47, 95% CI 0.40–0.54, p < 0.001) and Hispanic ethnicity (aOR 0.71, 95% CI 0.57–0.87, p = 0.001). Older age (50–60 vs. < 40: aOR 2.03, 95% CI 1.73–2.39, p < 0.001), uninsured status (aOR 1.58, 95% CI 1.25–1.98, p < 0.001), and non-Hispanic Black (NHB) race (aOR 1.48, 95% CI 1.32–1.65, p < 0.001) were associated with higher odds of refusal. In contrast, odds of refusal of surgery increased with stage (stage III vs. stage I: aOR 6.00, 95% CI 4.14–8.91, p < 0.001), older age (40–50 vs. < 40: aOR 2.11, 95% CI 1.39–3.32, p < 0.001), uninsured status (aOR 3.49, 95% CI 2.19–5.37, p < 0.001), and NHB race (aOR 2.04, 95% CI 1.53–2.71, p < 0.001). Radiation refusal showed associations with uninsured status (aOR 1.90, 95% CI 1.52–2.34, p < 0.001), NHB race (aOR 1.24, 95% CI 1.11–1.40, p < 0.001), and stage II (vs. stage I: aOR 1.44, 95% CI 1.28–1.62, p < 0.001) but not stage III. Conclusions: In non-metastatic TNBC, refusal of recommended therapy was uncommon but strongly predicted by age, stage, and sociodemographic factors. These findings suggest that treatment refusal in TNBC is driven in part by patient- and system-level factors, highlighting a need for studies examining specific reasons for treatment refusal.
Pooled analyses of clinical outcomes with afamitresgene autoleucel (afami-cel) in metastatic synovial sarcoma.
11505 Background: Afamitresgene autoleucel (afami-cel) is a melanoma-associated antigen A4 (MAGEA4)-directed genetically modified autologous T cell immunotherapy consisting of CD4 and CD8 positive T cells transduced with a self-inactivating lentiviral vector (LV) expressing an affinity-enhanced T cell receptor (TCR) specific for the human MAGE-A4. Here we report the pooled results of afami-cel in phase 1 and phase 2 trials in patients (pts) with advanced (unresectable/metastatic) synovial sarcoma (SyS). Methods: Pts who were HLA-A*02 positive with previously treated, advanced SyS positive for MAGE-A4 received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. The pooled analyses evaluated overall response rate (ORR) per RECIST v1.1 by investigator review, duration of response (DoR), ORR in sub-populations, overall survival (OS), safety and pharmacokinetics. Results: As of May 2025, 153 pts with advanced SyS received afami-cel (1.00 –9.99×10 9 MAGE-A4 TCR positive T cells). The median age was 40 years (range: 13–76 years), 54% of pts were male, and 86% of pts were white. The median MAGE-A4 expression by H-score was 256.0 (range: 60–300). All pts received prior anthracycline and/or ifosfamide therapy and received a median of 2 prior lines of therapy (range: 1–12). ORR by investigator review was 43.8% (95% CI 35.8, 52.0). Responses were observed across all subgroups, including pediatric SyS pts. The median DoR was 7.1 months (95% CI 4.7, 10.6) and ranged from 1 to 58+ months. Median OS was 18.7 months (95% CI: 14.1, 22.5) with 44% of pts censored at the data cut-off. The 12-month or longer and 24-month or longer OS probabilities were 64.4% and 40.5%, respectively. Among the 67 pts who had a RECIST response, the median OS was 37.5 months (95% CI 26.3, 50.5). The most common any-grade non-laboratory TEAEs (≥20% of pts) were cytokine release syndrome (CRS) (73.2%), nausea (64.1%), fatigue (45.8%), pyrexia (33.3%), vomiting (29.4%), constipation (28.1%), diarrhea (27.1%), headache (26.8%), and cough (20.9%). The most common Grade ≥3 laboratory TEAEs (≥20% of pts) were lymphopenia, neutropenia, leukopenia, and anemia. Afami-cel persisted long-term, including >3 years. Conclusions: To the best of our knowledge, this is the largest dataset of T-cell therapy treated pts with advanced SyS. The magnitude of ORR supported by DOR demonstrated with afami-cel treatment is considered clinically meaningful in this rare pt population with a poor prognosis and limited effective therapies. CRS and cytopenias were common and manageable. Pts with advanced SyS treated with afami-cel had encouraging survival, especially those pts with a RECIST response. Clinical trial information: NCT04044768 , NCT03132922
Trends in HIV, hepatitis B, and hepatitis C eligibility language in immune checkpoint inhibitor oncology trials: A ClinicalTrials.gov rule-based NLP analysis (2010–2025).
e23011 Background: Exclusion of people with HIV or viral hepatitis can limit generalizability of immune checkpoint inhibitor (ICI) trial evidence. Despite growing emphasis on risk-stratified inclusion, prevalence and temporal trends of HIV/HBV/HCV eligibility language remain incompletely characterized. We quantified these patterns in ICI oncology trials on ClinicalTrials.gov. Methods: Interventional ICI oncology trials first posted 2010–2025 on ClinicalTrials.gov were included (N = 8,924). Eligibility criteria were parsed with transparent, section-aware rule-based NLP at the criterion-line level and aggregated to trial-level classifications via prespecified precedence. For HIV/HBV/HCV, language was categorized as no mention, absolute exclusion, conditional eligibility, or mention–unclear. Primary HIV absolute exclusion was blanket exclusion for explicit HIV-positive status/known HIV infection/AIDS (strict); sensitivity included HIV-test–positive exclusions. HBV/HCV absolute exclusion was explicit chronic/known infection or serologic/virologic positivity without conditional qualifiers; conditional eligibility allowed controlled/suppressed/treated infection or limited exclusions to active/uncontrolled/detectable infection. Prevalence was summarized overall and by era (2010–2014, 2015–2019, 2020–2025). Temporal trends used adjusted logistic regression (binomial GLM, logit) estimating OR/year, adjusted for phase and industry sponsorship. Results: HIV/HBV/HCV language: no mention 2,345 (26.28%); conditional eligibility for ≥1 infection 5,352 (59.97%); absolute exclusion for ≥1 infection 990 (11.09%; sensitivity 12.19%, similar temporal pattern); mention–unclear 237 (2.66%). Infection-specific absolute exclusion was 9.72% (HIV), 1.48% (HBV), 0.30% (HCV). By era (2010–2014/2015–2019/2020–2025; n = 336/3,429/5,159), absolute exclusion for ≥1 infection was 10.12%/13.09%/9.83% and conditional eligibility 43.45%/64.30%/58.17%. Adjusted models showed decreasing HIV absolute exclusion (OR/year 0.956, 95% CI 0.935–0.977; p = 5.97×10⁻⁵) and absolute exclusion for ≥1 infection (OR/year 0.959, 95% CI 0.940–0.980; p = 9.25×10⁻⁵). HBV/HCV absolute exclusion was uncommon (132/27 events) with no significant temporal change. Stratified manual validation evaluated classification performance (n = 1,659). Conclusions: In ICI oncology trials posted 2010–2025, conditional eligibility for HIV/HBV/HCV was common, yet absolute exclusion persisted in ~1 in 9 trials (strict), peaking in 2015–2019 and declining in 2020–2025 largely due to decreasing HIV blanket exclusion. These findings support standardizing risk-stratified, evidence-based eligibility language to improve trial representativeness while maintaining safety.
Trends in mortality among older adults with coexisting ischemic heart disease and thoracic malignancies: A 25-year analysis of U.S. national data.
e24029 Background: Ischemic heart disease (IHD) and thoracic malignancies are leading causes of death in older adults, often coexisting due to shared risk factors such as smoking and aging. This study aimed to assess national mortality trends from 1999–2023 among adults aged ≥55 with both IHD and thoracic cancers, stratified by key demographic variables using the CDC WONDER database. Methods: We conducted a retrospective cohort study using CDC WONDER data (1999–2023) on U.S. adults aged ≥55 years. Eligible deaths listed ischemic heart disease (ICD-10: I20–I25) as the underlying cause and thoracic neoplasms (ICD-10: C33, C34, C38) as contributing causes. Age-adjusted mortality rates per 100,000 were calculated and stratified by year and sex. Joinpoint regression analysis identified temporal trends using annual percent change with 95% confidence intervals. Results: Over 24 years, age-adjusted mortality rates (AAMRs) for ischemic heart disease with thoracic neoplasms declined significantly from 1999–2016 (APC: –5.49; 95% CI: –7.32 to –3.54; p < 0.001), though disparities persisted. Males accounted for 65.15% of deaths versus 34.85% in females. Non-Hispanic Whites bore the highest burden (88.11% of deaths), and the Southern region exhibited elevated mortality (7.45%). Urban areas showed steeper AAMR declines (Large Central Metro APC: –5.94; p < 0.001) than rural settings. Notably, Pacific Islanders experienced increasing mortality post-2017 (APC: +14.16; p < 0.001). State-level variations were pronounced, with West Virginia's AAMR (5.1) nearly triple that of Wyoming (1.7). Despite overall improvement, findings reveal ongoing geographic and racial disparities, emphasizing the need for equity-focused interventions. Conclusions: From 1999–2023, mortality from IHD and thoracic neoplasms declined overall, with sharper decreases in males, Whites, and metropolitan areas. However, recent years showed plateauing in females and Hispanics, and rising trends in Pacific Islanders. Regional and urban–rural disparities persist, highlighting the need for focused public health action.
Impact of pre-existing autoimmune disease on outcomes of immune checkpoint inhibitors in non–small cell lung cancer: A real-world multi-institutional cohort study.
e20612 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have become a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC). Patients with pre-existing autoimmune disease (AD) are routinely excluded from ICI trials, resulting in limited data on the real-world safety and efficacy of ICIs in this population. We evaluated the real-world impacts of AD on survival and treatment-related outcomes in patients with NSCLC treated with ICIs. Methods: Using the TriNetX Research Network, we conducted a retrospective cohort study of adults (≥18 years) with NSCLC who received ICI therapy following diagnosis. ICI regimens included PD-1, PD-L1, and CTLA-4 based treatment. Patients with documented AD prior to ICI initiation were compared to those without AD. Propensity score matching (1:1) was performed for demographics, co-morbidities, laboratory values, and baseline steroid use. Outcomes included overall survival (OS) at 90 days, 1 year, and 3 years; infections, any hospital admission, ICU admission, and steroid exposure within 90 days; and immune-related adverse events (irAEs) within 180 days of ICI initiation. Outcomes were assessed using hazard ratios (HR), risk ratios (RR), and 95% confidence intervals (CI). Results: 426 patients with pre-existing AD and 10,027 patients without AD met inclusion criteria. Following 1:1 PSM there were 425 patients in each cohort. Patients with AD demonstrated similar OS at 90 days, 1 year, and 3 years compared with patients without AD (90-day HR = 0.99[0.68-1.43]; 1-year HR =1.15 [0.92-1.45]; 3-year HR =1.09 [0.90-1.32]). Rates of irAEs were comparable between cohorts (RR = 0.93 [0.51-1.70]). Steroid exposure was similar in the AD cohort compared with the non-AD cohort (RR =1.07 [0.97-1.18]). Rates of all-cause hospitalization and ICU admission were also similar between groups (all-cause RR = 0.95 [0.81-1.12]; ICU RR = 1.30 [0.88-1.92]). There was no statistically significant difference in rates of infection between patients with pre-existing AD compared to the no-AD group (RR =1.17 [0.93-1.48]). Conclusions: In this large real-world cohort study of NSCLC patients treated with ICIs, pre-existing AD was associated with similar OS, irAEs, rates of infection, and hospitalizations as patients without pre-existing AD. Our findings suggest that pre-existing AD alone should not affect candidacy for ICIs in appropriately selected patients. Outcome Pre-existing AD[n= 425] No-AD[n= 425] HR/RR [95% CI] 90-day OS 86.6% 86.4% 0.99 [0.68-1.43] 1-year OS 58.4% 63.9% 1.15 [0.92-1.45] 3-year OS 35.2% 37.9% 1.09 [0.90-1.32] Any irAE (180 days) 5.3% 5.7% 0.93 [0.51-1.70] Any Infection (90 days) 27.1% 23.1% 1.17 [0.93-1.48] Hospitalization (90 days) 40.0% 42.1% 0.95 [0.81-1.12] ICU Admission (90 days) 12.2% 9.4% 1.30 [0.88-1.92] Steroid Exposure (90 days) 67.5% 63.3% 1.07 [0.97-1.18]
Nivolumab plus ipilimumab with chemotherapy as first-line therapy for NSCLC: A single-center real-world experience.
e20630 Background: Dual immune checkpoint inhibition combined with platinum-based chemotherapy has become one of the standard first-line treatment options for advanced non-small cell lung cancer (NSCLC) following the CheckMate 9LA trial. According to our local practice dual immunotherapy is mostly offered to patients with PD-L1-negative tumors. However, real-world evidence on the effectiveness of this regimen remains limited. We report a single-center experience with a particular focus on outcomes in patients with PD-L1-negative disease. Methods: Patients with metastatic NSCLC without actionable driver mutations who received nivolumab plus ipilimumab with platinum-based chemotherapy as first-line systemic therapy between 2020 and 2024 at Moscow City Oncology Hospital No. 62 were retrospectively analyzed. Clinical characteristics, objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicity were evaluated. Survival outcomes were estimated using the Kaplan–Meier method and compared by the log-rank test. Cox proportional hazards models were applied to assess associations between clinical variables and outcomes. Results: A total of 184 patients were included; 88% were male. ECOG performance status was 0 in 12%, 1 in 47.2%, 2 in 34.4%, and 3 in 5.6%. Ninety percent received nivolumab plus ipilimumab with carboplatin and paclitaxel, whereas 10% received dual immunotherapy alone. Squamous cell carcinoma accounted for 35% of cases, and adenocarcinoma for 63.3%. PD-L1 expression was < 1% in 72.2%, 1-50% in 23.3%, and > 50% in 3.1% of patients. After a median follow-up of 31.7 months, median PFS was 7.3 months (95% CI, 5.5-9.7), median OS was 16.2 months, and the 3-year OS rate was 23.8%. ORR was 44.5%, including CR in 4.4% and PR in 37.5%; SD was observed in 11.2%. Radiologically confirmed pseudoprogression occurred in 4 patients (2.4%). Median PFS and OS were comparable between PD-L1-positive and PD-L1-negative subgroups: 10.3 versus 8.7 months for PFS (p = 0.99) and 15.9 versus 17.1 months for OS (p = 0.70), respectively. Median OS by objective response was not reached for CR, 23.9 months for PR, 21.3 months for SD, and 12.3 months for PD (p < 0.001). Grade ≥3 adverse events occurred in 24.2% of cases. Patients with grade ≥3 toxicity had longer median PFS (14.1 vs 6.7 months, p = 0.04; HR 0.63 (0.40-0.99) and OS (18.7 vs 12.5 months, p = 0.02; HR 0.57 (0.34-0.93)). Fourteen patients (8.3%) completed 2 years of immunotherapy. Conclusions: In routine clinical practice, nivolumab plus ipilimumab combined with chemotherapy demonstrated clinically meaningful efficacy as first-line therapy for metastatic NSCLC, independent of PD-L1 expression. Development of grade ≥3 toxicity was associated with improved progression-free survival and overall survival.
Safety of glucagon-like peptide-1 receptor agonists in patients with breast cancer: A real-world multicenter cohort study.
11139 Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for patients with breast cancer and coexisting type 2 diabetes mellitus (T2DM). While GLP-1RAs have demonstrated metabolic and cardiovascular benefits in the general population, data regarding their safety in patients with breast cancer remain limited. Methods: We conducted a retrospective cohort study using the TriNetX Research Network, which aggregates de-identified electronic health record data from over 140 international healthcare organizations. Adult patients (≥18 years) with breast cancer who received breast cancer–directed systemic therapy and antidiabetic medications were included. The exposed cohort comprised patients who received a GLP-1RA within 90 days of systemic therapy initiation, while the comparator cohort included patients who received non–GLP-1RA antidiabetic agents. To minimize confounding, 1:1 propensity score matching was performed using demographics, body mass index, hemoglobin A1c, metastatic disease, breast cancer-directed therapy, and comorbidities. Outcomes were evaluated over 12 months using Cox proportional hazards models. Primary safety outcomes included adverse events commonly associated with GLP-1RA use: pancreatitis, biliary disease, and gastrointestinal adverse events (gastroesophageal reflux disease [GERD], bowel obstruction, and nausea/vomiting). Secondary outcomes included all-cause mortality and major adverse cardiovascular events (MACE), defined as a composite of myocardial infarction, ischemic stroke, and cardiovascular death. Results: A total of 29,380 patients with breast cancer and T2DM were identified. After propensity score matching, 3,796 patients were included in each cohort. Over 12 months of follow-up, GLP-1RA use was not associated with an increased risk of pancreatitis compared with non–GLP-1RA use (hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.53–2.71). No significant differences were observed in biliary disease (HR, 0.93; 95% CI, 0.60–1.45) or bowel obstruction (HR, 0.70; 95% CI, 0.40–1.23). GLP-1RA use was associated with higher risks of GERD (HR, 1.48; 95% CI, 1.14–1.92) and nausea/vomiting (HR, 1.59; 95% CI, 1.26–2.00). Importantly, GLP-1RA use was associated with a lower risk of MACE (HR, 0.76; 95% CI, 0.59–0.99) and all-cause mortality (HR, 0.51; 95% CI, 0.37–0.69). Conclusions: In this study, GLP-1RA use was not associated with increased risks of serious gastrointestinal or biliary adverse events among patients with breast cancer receiving systemic therapy. While nausea/vomiting and GERD were more frequent, GLP-1RA use was associated with significant reductions in major adverse cardiovascular events and all-cause mortality. Prospective studies are warranted to confirm long-term safety and oncologic outcomes.
Prediction of anthracycline-related cardiomyopathy in long-term childhood cancer survivors: The power of survivor-specific polygenic risk score—A COG-ALTE03N1 study.
10005 Background: Cardiomyopathy is a major dose-limiting toxicity of anthracyclines in the treatment of childhood cancer. Inter-patient variability in cardiomyopathy risk suggests an underlying genetic susceptibility, providing an opportunity to identify survivors at high risk and enable personalized interventions. We evaluated whether addition of a curated survivor-specific PRS for anthracycline-related cardiomyopathy (PRS-S) or general population PRSs for heart failure (PRS-G) to a clinical model improved cardiomyopathy risk classification in CCS. Methods: In a matched case-control study of CCS (COG-ALTE03N1: matched on cancer diagnosis and year of diagnosis; controls followed at least as long as cases), anthracycline-exposed non-Hispanic White CCS were randomly split (80/20) into training (cases: n=106; controls: n=180) and test (cases: n=27; controls: n=44) sets. From >100 published genetic variants associated with anthracycline-related cardiomyopathy, we selected a prioritized list of 8 independently validated variants with demonstrated biologic plausibility (reduced drug efflux [ ABCC2 ] , altered drug metabolism [ SLC22A17, SLC28A3, UGT1A6 ] , reduced antioxidant capacity [ HAS3 ] , impaired TOP2B-mediated DNA damage response [ RARG ] , alternative splicing of TNNT2 , reducing cardiac pumping efficiency [ CELF4 ], and cardiac profibrotic pathway [ ROBO2] ) to construct a standardized weighted survivor-specific PRS (PRS-S). Area under the receiver operating characteristic curve (AUC) was used to compare the performance of a clinical model (age at cancer diagnosis, sex, anthracycline dose, chest radiation (Y/N)) v combined models incorporating either PRS-S or PRS-Gs. All models included PRS × anthracycline dose interaction terms and adjusted for matching variables. Risk scores derived from training model were applied to the test set for risk classification. Results: Median age at cancer diagnosis was 7.1y for cases and 8.6y for controls. Cases received higher anthracycline doses (median: 330 v 240 mg/m 2 ) and were more likely to have received chest radiation (24.8% v 19.2%). In the test set, PRS-S combined model significantly outperformed the clinical model (AUC clin+PRS8 =0.70, 95%CI=0.57-0.82 v AUC clin =0.63, 95%CI=0.50-0.76, p=0.04); 85% of all cases were classified as high risk and the adjusted negative predictive value was 95.1%. Importantly, none of the 11 PRS-G combined models (AUCs: 0.60-0.65) out-performed the clinical model. Conclusions: Integrating a survivor-specific PRS derived from a parsimonious set of biologically plausible genetic variants with readily-available clinical factors informs cardiomyopathy risk classification in CCS and provides an opportunity to develop personalized screening recommendations and behavioral/therapeutic interventions.