Citations

Abstract Background The ability of large language models (LLMs) to work collaboratively and screen studies in a systematic review (SR) is under-explored. Hence, we aimed to evaluate the effectiveness of LLMs in automating the process of screening in systematic reviews. Methods This is an observational study which included labeled data (title and abstracts) for five SRs. Originally, two reviewers screened the citations independently for eligibility. A third reviewer cross-checked each citation for quality assurance. GPT-4, Claude-3-Sonnet, and Gemini-Pro-1.0 were used using zero-shot chain-of-thought prompting. Collaborative approaches included (i): conflict resolution using benefit of the doubt, (ii) majority voting using an independent third LLM and (iii) conflict resolution using an informed third LLM. Performance was assessed using accuracy, precision for exclusion, and recall for inclusion. Work saved over samples (WSS) was computed to estimate the reduction in manual human effort. Results A total of 11300 articles were included in this study. The individual models, GPT-4, Claude-3-Sonnet, and Gemini-Pro-1.0 exhibited a high precision for exclusion, achieving 99.7%, 99.7%, and 99.2% and high recall for inclusion achieving 95.5%, 96.6% and 85.7%, respectively. However, the collaborative approach utilizing the two best-performing models (GPT-4 and Claude-3S) achieved an average precision of 99.9% and a recall of 98.5% (across all collaborative approaches). Furthermore, the proposed collaborative approach resulted in an average WSS of 63.5%, compared to the average WSS of 45.2% for individual models. Conversational LLM interactions showed a consistent pattern of results. Limitations This study was limited due to reliance on proprietary models, and evaluation on oncology datasets. Conclusion Evidence shows that collaborative LLMs enable efficient, high-performing screening in systematic reviews, supporting continuous evidence updates. Primary funding source NIH (U24CA265879-01-1) and Carolyn-Ann-Kennedy-Bacon Fund.

Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate by speeding conduction and/or prolonging repolarization via modulation of ion channel expression, although the mechanisms by which single-fraction radiation mediates durable changes in gene expression are incompletely understood. Here, we identify dynamic changes in the cardiomyocyte epigenome and transcriptome after irradiation (IR) in vivo and in vitro, including durably increased expression and chromatin accessibility of Scn5a (encodes the α subunit of the sodium channel, Na V 1.5), demonstrating a role for epigenetic memory in conduction velocity (CV) increases observed after STAR. Transcriptomic and epigenetic sequencing further identified dynamic changes in gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. These changes were mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration, highlighting important cellular processes that may mediate the therapeutic effects of STAR. Overall, we found that cardiomyocytes exposed to a single fraction of high-dose IR exhibited epigenetic reprogramming that mediated broad and dynamic physiologic responses.

Abstract Background: Antibody-drug conjugates (ADCs) are increasingly used in the treatment of breast cancer due to their superior efficacy compared to conventional chemotherapy. The management of male breast cancer is largely extrapolated from clinical data in females and evidence regarding the efficacy of ADCs in men remains limited. This study aimed to compare survival outcomes between male and female breast cancer patients treated with ADCs across the spectrum of human epidermal growth factor receptor 2 (HER2) expression. Methods: We included total of 2,954 (Male: 34, Female: 2,920 breast cancer samples) from patients who underwent treatment with ADCs. We excluded patients with triple-negative breast cancer status due to the rarity of this subtype in males and the worse prognosis of triple-negative breast cancer, so that the cohorts would be more homogeneous without overrepresentation of triple-negative breast cancer in females. We categorized patients by HER2 status as: HER2-null (if there was 0% stain on HER2 IHC), HER2-ultra low (if HER2 IHC was 0 but with stain 1-10%), HER2-low (if HER2 IHC was 1+ or 2+ with a negative chromogenic in situ hybridization [CISH] assay), and HER2-positive (if HER2 IHC was 3+ or 2+ with a positive CISH assay). Real-world median overall survival was derived from insurance claims and calculated from the start of first ADC with either trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1) or sacituzumab govitecan (SG) to last contact using Kaplan-Meier. Statistical significance was assessed using chi-square and Mann-Whitney U. Results: The distribution of sex by HER2 expression group was: HER2-null: 8 males vs 612 females; HER2-ultra low 6 males vs 467 females; HER2-low 11 males vs 903 females; HER2-positive 9 males vs 938 females. Median survival from treatment initiation with either T-DXd or SG in the HER2-null cohort was 21.31 months in males vs 15.72 months in females (HR 0.82, 95% CI 0.33 - 2.01, p=0.67); in the HER2-ultra low cohort was 17.73 months in males vs 14.47 months in females (HR 0.84, 95% CI 0.26 - 2.63, p=0.76); in the HER2-low cohort was 11.08 months in males vs 18.62 months in females (HR 1.53, 95% CI 0.63 - 3.7; p=0.34). In the HER2-positive cohort, 5/9 males (55.5%) and 544/938 females (58%) were treated with T-DXd. Median survival from treatment initiation with either T-DXd or T-DM1 in the HER2-positive cohort was 36.55 months in males vs 46.52 months in females (HR 1.77, 95% CI 0.84 - 3.74, p=0.12). Conclusions: In this study, survival appears to be comparable between males and females with breast cancer across the spectrum of HER2 expression when both are treated with ADCs, although the survival in the HER2-positive cohort appears numerically lower in males, consistent with data on HER2-positive MaBC. An important limitation is the small sample size of the male breast cancer cohorts, and the lack of a categorization of HER2 in HR+ vs HR-, for the small MaBC sample size. However, to our knowledge this is the first analysis evaluating outcomes of men treated with ADCs across the spectrum of HER2 expression. Citation Format: D. Trapani, S. Deshmukh, S. Wu, J. Xiu, N. Lin, G. Curigliano, P. Spanheimer, S. Gandhi, S. Chumsri, S. Graff, M. Lustberg, G. Sledge Jr, S. Tolaney, J. Leone. Comparative efficacy of antibody drug conjugates (ADCs) in male versus female breast cancer across the spectrum of HER2 expression [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-01-13.

Abstract Introduction: Endocrine therapy (ET) is central to treating hormone receptor-positive breast cancer (BC), but its side effects impact adherence and quality of life, especially in patients with metabolic dysfunction. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer cardiometabolic benefits, potentially improving inflammation, glycemic control, and physical well-being. However, data on SGLT-2 use in BC patients is scarce. This study is the first to evaluate the real-world effects of SGLT-2 inhibitors on all-cause mortality and ET tolerability in BC patients. Methodology: We conducted a real-world analysis using the TrinetX database, which includes data from 184 million patients in 156 healthcare organizations, to identify BC patients on ET (letrozole, anastrozole, exemestane, tamoxifen) who received SGLT-2 inhibitors vs. those who did not. Patients were grouped by age (≤50 and ≥51 years as a surrogate for menopausal status. Primary outcome: all-cause mortality from the start of the index event, defined as the first day meeting BC diagnosis and ET use, with or without SGLT-2. Secondary endpoint: ET tolerability. Propensity score matching completed by TriNetX adjusted for confounders. Multivariate analysis yielded odds ratios and risk differences with 95% CI. Results: Among 1,136 BC patients ≤50 years, 568 were assigned to each group (SGLT-2 vs non-SGLT-2). For patients ≥51 years (n=28,600), each group included 14,300. Demographics across cohorts were comparable. No mortality benefit was seen in premenopausal patients. In postmenopausal women, SGLT-2 use reduced all-cause mortality—647/13,676 events (SGLT-2) vs 953/13,517 (non-SGLT-2) [OR: 0.655 (0.591-0.726)]. In premenopausal patients, SGLT-2 reduced endometrial cancer risk [RD: -0.018 (-0.029, -0.007)] but increased diarrhea risk [OR: 2.305 (1.078, 4.930)]. No significant differences were found in hot flashes, PE, DVT, depression, osteoporosis, joint pain, fatigue, nausea/vomiting, abdominal pain, or dizziness. Among postmenopausal patients, SGLT-2 reduced PE [OR: 0.757 (0.605-0.948)] and osteoporosis [OR: 0.877 (0.784-0.981)], but increased risks of depression [OR: 1.153 (1.007-1.319)], nausea/vomiting [OR: 1.120 (1.001-1.253)], diarrhea [OR: 1.193 (1.058-1.345)], and dizziness [OR: 1.234 (1.103-1.380)]. No significant differences were found for hot flashes, DVT, EC, joint pain, fatigue, or abdominal pain. Conclusion: This analysis reveals novel evidence supporting the cardiometabolic potential of SGLT-2 inhibitors in hormone receptor-positive BC, particularly postmenopausal populations. These agents were linked to lower all-cause mortality and improved tolerance of specific ET-related effects. However, certain adverse risks require caution. Future prospective studies are essential to validate their role and safety in oncologic care. Citation Format: C. Jones, J. Michalek, E. Obomanu, Y. Arya, A. Syal, S. Haddad, V. Kaklamani, S. Shaikh. Evaluating all-cause mortality and endocrine therapy tolerability with sodium glucose cotransporter-2 inhibitors in hormone receptor-positive breast cancer: A real-world analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-05-28.

Abstract Introduction: Endocrine therapy (ET) improves survival in hormone receptor-positive breast cancer (BC) but has side effects that may affect compliance. GLP-1 receptor agonists (GLP-1 RA), used for diabetes and obesity, possess anti-inflammatory properties and may reduce cancer incidence. Their impact on all-cause mortality and ET tolerability remains underexplored. This real-world analysis is the first of its kind to examine the effects of GLP-1 RA on these outcomes. Methods: We used de-identified data across 130 million patients and 108 health systems from the TriNetX database to identify obese women (BMI ≥30) with BC receiving ET. Patients were grouped by GLP-1 RA exposure into age cohorts (≤50 and ≥51 years, as a surrogate for menopause). The primary endpoint was all-cause mortality; the secondary endpoint was ET tolerability. The index event was the first day meeting all criteria: BC and obesity diagnoses, and initiation of ET ± GLP-1 RA. Patients with outcomes before the study window were excluded. Propensity score matching performed by TriNetX adjusted for demographics, diabetes, comorbidities, cancer stage, and prior chemotherapy. Multivariate logistic regression assessed associations (risk ratios [RR], 95% CIs). Results: After matching, 2,574 patients were assigned to the age ≤50 group: Cohort A (GLP-1 RA exposure, n=1,287) and Cohort B (non-exposure, n=1,287). 13,012 patients were in the age ≥51 group: Cohort C (GLP-1 RA exposure, n=6,506) and Cohort D (non-exposure, n=6,506). In the ≤50 group, the mean age at index event was 42.3 ± 5.2, 99.5% female, 68.9% White, 16.9% Black, and a mean BMI of 37 in Cohort A, with similar demographics and BMI in Cohort B. In the ≥51 group, there was a mean age at index event of 61.8 ± 7.7, 99% female, 71.7% White, 17.4% Black, and a mean BMI of 37 in Cohort C with similar demographics and BMI in Cohort D. GLP-1 RA use significantly reduced all-cause mortality in all cohorts. In the age ≤50 group, there were 29/1,242 events in Cohort A and 71/1,258 in Cohort B [RR 0.414 (0.271-0.633)]. In the age ≥51 group, there were 240/6,287 events in Cohort C and 400/6,285 in Cohort D [RR 0.600 (0.513-0.701)]. GLP-1 RA use worsened ET side effects. In the age ≤50 group, GLP-1RA increased the risk of hot flashes [RR: 1.473 (1.235-1.756)], venous thromboembolism (VTE) [RR: 1.439 (1.090-1.902)], nausea/vomiting [RR: 1.460 (1.242-1.717)], abdominal pain [RR: 1.353 (1.184-1.545)], diarrhea [RR: 1.319 (1.096-1.589)], joint pain [RR: 1.382 (1.243-1.536)], and depression [RR:1.634 (1.382-1.932)]. No significant risk was found in endometrial cancer (EC) and osteoporosis. In the age ≥ 51 group, GLP-1 RA use increased hot flashes [RR: 0.1.239 (1.091-1.407)], [RR:0.591 (0.482-0.724)], nausea/vomiting [RR: 1.429 (1.324-1.542)], abdominal pain [RR: 1.310 (1.227—1.399)], diarrhea [RR: 1.446 (1.328-1.575)], joint pain [RR: 1.334 (1.270-1.400)], osteoporosis [RR: 1.110 (1.026-1.201)], and depression [RR: 1.536 (1.413-1.670)]. No significant differences were noted in VTE and EC risk. Conclusion: This real-world analysis demonstrates that GLP-1RA use is associated with a significant reduction in all-cause mortality among obese BC patients undergoing ET. However, GLP-1 RA exposure appears to exacerbate several ET-related adverse effects. Future prospective studies are needed to determine these associations as they may warrant clinical consideration. Citation Format: C. Jones, J. Michalek, E. Obomanu, Y. Arya, A. Syal, S. Haddad, V. Kaklamani, S. Shaikh. Real-world Analysis on the Impact of GLP-1 Receptor Agonists on All-cause Mortality and Endocrine Therapy-Tolerability in Obese Breast Cancer Patients [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD8-06.

ABSTRACT Background and Aims Cellular senescence is a hallmark of several liver diseases, including primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Senescent cholangiocytes exhibit a senescence‐associated secretory phenotype (SASP), characterized by profibroinflammatory mediator release. Current cost‐effective biomarkers predicting disease progression, particularly for PSC, are limited and often lack mechanistic relevance. We sought to define a plasma biomarker signature for PSC and PBC. Methods Plasma from early‐ and late‐stage PSC and PBC, alcoholic liver disease (ALD), inflammatory bowel disease (IBD) patients, and healthy controls was analyzed. Seventy‐one analytes were quantified using Luminex Multiplex Immunoassay or enzyme‐linked immunosorbent assay (ELISA). Principal component analysis (PCA) identified key patterns. Findings from the PSC cohort were then applied to additional cohorts. Results Second principal component (PC2) (17 analytes, 17.1% variability) best separated PSC from controls. ANOVA showed significant differences in PC2 between early PSC vs. controls ( p = 0.0001), late PSC vs. controls ( p < 0.0001), and early vs. late PSC ( p < 0.0001). PC2 analytes also distinguished early PBC vs. controls ( p < 0.0332), late PBC ( p < 0.0001), and ALD ( p < 0.0001), and early vs. late PBC ( p < 0.0001), but not IBD vs. controls ( p = 0.119). Logistic regression using PC2 demonstrated strong discrimination of early‐ and late‐stage PSC (AUC = 0.86) and control vs. early‐stage PSC (AUC = 0.83). Conclusion This is the first study to define a plasma SASP biomarker signature associated with cholestatic liver disease. These analytes track disease stage and represent both mechanistic indicators and potential clinical trial endpoints.

Abstract Objective To test the effectiveness of a surgical web‐based decision aid (DA) in improving knowledge. Summary of Background Data DAs support decision making by providing information about the options. Methods A stepped wedge trial was conducted in 10 National Cancer Institute Community Oncology Research Program clinics (Alliance for Clinical Trials in Oncology). Clinics were randomized to time of transition from usual care (UC) to delivery of a web‐based DA. Patients with stage 0 through 3 breast cancer being considered for surgery were enrolled. Knowledge (primary outcome) was measured using the Breast Cancer Surgery Decision Quality Instrument and patients were asked, “How informed do you feel?” Intervention effects were tested with linear mixed‐effects models, accounting for surgeon and clinic‐level clustering, time, and enrollment after COVID. Additional models controlled for demographics. Results A total of 44% of DA arm patients reviewed the DA and 58% in UC arm reported reviewing “any information.” Being in the DA arm versus UC was not associated with knowledge. However, “review of information” was associated with higher knowledge. In addition, non‐White race and lower education were associated with lower knowledge. The DA arm was associated with higher perceptions of feeling informed (parameter estimate 1.36; 95% CI, 0.18–2.55; p = .02); this persisted even when controlling for review of information or demographics. Conclusion Improved knowledge was not demonstrate with a web‐based DA versus UC. Interestingly, the DA was associated with a higher likelihood of feeling informed. Future research will explore the discrepancy between patients feeling informed but having low knowledge, especially for disadvantaged patients. Trial Registration ClinicalTrials.gov Identifier: NCT0376600

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vaginal Cancer outline the recommended diagnostic workup, staging considerations, and treatment options for this rare malignancy. Because vaginal cancer is uncommon and shares many biologic and clinical characteristics with cervical cancer, several management recommendations, particularly systemic therapy, are extrapolated from evidence and practices established for cervical cancer. This guideline excerpt summarizes key components of management, including diagnostic evaluation and workup, principles of staging, pathology considerations, radiation therapy principles, and primary treatment recommendations for both early-stage and advanced disease. It also details approaches to manage relapses, including locoregional recurrence and distant metastases, and provides an in-depth overview of systemic therapy recommendations for vaginal cancer.

ABSTRACT Background Sentinel lymph node (SLN) biopsy is a critical staging tool in skin and soft tissue cancers. Although technetium lymphoscintigraphy is the most common adjunct, indocyanine green (ICG) demonstrates a promising alternative in pediatric, adolescent, and young adult (AYA) skin and soft tissue cancers. Methods and Objectives Evaluate the safety and efficacy of ICG in SLN biopsy (SLNB) in diverse pediatric and AYA solid cancers in a multi‐institutional environment. This is a prospective, observational study conducted at 13 member institutions in the Pediatric Surgical Oncology Research Collaborative between 2019 and 2023. Eligible patients underwent SLNB for primary or recurrent solid skin and soft tissue tumors. Peritumoral ICG was administered intraoperatively. Outcomes included SLN detection rates, histopathology of excised specimens, and surgeon‐reported assessment of utility. Safety was assessed through adverse event reporting. Results Forty SLNB procedures yielded 84 specimens: 13 melanoma (32.5%), 12 squamous cell carcinoma (30%), 11 non‐rhabdomyosarcoma soft tissue sarcoma (27.5%), two rhabdomyosarcoma (5%), one Ewing sarcoma (2.5%), and one malignant peripheral nerve sheath tumor (2.5%). Histologic evaluation identified 81 lymph nodes, 75 benign (89.3%) and six malignant (7.1%); three specimens were adipose tissue (3.6%). Of 81 lymph nodes, 76% were ICG‐positive. ICG had a sensitivity of 79.5%, a specificity of 33%, and a positive predictive value of 96%. All malignant nodes were ICG‐avid. There were no adverse reactions to ICG at 30 days. Conclusions ICG is a safe and effective adjunct for SLNB in pediatric and AYA soft tissue and skin malignancies.

Abstract Diffuse hemispheric glioma, H3 G34‐mutant (DHG‐H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high‐resolution copy number profiling of a series of 60 DHG‐H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187‐gene mutation and fusion targeted neuro‐oncology next‐generation sequencing panel ( n = 60) and Oncoscan chromosomal microarray ( n = 26) by a single laboratory (2018–2022). A subset of cases had immunohistochemical results for OLIG2 ( n = 42), p53 ( n = 48), and ATRX ( n = 46), and methylation array data ( n = 8). Median age at testing was 21 years (range, 12–50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3‐3A G34 mutations included G34R ( n = 56; 94%), G34V ( n = 3), and a non‐canonical G34E ( n = 1). Concurrent mutations most often involved TP53 ( n = 55; 92%), ATRX ( n = 50; 83%), and PDGFRA ( n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy‐neutral loss of heterozygosity (cnLOH) encompassing TP53 . This copy number profile was reminiscent of that seen in Grade 4 IDH‐mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high‐resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG‐H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH—a copy number abnormality that has been largely unrecognized—for this new 2021 World Health Organization central nervous system tumor type.