Citations

Abstract Background Radiologist burnout affects approximately 40% of US radiologists. Large language models (LLMs) may improve workflow efficiency, but real-world implementation data are limited. Objective To evaluate LLM-assisted workflow impact on radiologist efficiency using the Unified Theory of Acceptance and Use of Technology (UTAUT) framework. Design, Setting, and Participants: HIPAA-compliant, IRB-approved retrospective cohort study of a single fellowship-trained abdominal radiologist at Mayo Clinic Arizona. We compared baseline (January–April 2024) and post-implementation (December 2025–February 2026) periods. A custom generative pre-trained transformer was developed using ChatGPT Enterprise with disease-specific templates. Main Outcome Measures: Inter-study interval time (proxy for interpretation time) compared using Wilcoxon rank-sum tests with Bonferroni correction (α = 0.0125). UTAUT constructs assessed: performance expectancy (efficiency), effort expectancy (training burden), facilitating conditions (infrastructure), and behavioral intention (satisfaction). Results We analyzed 609 studies (495 CT, 114 MRI). LLM assistance significantly reduced inter-study intervals for outpatient CT with contrast (23.0 vs 13.0 minutes; difference 10 minutes; p = 0.0021) and without contrast (18.5 vs 7.0 minutes; difference 11.5 minutes; p = 0.0017). No improvement occurred for MRI with contrast (14.0 vs 16.0 minutes; p = 0.2808) or without contrast (14.0 vs 7.0 minutes; p = 0.0889). The radiologist reported improved work-life balance for CT but neutral satisfaction for complex MRI templates. Training required 10 hours over 5 days. Conclusions LLM-assisted workflow reduced interpretation times for standardized CT studies but not heterogeneous MRI examinations, supporting UTAUT's emphasis on performance expectancy and task–technology fit as adoption drivers. Efficiency gains may reduce documentation burden when tools align with task complexity.

Abstract Neuroblastoma (NB) accounts for approximately 10% of pediatric cancer-related deaths. High-risk NB is often metastatic at diagnosis with a poor 5-year survival rate (<50%) despite intensive multimodal therapy. GD2, a disialoganglioside glycolipid expressed in nearly all NBs, is a well-validated immunotherapy target. Although GD2-CAR-T cells have been clinically evaluated, their efficacy remains limited due to poor tumor infiltration and the immunosuppressive tumor microenvironment (TME), underscoring the need for alternative immune-based approaches. Given the inherent capacity of macrophages to infiltrate solid tumors, phagocytose cancer cells, and modulate the TME, we engineered the GD2-CAR macrophage (GD2-CAR-M) as a novel therapeutic platform for NB. GD2-specific CAR constructs containing the Hu3F8 single-chain variable fragment (scFv) were designed, validated, and introduced into multiple human and murine monocyte/macrophage cell lines via lentiviral transduction. Fluorescence microscopy and flow cytometry demonstrated a significant enhancement in the phagocytosis of GD2-high NB cells and the phagocytic efficiency correlating positively with GD2 expression levels, suggesting antigen-specific phagocytosis by GD2-CAR-M. Our further in vivo studies using an immunocompetent MYCN-driven NB non-genetically engineered mouse model (MYCN-NGEMM) showed that treatment with GD2-CAR-M markedly reduced tumor burden and prolonged survival compared with controls. Notably, mice bearing GD2-high-tumors exhibited significantly improved survival, including one complete remission among ten treated animals. Histological analyses revealed increased connective tissue deposition and decreased tumor cell density, suggesting TME remodeling. Single-cell RNA sequencing and immunohistochemistry further demonstrated enhanced infiltration of macrophages, neutrophils, and T cells, indicating a shift from a “cold” to a “hot” immune TME following GD2-CAR-M treatment. Consistent antitumor effects were also observed in our dbh-MYCN transgenic zebrafish with spontaneous development of NB following GD2-CAR-M administration. Taken together, GD2-CAR-M exhibits potent antigen-specific antitumor activity and promotes favorable TME remodeling in NB models. These findings highlight GD2-CAR-M as a promising translational immunotherapy strategy for high-risk NB. Citation Format: Shizhen (Jane) Zhu, Ke-En Tan, Kok Siong Yeo, Cheng Zhang, Caleb T. Baker, Alexis M. Sosic, Eddie Lim . Yat Yuen, Choong Yong Ung, Stephanie F. Polites, Yi Lin, William A. Weiss, Hu Li. Harnessing GD2-CAR macrophages to target high-risk neuroblastoma [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B005.

Abstract Background: Pathogenic variants (PVs) in PALB2 are known to confer high-to-moderate risk for breast cancer. However, breast cancer risk estimates for PALB2 PVs for different populations are not well defined and associations with other cancers are still unclear. Using data from a large clinical genetic testing cohort we have established cancer-specific risks associated with PALB2 PVs. Methods: We analyzed the associations of PALB2 PVs with breast, ovarian, prostate, and pancreatic cancers in individuals tested at Ambry Genetics. Cancer-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated by comparing PV carrier frequencies in cancer cases to population controls from AllofUs matched by sex and adjusting for age and genetic ancestry and gnomAD v4.1 matched by sex and adjusting for ancestry. Two-sided p-values are reported. Results: Of 1,119,667 individuals tested, 357,109 had breast cancer, 37,468 ovarian cancer, 22,112 pancreatic cancer and 32,738 prostate cancer. PALB2 PVs were observed in 0.79% of breast cancer cases, 0.30% of ovarian cancer cases, 0.78% of pancreatic cancer cases, and 0.47% of prostate cancer cases, with mean age at diagnosis of 54.2 years for breast, 60.1 years for ovarian, 62.8 years for pancreatic and 66.7 years for prostate. Whereas only 2.4% of breast cancer cases with PVs had a personal history of ovarian or pancreatic, 13.4% of ovarian cases and 33.3% of pancreatic cases had a history of breast cancer. Analysis of PV types found that frameshift PVs accounted for 50% of PVs, nonsense for 30%, canonical splice sites for 5% and copy number variants for 8-9% of cases in all cancer types. Among 10,077 individuals with multiple primary cancers, PALB2 PVs were detected in 0.65% of cases, with the highest frequencies observed in combinations of breast and pancreatic cancer (1.87%) and pancreatic and prostate cancer (0.79%). To refine estimates of risks for breast cancer, association studies were performed separately with GnomAD v4.1 and AllofUs controls. PALB2 PVs were consistently associated with high risks of breast cancer with lower 95%CI above 4 (GnomADv.4.1 OR=6.85, 95%CI=5.94-7.96, p=3.05x10-145; AllofUs OR=5.65, 95%CI=4.83-6.65, p=2.54x10-155). This was significantly different and increased over breast cancer risk estimates from the CARRIERS and BRIDGES population-based studies (OR=4.67, 95%CI=3.73-5.85, p=3.95x10-27) and the UK Biobank population-based study (OR=3.87, 95%CI=3.09-4.83, p=4.62x10-27). Similarly, high risks of pancreatic cancer were confirmed (GnomADv.4.1 OR=5.14, 95%CI=4.15-6.32, p=3.38x10-52; AllofUs OR=5.59, 95%CI=3.92-7.85, p=2.78x10-18). Importantly, associations between PALB2 PVs and moderate risks of both ovarian cancer (GnomADv.4.1 OR=2.68, 95%CI=2.11-3.40, p=5.94x10-16; AllofUs OR=2.15, 95%CI=1.62-2.85, p=2.97x10-7) and prostate cancer (enriched for aggressive disease) (GnomADv.4.1 OR=2.45, 95%CI=2.01-2.97, p=1.52x10-19) were observed. Conclusions: This large-scale study provides robust estimates of PALB2 PV prevalence and associated cancer risks in a U.S. clinical genetic testing population. The findings provide refined risk estimates for breast and pancreatic cancers but also establish that PALB2 PVs confer increased risk for ovarian and prostate cancers. These results help clarify ongoing uncertainty, particularly for ovarian and prostate cancer, and highlight the importance of PALB2 in broader hereditary cancer risk assessment and multigene panel testing. Citation Format: Y. Y. Tan, C. Hu, H. Huang, N. J. Boddicker, W. Chen, M. Kaul, T. J. Rao, A. N. Monteiro, T. Pesaran, R. Karam, S. M. Domchek, S. Yadav, M. E. Richardson, F. J. Couch. Cancer-specific risks associated with germline PALB2 pathogenic variants from a large clinical genetic testing cohort [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 RF5-01.

Abstract Background: Clinical benefit with PARP inhibitors (PARPi) has been demonstrated in patients (pts) with HER2-negative (HER2−) metastatic breast cancer (mBC) and germline or tumor mutations in BRCA1 or BRCA2 (g/tBRCAm). Understanding real-world PARPi use and its impact on clinical outcomes may improve the treatment of pts with BRCAm HER2− mBC. Methods: This retrospective study captured data from US pts aged ≥18 years diagnosed with HER2− mBC from January 12, 2018, to March 31, 2024, in the deidentified electronic health record-derived Flatiron Health Research Database. PARPi use and outcomes were described by tumor subtype (hormone receptor-positive [HR+]/HER2− mBC or triple-negative mBC [mTNBC]), g/tBRCA status, disease stage at diagnosis (de novo or recurrent), line of therapy (LoT), and prior treatments. Real-world overall survival (rwOS) by PARPi use was estimated using the Kaplan-Meier method. Results: Of 848 pts with gBRCAm mBC, 352 (42%) received PARPi (Table), with consistent PARPi initiation rates of 42%-48% from 2018-2022. PARPi was initiated in 223/566 (39%) pts with gBRCAm HR+/HER2− mBC, 125/275 (45%) pts with gBRCAm mTNBC, and 4/7 (57%) pts with unknown tumor subtype. Among 304 pts with gBRCAm who had received ≥3 LoT by the end of follow-up, 93/225 (41%) pts with HR+/HER2− mBC and 18/78 (23%) pts with mTNBC received PARPi in the third LoT or later (3L+); 50/103 (49%) pts with de novo mBC and 54/184 (29%) pts with recurrent mBC received PARPi in 3L+. PARPi was also initiated in 13/231 (6%) pts with gBRCA variants of uncertain significance (VUS) and 176/662 (27%) pts with tBRCAm and non-gBRCAm/unknown gBRCAm status. Among 539/1573 (34%) pts with g/tBRCAm who received PARPi, 167 had not received prior chemotherapy in any setting; 40 of these pts (39 with HR+/HER2− mBC and 1 with mTNBC) received PARPi in 3L+. With a median follow-up of 17.0 months from initiation of 1L therapy, median rwOS was numerically longer among pts with gBRCAm who received PARPi versus pts who did not (HR+/HER2− mBC: 39.3 months [95% CI: 35.5-46.8], n=208 vs 24.2 months [95% CI: 21.4-33.0], n=259; mTNBC: 27.6 months [95% CI: 18.0-41.7], n=119 vs 16.9 months [95% CI: 14.5-31.9], n=81). Among pts with tBRCAm who were negative for gBRCAm, median rwOS was numerically longer in pts who received PARPi versus pts who did not. Conclusions: Pts with HR+/HER2− mBC had slightly lower rates of PARPi use, and received PARPi later, than pts with mTNBC. Although improved efficacy with PARPi use in earlier LoT has been demonstrated, many pts first received PARPi in 3L+, suggesting unmet potential to ensure timely testing and optimize treatment. Although immortal time bias and other factors should be considered, rwOS was numerically longer in pts with BRCAm HR+/HER2− mBC and with BRCAm mTNBC who initiated PARPi versus pts who did not. Further research into PARPi use and survival trends in pts with BRCAm and/or other actionable biomarkers in mBC is needed. Citation Format: S. Yadav, Q. Li, Z. Tan, K. E. Mishkin, J. F. Hayes, X. Xu, F. J. Couch. Real-world PARP inhibitor use and clinical outcomes in US patients with HER2-negative metastatic breast cancer [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 PS2-02-08.

Abstract Background: International guidelines recommend that all patients (pts) with metastatic breast cancer (mBC) are offered testing for germline BRCA1/BRCA2 mutations (gBRCAm) and other biomarkers to aid treatment decisions. This retrospective study describes real-world testing patterns for germline/tumor (g/t)BRCAm and other biomarkers among US pts with HER2-negative [HER2−] mBC. Methods: Data were captured from US pts aged ≥18 years with HER2− mBC from January 12, 2018, to March 31, 2024, in the deidentified, electronic health record-derived Flatiron Health Research Database. Demographics, clinical characteristics, and testing patterns for g/tBRCAm and other actionable biomarkers were examined. Testing rates, test timing, and biomarker status were described across subgroups defined by demographics (including age, race, and ethnicity), tumor subtype (hormone receptor-positive [HR+]/HER2− mBC or triple-negative mBC [mTNBC]), and disease stage at mBC diagnosis (recurrent/de novo). Results: The BRCA testing rate among pts with mBC increased from 2018 (48%) to 2023 (62%); the overall testing rate was 19,820/34,379 (58%): 5880 pts (17%) received a gBRCA test only, 7285 (21%) received a tBRCA test only, and 6655 (19%) received both gBRCA and tBRCA tests. BRCA testing rates were numerically lower in pts with HR+/HER2− mBC (56%) versus mTNBC (68%), and in pts aged >65 years (HR+/HER2− mBC, 48%; mTNBC, 62%) versus ≤65 years (HR+/HER2− mBC, 64%; mTNBC, 74%; Table). The proportion of pts who received a test before initiation of first-line (1L) therapy was lower among pts with HR+/HER2− mBC than with mTNBC (recurrent, 60% vs 81%; de novo, 37% vs 57%). Among tested pts, 1067/15,168 (7%) with HR+/HER2− mBC and 494/4539 (11%) with mTNBC had a positive result for g/tBRCAm; 365/1067 (34%) pts with g/tBRCAm HR+/HER2− mBC and 138/494 (28%) pts with g/tBRCAm mTNBC were aged >65 years. Among 528 pts with gBRCAm HR+/HER2− mBC, co-mutations in PIK3CA, ESR1, PTEN, and AKT1 were identified in 48 (9%), 38 (7%), 20 (4%), and 3 (<1%) pts, respectively. Among pts diagnosed with gBRCAm HR+/HER2− mBC in 2020-2023 (median follow-up: 15 months), 175/371 (47%) did not receive a test for PIK3CA mutations at any time, and 48/97 (49%) pts diagnosed in 2023 (median follow-up: 6 months) did not receive a test for ESR1 mutations. In 2021-2023, 72/256 (28%) pts with g/tBRCAm mTNBC had tumors with programmed cell death-ligand 1 (PD-L1) combined positive score ≥10; 88 (34%) pts did not receive a PD-L1 test. Conclusions: Although BRCA testing rates increased from 2018 to 2023, 38% of US pts diagnosed with HER2− mBC in 2023 did not receive any BRCA test. BRCA testing rates were low among pts with HR+/HER2− mBC and/or aged >65 years, suggesting that many g/tBRCAm remained undetected. Wider and timelier testing for germline and tumor biomarkers is warranted to identify pts who are eligible for targeted therapies. Citation Format: S. Yadav, Q. Li, Z. Tan, K. E. Mishkin, J. F. Hayes, X. Xu, F. J. Couch. Real-world biomarker testing patterns in US patients with HER2-negative metastatic breast cancer [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 PD4-08.

Abstract Background: BRCA2 variants with partially aberrant RNA splicing have been associated with a relatively lower breast cancer risk (reduced penetrance) relative to canonical pathogenic variants. However, the existence of partial loss of function (hypomorphic) missense variants, conferring reduced penetrance, is less certain. Identification and assessment of the clinical relevance of such reduced penetrance pathogenic variants (RPPVs) is needed to provide accurate risk estimates. Methods: Comprehensive functional characterization of hypomorphic missense variants (n=70) in the BRCA2 DNA-binding domain, initially identified through homology-directed DNA repair (HDR) assays, was conducted through multiple independent functional assays, including HDR, CRISPR/Cas9-based endogenous targeting, RAD51 foci formation assay, and Poly(ADP-ribose) polymerase (PARP) inhibitor response assay. Risk estimates were obtained using two large datasets from patients referred for hereditary cancer testing. A ClinGen/ACMG/AMP model was used for clinical classification. Results: The variants consistently demonstrated hypomorphic HDR activity and endogenous survival in HAP1 targeted cells, decreased RAD51 foci formation, and increased sensitivity to PARP inhibitors. These variants were associated with a moderate increase in breast cancer risk, as shown in two independent studies: one using multivariable logistic analysis adjusted for age, ancestry and family history (OR=2.41, 95%CI=1.51-3.85) and another comparing frequencies of variants in breast cancer cases to public reference controls adjusted for ancestry (OR=2.09, 95% CI=1.16-4.08). The mean age of breast cancer diagnosis for carriers of hypomorphic variants was 57 years, which was significantly older than the mean age of diagnosis of 51 years for carriers of protein truncating variants. Functional data were combined with other evidence sources in a ClinGen/ACMG/AMP model to classify 14 variants as “likely pathogenic”. Conclusions: We identified partially functional, hypomorphic missense variants associated with reduced penetrance for breast cancer. Cancer risk management guidelines for this new category of variants should be revisited given that the associated breast cancer risks warrant high risk screening but do not meet the threshold at which risk reducing mastectomy is offered. This study supports a shift in paradigm to considering variant-based risks on a continuum, with implications for risk-appropriate cancer risk management. Citation Format: H. Huang, C. Hu, J. Na, M. Kucera, T. Simmons, E. Mundt, C. C. Young, Z. Heidari, P. C. Lyra, Y. Y. Tan, K. L. Nathanson, T. Pal, R. Karam, T. Pesaran, S. Yadav, S. M. Domchek, A. N. Monteiro, E. Hughes, N. Boddicker, W. Chen, M. E. Richardson, F. J. Couch. Partially functional (hypomorphic) missense variants in BRCA2 are reduced penetrance pathogenic variants [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 PD4-05.

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

Convergent framework for future POC cancer diagnostics aligning clinical needs (why), enabling technologies (how), and translational bridges. It integrates lab-on-chip biosensing and analytics for decentralized, early, longitudinal care.

Background: Upfront resectable pancreatic ductal adenocarcinoma (PDAC) is defined by the NCCN as disease with ≤180° portomesenteric vein (PMV) abutment. However, the clinical significance of PMV abutment in this cohort remains unexplored, and we sought to investigate its impact. Methods: This multi-institutional study included patients who underwent pancreatoduodenectomy (PD) for upfront resectable PDAC from 2002 to 2023. Patients with PDAC with ≤180° PMV abutment were compared with those without. Overall survival (OS) was compared and stratified based on whether patients underwent upfront surgery or neoadjuvant therapy (NAT). Results: Among 1,446 patients included, 521 (36.0%) had PMV abutment. Median OS for patients with PMV abutment was 28.8 months compared with 31.2 months for those without ( P =.17). In a stratified analysis of patients who underwent upfront surgery, patients with PMV abutment had worse OS (19.2 vs 27.6 months; P <.05) and lower R0 resection rates (63.1% vs 87.2%; P <.05) compared with those without. However, in patients who underwent NAT, this difference in R0 resection rate was not observed (91.4% vs 94.0%, respectively; P =.27). Furthermore, there was no significant difference in median OS with NAT (42.5 vs 51.6 months, respectively; P =.48). Conclusions: In this largest cohort to date of patients with upfront resectable PDAC, PMV abutment was associated with worse OS compared with no PMV abutment when an upfront resection strategy was used. The use of NAT in patients with PMV abutment mitigated this survival difference with increased R0 resection rates. These findings suggest that patients with upfront resectable PDAC with PMV abutment benefit from a NAT approach for optimal survival outcomes, and that the current criteria guidelines need to be redefined.