Citations

e15024 Background: Anetumab ravtansine (AR) is an antibody-drug conjugate (ADC) containing the microtubule inhibitor DM4. ADC drugs have high interpatient variability in pharmacokinetics and pharmacodynamics (PK/PD), which raises concerns whether current dosing based on body weight (mg/kg) is optimal. Thus, we evaluated the effects of patient characteristics, including novel biomarkers of the innate immune system (IIS), on the PK/PD of AR. Methods: Studies were performed in patients in three clinical trials of different cancers with AR as part of treatment: 1) platinum-resistant or refractory high-grade ovarian cancer treated with AR at 2.2mg/kg IV weekly plus bevacizumab(N = 19); 2) pleural mesothelioma treated with AR at 6.5 mg/kg IV every 3 weeks plus pembrolizumab(N = 28); and 3) mesothelin-positive advanced pancreatic adenocarcinoma treated with AR at 5.5-6.5 mg/kg IV every 3 weeks plus nivolumab (and ipilimumab or gemcitabine, N = 27). Intensive plasma PK sampling was performed after the first dose to calculate clearance (CL), volume of distribution (Vd), and area-under-the-plasma-concentration-time curve (AUC 0-inf ). The relationship between biomarkers of FcɣRs (CD64, CD32, CD16) on IIS blood cells, total body weight (TBW), body surface area (BSA), lean body mass (LBM), and sex with PK parameters and clinical outcomes were evaluated by pearson correlation, t-test and multivariate regression analysis. Population PK (popPK) methods further evaluated patient covariates and variability in PK. Results: Patients with higher IIS FcγR CD64 and/or higher TBW or higher BSA had higher AR ADC CL (p < 0.05). AR ADC CL was lower in females (0.030 ± 0.007 L/h) versus males (0.042 ± 0.006 L/h) (p < 0.05). Patients with stable disease and partial response had higher AR ADC AUC 0-inf versus patients with progressive disease AR ADC disposition was described by linear CL with two pathways for the release of the payload DM4, hydrolysis and the IIS. A time-varying drug-to-antibody ratio predicted the release of the DM4 payload. In the PopPK model, LBM and albumin were associated with CL of the AR ADC, LBM and IIS FcγR CD64 were associated with the Vd of the AR ADC, and LBM and age were associated with the CL of the released DM4. Conclusions: These results suggest that TBW-based dosing of AR ADC is not optimal, whereas precision dosing of antibodies and ADCs based on the use of novel metrics of body habitus, IIS biomarkers, and sex may be more appropriate to reduce PK variability and improve response.

e16457 Background: Patients with inoperable stage II-III pancreatic cancer commonly undergo sequential stereotactic body radiation therapy (SBRT) and chemotherapy. However, there is variability in clinical outcomes, and the predictors of high-risk patients with rapid tumor progression (within 3 months) and poor overall survival (OS) despite treatment are not well characterized. We developed a radiomic (imaging-derived features) signature (RS) that predicts rapid progression. We then investigated clinical characteristics, including pathologic features and treatments received, and RS in a combined analysis to develop and validate the highest-performing model to predict OS from the time of SBRT initiation. We identified the most predictive feature from the combined model that best predicts OS. Methods: In our retrospective study, we examined a cohort of 124 stage II-III pancreatic cancer patients who underwent sequential SBRT and systemic chemotherapy and had pre-treatment pancreatic protocol computed tomography (CT) imaging. We examined 10 clinical features and extracted 900 radiomic features from each segmented tumor per patient using PyRadiomics. Dividing our cohort into training and test sets (60:40), we built a prediction model for rapid tumor progression using radiomic data on the training set (n = 74), applying a LASSO-based algorithm for feature selection and 5-fold cross-validation for parameter optimization. We validated the model performance on the held-out test set (n = 50) and generated the RS for predicting rapid progression. We examined the performance of clinical features and RS in predicting OS in univariate and multivariate Cox regression models. Results: Analysis on our cohort (57 men, 67 women; mean age 67 ± 11 years) generated a 43-feature RS that predicted rapid tumor progression (AUC 0.83, 95% CI: 0.70–0.94) in the test set. High RS was a significant predictor of mortality with hazard ratio (HR) 2.22 (95% CI: 1.32–3.73, p = 0.003) within the first year and 2.85 (95% CI: 1.35–6.03, p = 0.006) thereafter. Non-intensive chemotherapy increased only early mortality risk (HR 1.95, 95% CI: 1.08–3.53, p = 0.03), while older age was significant in later years (HR 1.80, 95% CI: 1.02–3.15, p = 0.04). Conclusions: CT-derived RS accurately predicted rapid tumor progression in stage II-III pancreatic cancer patients undergoing SBRT sequentially with chemotherapy. High RS was the strongest prognostic indicator for increased mortality risk, suggesting its utility for guiding treatment or selection for clinical trials.

BACKGROUND AND IMPORTANCE: Basilar artery fenestration aneurysms (BAFAs) present significant clinical challenges because of their high rupture risk and complex anatomy. Comprehensive management strategies are required, including thorough vascular assessment and post-treatment surveillance. Integration of complementary analyses such as computational fluid dynamics (CFD) holds promise in facilitating preoperative planning for these intricate lesions. CLINICAL PRESENTATION: A 60-year-old female was diagnosed with a BAFA during evaluation for headaches. Digital subtraction angiography revealed the aneurysm projecting posteriorly with a neck predominantly based on the right limb of the fenestration. After initial treatment with a pipeline embolization device, the aneurysm remained patent, requiring further treatment. A secondary approach with stent-assisted loose-packing coil embolization was then performed, resulting in complete occlusion of the aneurysm. Analysis of pretreatment 3-dimensional rotational angiogram images with CFD provided critical hemodynamic insights. It identified that 38.89% of the aneurysm area was exposed to low wall shear stress (WSS) and 11.5% was exposed to high WSS, indicating a high rupture risk profile with significant areas of both low and high WSS. In addition, low WSS was observed in regions corresponding to daughter sacs, suggesting a higher rupture risk. Streamline analysis indicated increased inflow through the right vertebral artery and the right limb of the fenestration, supporting the initial angiographic impression and guiding the choice of therapeutic strategy. CONCLUSION: This is the first study to analyze the morphology and pretreatment hemodynamics of a BAFA using CFD, illustrating the potential for future development of individualized therapeutic approach–based CFD in complex aneurysms.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Importance Use of modern neoadjuvant chemotherapy (NAC) regimens has markedly increased rates of pathologic complete response (pCR) in breast cancer, raising the question of whether surgical removal of the primary tumor is required for patients with pCR. For surgery to be omitted, one must be able to accurately predict pCR before surgery. Objective To investigate if adding post-NAC core needle biopsy of the tumor bed to trimodality imaging in patients who have clinical complete response (cCR) will predict pCR (resolution of both invasive disease and ductal carcinoma in situ) in 90% or more cases. Design, Setting, and Participants This was a phase 2, prospective, nonrandomized clinical trial. Patients were enrolled from August 2017 to June 2019. This is the final analysis, which was completed in December 2023. The setting included academic and community hospital center members of NRG (ie, the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group) in the US and Canada. Patients with operable (T1-T3, stage I-III) invasive ductal carcinoma who completed NAC and achieved cCR and radiological complete response (rCR) or near rCR by mammography (mass ≤1 cm and no malignant microcalcifications), ultrasound (mass ≤2 cm), and magnetic resonance imaging (no mass with rapid rise or washout kinetics). Interventions Patients underwent marker-directed stereotactic multiple-core needle biopsy of the tumor bed with marker placement before breast-conservation surgery. Main Outcomes and Measures End points were negative predictive value (NPV) and sensitivity of the biopsy. Results A total of 105 patients were enrolled with 101 evaluable (mean [SD] age, 52.8 [10.5] years); 77 patients (76.2%) were younger than 60 years, and all breast cancer subtypes were represented with 32 (31.7%) triple-negative breast cancer, 21 (20.8%) hormone receptor–positive/epidermal growth factor receptor 2 ( ERBB2 ; formerly HER2 )–negative ( ERBB2 −) breast cancer, and 46 (45.5%) ERBB2 -positive ( ERBB2 +) breast cancer. In 101 evaluable patients, 36 had residual disease at surgery (pCR = 64%). With imaging criteria, NPV of the biopsy was 78.3% (95% CI, 67.9%-86.6%), and the sensitivity of the biopsy was 50% (95% CI, 32.9%-67.1%). In an exploratory subset analysis, the NPV in patients with ERBB2 + breast cancer was 90% (95% CI, 76.3%-97.2%). On retrospective central review, 62 of 101 enrolled patients met imaging eligibility criteria. In this exploratory post hoc analysis, NPV in these patients was 86.8% (95% CI, 74.7%-94.5%). Conclusions and Relevance These findings do not support breast conservation treatment without surgery based on the study criteria for cCR and rCR/near rCR by trimodality imaging and negative tumor-bed biopsy. Strict adherence to imaging criteria may be required to achieve acceptable predictive values. TRIAL Registration ClinicalTrials.gov Identifier: NCT03188393

Abstract Invasive lobular carcinoma (ILC) accounts for 10-15% of all breast cancers, making it the most common special histological subtype of breast cancer. Initially, ILC is associated with a better response to adjuvant hormonal therapy compared to invasive ductal breast cancer (IDC). However, patients with ILC often experience a worse long-term outcome. Over 90% of ILCs are estrogen receptor positive (ER+) and do not express functional E-cadherin (CDH1). There are limited studies aimed at improved understanding of the tumor microenvironment (TME) in ILC. Therefore, we set out to generate and characterize a syngeneic mouse cell line model that mimics the genetic loss of CDH1 seen in ILC. We created an ER+ ILC-like mammary cancer model using the syngeneic SSM3 cell line, derived from an ER+ mouse mammary tumor in STAT1-deficient mice. To mimic the hallmark feature of ILC, we used CRISPR-Cas9 to knock out Cdh1. In vitro assays were performed to evaluate the effects of Cdh1 knockout (KO) in both 2D and 3D environments, focusing on cell proliferation and estrogen sensitivity. These experiments demonstrated increased growth of Cdh1 KO SSM3 cells in both 2D and 3D environments, together with altered cell morphology and increased sensitivity to estrogen.For in vivo characterization, we focused on tumor growth and metastasis. SSM3 Scr and Cdh1 KO cells were injected into the mammary fat pad of mice. Initial findings revealed increased tumor growth in mice injected with SSM3 Cdh1 KO cells, while metastasis studies are ongoing. RNA-seq analysis of both SSM3 cells grown in vitro, and in vivo tumor tissues is ongoing and will help to identify distinctive gene expression changes in the Cdh1 KO model. We will also analyze changes in the TME, such as immune cells, ECM and fibroblasts. In summary, we have successfully generated an ER+ syngeneic ILC model, and we expect that growing the cells in vitro and in vivo represents a valuable tool for studying ILC and holds promise for advancing the development of targeted immunotherapies and endocrine therapies for this breast cancer subtype. Citation Format: Insa Thale, Dixcy J. John Mary, Sarah Wang, Lora Rigatti, Jagmohan Hooda, Peter Lucas, George C. Tseng, Adrian V. Lee, Steffi Oesterreich. In vitro and in vivo characterization of Cdh1 CRISPR knockout in syngeneic ER+ SSM3 mouse mammary tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3925.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the activated B cell–like subtype (ABC-DLBCL) is associated with particularly poor outcome. Many ABC-DLBCLs harbor gain-of-function mutations that cause inappropriate assembly of the CARMA1-BCL10-MALT1 (CBM) signalosome, a cytoplasmic complex that drives downstream NF-κB signaling. MALT1 is the effector protein of the CBM signalosome such that its recruitment to the signalosome via interaction with BCL10 allows it to exert both protease and scaffolding activities that together synergize in driving NF-κB. Here, we demonstrate that a molecular groove located between two adjacent immunoglobulin-like domains within MALT1 represents a binding pocket for BCL10. Leveraging this discovery, we performed an in silico screen to identify small molecules that dock within this MALT1 groove and act as BCL10-MALT1 protein-protein interaction (PPI) inhibitors. We report the identification of M1i-124 as a first-in-class compound that blocks BCL10-MALT1 interaction, abrogates MALT1 scaffolding and protease activities, promotes degradation of BCL10 and MALT1 proteins, and specifically targets ABC-DLBCLs characterized by dysregulated MALT1. Our findings demonstrate that small-molecule inhibitors of BCL10-MALT1 interaction can function as potent agents to block MALT1 signaling in selected lymphomas, and provide a road map for clinical development of a new class of precision-medicine therapeutics.

Abstract Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel–Lindau disease, desirable personalized surveillance programs are lacking due to insufficient data on genotype-specific risk profiles of individual mutations. To describe neoplastic risk profiles for carriers of pathogenic and likely pathogenic VHL germline mutations, our observational study recruited 1,350 participants from 40 centers worldwide. 432 different VHL germline mutations were observed, with p.Asn78Ser, p.Arg161Ter, p.Arg161Gln, p.Arg167Gln, p.Arg167Trp and p.Tyr98His being the six most frequent, occurring in a total of 493 carriers (36.5%) and in ≥30 patients each. Age-related penetrance risks for retinal hemangioblastoma, central nervous system hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma in carriers of the most frequent VHL mutations were assessed. In addition, the number of organs affected, the frequency of surgery and the outcome are reported. Pairwise comparisons of the age-dependent tumor penetrance of these six mutations showed that 47 out of 90 pairs were significantly different. The most significant associations were found in p.Tyr98His (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P &lt; 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL mutation type and location, but did not differ between the truncating mutation p.Arg161Ter and the missense mutation p.Asn78Ser. Our study demonstrates the importance of mutation-specific phenotype prediction. With appropriate validation, the data have important implications for risk assessment and decision making in tumor prevention for carriers of the respective VHL mutations.