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Regional and gender disparities in lung cancer mortality in Guatemala.

8074 Background: Lung cancer is the leading cause of cancer-related deaths worldwide and a major contributor in Latin America, where rates are generally lower. To date, there are no published population analyses describing lung cancer trends in Guatemala. Methods: Secondary analysis of publicly available national mortality data (Guatemala’s National Institute of Statistics), extracting lung cancer deaths from 2012 to 2022. Deaths were summarized by region, department, year, and sex. Annual crude mortality rates (deaths per 100,000 inhabitants) using corresponding population denominators. Results: Between 2012 and 2022 Guatemala recorded 4273 lung cancer deaths (mean age 66,SD:16.17), concentrated in three regions (66.58%,n=2845): Metropolitan, Southwest and Central with the highest department-level counts in Guatemala (37.66%,n=1609), Quetzaltenango (6.53%,n=279), Huehuetenango (5.41%,n=231), San Marcos (5.24%,n=224) and Escuintla (5.29%,n=226). Crude lung cancer mortality ranged from 2.24 to 2.66 deaths per 100,000 inhabitants—highest in 2019 and 2020. Deaths were more frequent among men (54%,n=2,317), but deaths among women increased throughout the study period, resulting in a male-to-female ratio decline from 1.53 in 2012 to 1.07 in 2022. Conclusions: Guatemala’s lung cancer mortality rates were lower compared to global estimates with nearly two-thirds of deaths concentrated in three regions —especially in Guatemala department— reflecting the concentration of health services in this region. Globally, lung cancer deaths show a marked sex disparity, with men accounting for about 68%. In contrast, Guatemala demonstrated a narrowing sex gap, with male-to-female mortality of nearly 1:1 by 2022, with rising mortality among women. These differences may reflect variations in smoking prevalence, access to early diagnosis, and health system capacity, with post-2020 shifts possibly influenced by COVID-19-related disruptions in diagnosis, treatment, referral pathways, or cause of death-of-death reporting. Lung cancer deaths. Region(Departments) 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 No(%) Metropolitan(Guatemala) 132 129 121 125 144 148 156 175 182 146 151 1609(37.66) North(Baja Verapaz, Alta Verapaz) 14 16 8 15 16 14 20 12 14 12 15 156(3.65) Northeast(Izabal, Zacapa, Chiquimula, El Progreso) 27 32 37 28 44 32 36 35 25 42 30 368(8.61) Southeast(Jalapa, Jutiapa) 50 33 41 39 33 27 32 45 40 30 33 403(9.43) Central(Sacatepequez, Chimaltenango, Escuintla) 37 32 54 31 43 42 41 47 56 52 54 489(11.44) Southwest(Solola, Totonicapan, Quetzaltenango, Suchitepequez, Retalhuleu, San Marcos) 45 70 52 64 82 67 74 70 79 76 68 747(17.48) Northwest(Huehuetenango, Quiche) 21 28 34 37 29 32 40 43 41 38 28 371(8.68) Petén 11 8 15 10 13 13 10 15 10 16 9 130(3.04) Deaths(Mortality x 100k hab) 337(2.28) 348(2.31) 362(2.37) 349(2.24) 404(2.55) 375(2.33) 409(2.50) 442(2.66) 447(2.65) 412(2.41) 388(2.24) 4273

Impact of preoperative breast MRI on locoregional staging and management in early breast cancer.

e12510 Background: The role of preoperative breast MRI in early breast cancer remains controversial. We evaluated the impact of MRI compared with mammography and ultrasonography on staging accuracy and treatment decisions. Methods: We conducted a retrospective cohort study of 154 patients with early breast cancer who underwent preoperative mammography, ultrasonography, and breast MRI. Imaging findings were compared within the same patients. Changes in staging, lymph node positive finding, and treatment recommendations following MRI were investigated. Results: Breast MRI detected multicentric disease in 26.0% of patients versus 7.8% on conventional imaging and upstaged tumors to T3 in 7.1% of cases not identified by mammography or ultrasonography. MRI identified lymph node involvement in 31.2% of patients compared with 22.1% on ultrasonography. Overall, MRI led to changes in staging or treatment decisions in 31% (48/154) of patients. Breast-conserving surgery was recommended less frequently after MRI, while neoadjuvant chemotherapy followed by modified radical mastectomy was more commonly selected. Management changes occurred predominantly in patients with aggressive tumor biology. Conclusions: Preoperative breast MRI changes staging and treatment decisions in approximately one-third of patients with early breast cancer, particularly among those with aggressive disease features. These findings support the selective use of MRI to optimize individualized treatment planning.

Prognostic significance of HMGB1 expression as a biomarker of immunogenic cell death in patients with leiomyosarcoma and undifferentiated pleomorphic sarcoma treated with chemo-immuno–based regimens.

e23526 Background: Immunogenic cell death (ICD) is a functionally unique form of apoptosis that triggers a robust tumor-specific immune response by releasing damage-associated molecular patterns (DAMPs). High Mobility Group Box 1 (HMGB1) is a canonical DAMP and a key biomarker of ICD. Anthracycline-based chemotherapy, the standard of care for soft-tissue sarcomas (STS) such as leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS), is a known inducer of ICD. We sought to determine the prognostic value of HMGB1 expression variation for predicting progression-free survival (PFS) in patients treated with an anthracycline-based chemotherapy regimen combined with an anti-PD-1 inhibitor. Methods: We analyzed HMGB1 expression levels in a cohort of 32 patients with LMS and UPS undergoing anthracycline-based treatment combined with nivolumab, within the IMMUNOSARC clinical trial. Maximally selected log-rank statistics (Maxstat) were utilized to identify the optimal cut-off for HMGB1 expression variation (percentage of variation between baseline and the first radiologic evaluation) to segregate patients into two distinct prognostic groups for PFS. The variation in HMGB1 expression was also correlated with overall survival (OS). Results: The Maxstat analysis identified an optimal prognostic cut-off for HMGB1 expression variation at 13.2%. The group with HMGB1 expression variation > 13.2% demonstrated significantly superior PFS compared to the HMGB1 expression variation ≤13.2% group (13.5 months [95% CI, 11.1-16.0] vs. 8.4 months [95% CI, 6.2-10.5], p = 0.006). This threshold did not demonstrate significant prognostic value for OS (not reached, vs. 17.7 months [95% CI, not reached], p = 0.076). Conclusions: Increased variation in HMGB1 expression is a significant predictor of improved PFS in patients with LMS and UPS treated with chemo-immunotherapy regimens, suggesting that HMGB1 may serve as a valuable circulatory biomarker to monitor treatment efficacy and guide clinical decision-making. Ongoing analyses are evaluating HMGB1 variation at the time of disease progression to determine if the dynamic expression of this protein can predict clinical progression.

Design of an innovative clinical development program using randomized controlled phase 2 trial data and real-world evidence from an expanded access protocol to assess mifomelatide (TCMCB07) in GI cancer cachexia.

TPS11200 Background: Cachexia is common in GI cancers, occurring in ~50% of patients with colorectal cancer (CRC) and up to 80% of patients with pancreatic ductal adenocarcinoma (PDAC). Resulting muscle mass and energy store depletion reduces chemotherapy tolerance, often leading to dose reductions, treatment delays/discontinuation, and poorer survival outcomes (Franko J, Eur J Cancer ; 2022:174; Dunne RF, J Cachexia Sarcopenia Muscle . 2024;15:1628). Therefore, body weight preservation during chemotherapy may improve treatment effectiveness and outcomes for patients with GI cancer. The central melanocortin (MC) system, including MC3 and MC4 receptors, plays essential roles in regulating appetite, body mass, and energy homeostasis and is a logical therapeutic target to prevent and treat cachexia. Mifomelatide is a novel peptide MC3R/MC4R dual antagonist that is being studied for cancer and chemotherapy-associated weight loss. Our previously published work showed that mifomelatide was safe and effectively ameliorated cancer- and chemotherapy-associated cachexia in preclinical studies of mice, rats, and pet dogs. In a Phase 1 trial, healthy volunteers tolerated mifomelatide and did not experience vital sign or CV abnormalities or drug-related SAEs; they also experienced a modest increase in body weight and hunger compared with placebo. These findings warranted further clinical development of mifomelatide. Methods: The mifomelatide clinical development program is designed to generate a multidimensional body of evidence from clinical trial and real-world datasets that span GI cancer types and cachexia stages. First, a randomized, double-blind, placebo-controlled Phase 2 trial is evaluating mifomelatide’s effects in 120 patients with newly diagnosed mCRC and pre-cachexia or early weight loss (NCT06937177). Additionally, an intermediate-size Expanded Access Protocol (EAP) was cleared by the US Food and Drug Administration in January, 2026 to make mifomelatide available to 100 eligible cachectic PDAC patients (NCT number pending). In addition to providing mifomelatide for compassionate use to patients with PDAC who have high unmet need and no approved treatment options for their cancer cachexia, the EAP will also facilitate the collection of real-world data that, when combined with findings from the Phase 2 trial, will deepen our understanding of mifomelatide’s safety, tolerability, and potential to optimize body weight in patients with GI cancer. Collectively, our innovative hybrid approach to the mifomelatide clinical development program will generate robust insights into the benefit–risk profile of MC3R/MC4R dual antagonism with mifomelatide to treat cachexia across GI cancers and guide key design considerations for a subsequent pivotal trial. Clinical trial information: NCT06937177 .

Clinical benefits of early-phase clinical trials for rare malignancies: Asian single-center analysis.

e15202 Background: The available chemotherapies for patients with rare malignancies are limited. Enrollment in early-phase clinical trials (EPCTs) is a promising approach to expand treatment options. However, clinical data about the venue of EPCTs remains scarce worldwide. Methods: Medical records of 1,291 patients referred to our department between 2021-2025 were reviewed. Based on the Rare Cancers in Europe definition, we categorized respective patient as having either a rare malignancy, with annual incidence of < 6 per 100,000 people per year or a common malignancy. We analyzed the patient backgrounds, enrollment status in EPCTs, and clinical outcomes. The trial enrollment rate was calculated as follows: the number of patients who received some investigational drug at least once divided by the number of patients referred to our department. We further defined an ultra-rare malignancy as having an incidence of < 0.2 per 100,000 people per year in a rare malignancy group and examined the enrollment status. Results: A rare malignancy accounted for 43% of all analyzed cases. The most frequently represented cancer types included in this group were ovarian cancer (n = 146), biliary tract cancer (n = 74), esophageal cancer (n = 57), and sarcoma (n = 49). Patients with common malignancies was heavily treated before trial enrollment than those with rare malignancies (average 2.7 regimens, range 0-15 vs. 2.3 regimens, range 0-10). The enrollment rate in EPCTs was similar (31% vs. 28%) for the two groups. The rates for representative cancer types as follows: 42% for ovarian cacer, 16% for biliary tract cancer, 37% for esophageal cancer, 29% for sarcoma, 34% for cervical cancer, and 43% for head and neck cancer. Remarkably, three patients with rare malignancy (two with ovarian cancer and one with cervical cancer) received three investigational drugs. The overall response rate (ORR) in the rare malignancy and common malignancy groups was 25% and 18%, respectively. Median progression-free survival in the both groups was 3.0 and 2.3 months, respectively. The ORR varied among cancer types (37% for ovarian cancer; 35% for esophageal cancer; 17% for head and neck cancer; 6% for cervival cancer; 0% for biliary tract cancer; 0% for sarcoma). Of the 88 patients with ultra-rare malignancies, 24 patients (27%) were enrolled, including those with ovarian cancer (n = 12), melanoma (n = 3), sarcoma (n = 3), and endometrial cancer (n = 3). The ORR was 26%. Conclusions: Our analysis suggests that patients with rare malignanicies as a whole had comparable clinical benefits from EPCT enrollment as those with common malignancies. However, tumor response was various among types of cancer, partly due to their different biological behaviors. Our data confirm that ovarian cancer is a promising target, as multiple EPCTs are underway. Concurrently, there is an urgent need for clinical development of rare entities such as sarcoma and biliary tract cancer.

Opportunistic plasma ctDNAtesting in EGFR-mutant mNSCLC using a hospital-validated sequencing platform: A real-world experience.

e20564 Background: In metastatic EGFR-mutant non-small cell lung cancer (mNSCLC), rapid identification of targetable alterations is essential for treatment. Plasma circulating tumor DNA (ctDNA) testing may complement tissue genotyping, particularly when tissue is limited or results are delayed. However, real-world data on ctDNA testing using non-standardized sampling in EGFR-mutant disease remain limited. Methods: We conducted a prospective observational study including patients with EGFR-mutant mNSCLC who underwent opportunistic plasma ctDNA testing using a validated, hospital-based next-generation sequencing assay. Clinical characteristics, ctDNA timing, detected EGFR alterations, and concordance with available tissue molecular results were analyzed descriptively. Results: Our cohort included 29 EGFR-mutant mNSCLC patients; 59% female, 62% never-smokers; median age 67 (32–97). Most patients (86%) had de novo metastatic disease. Among these patients, 13% had bone-only disease, 87% had visceral involvement and 27% had CNS involvement. Plasma ctDNA was collected at metastatic diagnosis in 26 patients and at disease progression in 3 patients. Among those tested at metastatic diagnosis, 27% had ctDNA plasma collected before treatment initiation and 73% on or after treatment initiation. Most ctDNA samples (52%) were collected on the day of treatment initiation, with median time from treatment initiation to collection of 5 days (range 1–30). Osimertinib monotherapy was used in 96% of patients. Among patients tested for ctDNA at stage IV, the median time from tissue biopsy to plasma ctDNA collection was 28 days (range 11-135). Among patients tested at progression, median time from initial tissue biopsy to plasma ctDNA was 37 months. EGFR mutations identified in tissue included L858R (41%), exon 19 deletions (45%), exon 20 mutations (7%), and L747P-exon 19 (7%). Discordance between tissue and plasma ctDNA was observed in 11 patients (38%), with no variants detected in ctDNA despite the presence of EGFR mutations in tissue. Among discordant cases, three patients had plasma collected at recurrence to stage IV, two at disease progression, and six had de novo metastatic disease, with ctDNA collected before treatment initiation in one patient and within 0–7 days after treatment initiation in five patients. EGFR L858R and exon 19 deletions each accounted for 45.5% of discordant cases; exon 20 mutations accounted for 9%. Among discordant patients, metastatic sites included bone-only (n = 1), isolated brain metastasis (n = 1), and visceral disease (n = 9). Conclusions: Plasma ctDNA testing is useful when rapid results are needed; however, in this small real-world cohort, EGFR mutations were missed in 38% of samples. This highlights the ongoing importance of tissue genotyping and the need to better define the timing and role of plasma ctDNA testing in EGFR-mutant lung cancer.

Predictors of meaning and purpose among patients with cancer and with elevated psychological distress.

e24123 Background: Patients with cancer frequently experience psychological distress and existential concerns. Meaning and purpose are often emphasized in oncologic end-of-life settings. But many patients don’t find meaning and purpose during the cancer trajectory. Studies have not described clinical and demographic features associated with meaning and purpose. Methods: We conducted a retrospective analysis of 96 patients at a single-institution dedicated cancer center undergoing psychosocial evaluation. Demographics, disease characteristics, and psychiatric diagnoses were collected. PROMIS short forms measured emotional distress (anxiety, depression, social isolation), meaning and purpose, and concern for death and dying. PROMIS measures are standardized using a T-score metric with a mean of 50 and standard deviation of 10, based on the U.S. general population. Linear regression models were used to assess predictors of meaning and purpose. Results: The cohort had a mean age of 60.2 years (SD = 16.9), and 53.8% were female. Most patients had localized cancer (65.6%) and were receiving cancer treatment (89.3%). Mean PROMIS scores indicated lower-than-average meaning and purpose (46.2, SD 9.0), elevated concern for death and dying (55.1, SD = 8.9) and anxiety (58.6, SD = 8.6) and depression (55.9, SD = 7.7), with average social isolation (50.3 SD = 7.8). In univariate analysis, metastatic disease (t = 2.35, p = .02), anxiety (t = -3.2, p = .05), depression (t = -0.37), and social isolation (t = -4.2, p = 0.03), were significantly associated with meaning and purpose. The multivariable regression model below predicted 32% of meaning and purpose variance. Adjusted R 2 = .32. Conclusions: Although meaning and purpose is lower for this standard cohort of patients with localized and metastatic cancer than the general population, patients with metastatic disease were more likely to express meaning and purpose while social and depression were independently associated with lower meaning and purpose. Addressing depression and social isolation and meaning and purpose in patients with localized cancer may increase quality of life for patients with cancer and warrants further research. Variables Mean (SD) β Coefficient 95% CI P -value PROMIS forms Anxiety 58.6 (8.6) -0.189 -.042, .044 0.11 Depression 55.9 (7.7) -0.307 -0.63, -0.14 0.003* Social Isolation 50.3 (7.9) -0.311 -0.60, -0.13 0.003* Demographics/Clinical Metastatic (yes) N=34 0.189 0.08,7.50 0.05*

Security enhancement using scalable Blockchain-based Multi-Factor Authentication (BMFA)

As digital interactions continue to expand, securing online systems has become a fundamental priority. Multifactor authentication (MFA) plays a pivotal role in modern cybersecurity frameworks. Traditional approaches often exhibit weaknesses such as centralized vulnerabilities and limited adaptability to emerging threats. To address these concerns, this research introduces a novel Blockchain- based Multifactor Authentication (BMFA) system that enhances security, resilience, and scalability. This study provides an in-depth exploration of BMFA’s conceptual architecture, operational mechanisms, and potential applications. By decentralizing authentication processes, BMFA reduces single points of failure and fortifies data integrity through cryptographic safeguards. Unlike conventional models, this approach distributes authentication data across multiple blockchain nodes. This reduces the risk of breaches while ensuring continuous availability. Moreover, BMFA improves user privacy via distributed consensus, minimizing dependency on centralized authentication servers. The proposed system demonstrates enhanced load-balancing (LB)capabilities. This makes it more suitable for high-demand environments as compared to existing MFA methods. The proposed system demonstrates improved load-balancing behavior under simulated conditions and distributes authentication verification across multiple nodes. The results indicate potential resilience improvements compared with centralized MFA approaches. However, the findings are based on analytical and simulation evaluation, and real-world deployment assessment remains future work.

Inside Back Cover: Mapping the Reactivity of the C═C Bond of Cyclic Enol Ether Derivatives of Sugars: Nucleophilicity Parameters of Glycals (Angew. Chem. Int. Ed. 23/2026)

Unveiling the Valence‐Driven Charge Compensation Mechanism to Direct Phase Engineering in Ru‐Based Catalysts for Acidic Water Electrolysis

ABSTRACT Phase engineering is pivotal for optimizing the electronic structure and reaction pathways of electrocatalysts, balancing high‐efficiency charge transfer in single‐phase structures against synergistic effects in mixed‐phase structures. However, the underlying principles governing phase evolution remain poorly understood. Herein, a valence‐driven phase engineering paradigm is established that enables deterministic control over Ru‐based catalysts. We reveal that phase formation trajectories are intrinsically dictated by charge compensation mechanisms: tetravalent dopants (Hf, Mn, Sn) maintain single‐phase RuO 2 via charge neutrality and lattice matching; trivalent dopants (Cr, Fe, Ga) induce a synergistic RuO 2 ‐Ru hetero‐phase structure; whereas divalent dopants (Ni, Cu, Zn) trigger oxide phase separation due to severe charge mismatch. As a demonstration, the RuGa mixed‐phase catalyst delivers an exceptional overpotential of 180 mV at 10 mA cm −2 and survives 500 h in acidic media. When integrated into a PEMWE cell, it achieves 1 A cm −2 at only 1.63 V with robust stability of 100 h at 500 mA cm −2 . This work provides a fundamental framework for rationally designing durable acidic OER catalysts via valence‐controlled phase regulation.

Development and optimization of tivozanib loaded amine functionalized mesoporous silica nanoparticles for enhanced drug delivery

Time as an unmeasured ‘dose’ in oncology: introducing time budgeting as a design principle for cancer care

Bioinspired Light‐Scattering Structures for Passive Daytime Radiative Cooling

ABSTRACT With the intensifying effects of global warming and the growing demand for cooling, passive daytime radiative cooling (PDRC) has emerged as a promising and sustainable solution, in which PDRC reflects solar radiation and dissipates heat through the 8–13 µm atmospheric window without energy consumption, offering a viable approach to reducing electricity usage for cooling. A key factor in enhancing PDRC performance is the use of bioinspired light‐scattering structures, which effectively regulate solar reflection and long‐wave infrared emission. This review systematically outlines the design principles and regulation strategies of scattering structures in radiative cooling materials, focusing on two primary systems: scattering particles and porous architecture. It examines their individual contributions and synergistic effects in improving both solar reflectivity and infrared emissivity. Special emphasis is placed on bioinspired structural designs, exploring how nature‐inspired patterns can enhance spectral selectivity and scattering efficiency. The review also summarizes representative applications in building energy conservation, photovoltaic thermal management, wearable electronics, and agricultural environments regulation. Finally, it discusses current technical challenges and offers perspectives on future developments in structural design and scalable fabrication methods, aiming to provide both theoretical insights and practical guidance for the advancement of radiative cooling technologies.

Opinion-driven vaccination and epidemic dynamics on heterogeneous networks

Hydrogelation via Supramolecular Copolymerization of Structural Water within Adaptive Metal–Organic Fibers

ABSTRACT Water is conventionally viewed as a disruptive solvent for supramolecular materials, destabilizing directional noncovalent interactions. Here, we report a metal–organic material in which water instead acts as a structural co‐monomer driving the formation of supramolecular fibers. A zinc(II) bisphenoxyimine (“Salphen”) complex featuring convergent hydrogen‐bond acceptor sites assembles in bulk water into long, hollow nanofibers stabilized by confined structural water molecules. Single‐particle analysis and density functional theory reveal tubular architectures in which intercalated water bridges the metal centers and defines a hydrophilic inner channel. The fibers form hydrogels with thermomechanical response, chemically triggerable disassembly and enable selective chiral recognition of amino acids via water‐mediated molecular–to–supramolecular information transfer. In organic solvents, the water content can be used for control over supramolecular self‐assembly and hence gelation and liquefaction. Our findings establish structural water as a design element for creating adaptive, chiral, and dynamically reconfigurable metal–organic materials, offering a new paradigm to unlock this sustainable building block in supramolecular materials design.

The dynamic pool of Rec8-cohesin is crucial for meiotic recombination and transcription regulation in the yeast Saccharomyces cerevisiae

Collaborative education to advance equitable prostate cancer care in geographically diverse communities.

9033 Background: Although 15%-19% of the US population resides in rural areas, less than 10% of oncologists practice there, driving significant inequities in prostate cancer care. Community clinicians face barriers including limited subspecialist access, multidisciplinary gaps, biomarker testing delays, and low clinical trial participation. As biomarker testing, imaging, and individualized treatments evolve, targeted education is vital to support evidence-based decision-making and equitable delivery. Methods: Talem Health implemented a multicomponent CME/CE-accredited initiative for community oncologists managing prostate cancer across the disease spectrum. The initiative featured a 1-hour virtual session at the 2025 Oncology Congress, a 7-session longitudinal Project ECHO (Extension for Community Healthcare Outcomes) telementoring series, and a 1-hour "lessons learned" online activity. Outcomes were assessed via mixed methods: quantitative pre/post-activity assessments and polling, and qualitative data from ECHO case discussions and interviews. Analyses evaluated changes in knowledge, competence, and planned behaviors using Chi-square tests and effect size calculations. Results: Over 600 clinicians participated; 91% were hematology/oncology specialists, 93% practiced in community/non-academic settings, and 90% served rural or underserved populations. Identified barriers included limited testing access (36%), treatment access challenges (27%), multidisciplinary gaps (25%), and guideline unfamiliarity (23%). Statistically significant improvements occurred across all knowledge and competence outcomes ( P < .05 to P < .01). Clinicians reported increased intent to incorporate genomic/germline testing; align nmCRPC decisions with guidelines; utilize combination strategies for mHSPC; personalize mCRPC therapy; and implement shared decision-making. Qualitative findings from the ECHO series emphasized the value of peer-to-peer learning. Participants reported higher confidence in managing complex cases and contextualizing new evidence within real-world practice. Ongoing needs were identified regarding risk stratification, rural access barriers, and artificial intelligence applications. Repeated participation in ECHO sessions enabled clinicians to apply new evidence across multiple patient cases over time, reinforcing clinical decision-making through iterative discussion and shared problem-solving. Conclusions: This longitudinal educational design effectively supported community oncologists, yielding meaningful gains in knowledge, confidence, and intended practice behaviors. These results demonstrate that tailored education can expand clinician capacity and improve care for patients with prostate cancer in rural and underserved settings.

Impact of UGT1A1 polymorphism on safety and dose management of sacituzumab govitecan in the treatment of advanced breast cancer patients.

e15143 Background: Sacituzumab govitecan (SG) is an antibody-drug conjugate approved for advanced triple-negative and HR+/HER2- breast cancer. Its drug, SN-38, is metabolized by UGT1A1. Although some studies suggest higher toxicity in patients carrying the UGT1A1*28 allele, evidence on the impact of UGT1A1 variants on dose management and treatment exposure remains limited. We explored SG safety and tolerability according to UGT1A1 genotype. Methods: We conduct a single-center retrospective observational study of patients with advanced breast cancer treated with SG. Patients are grouped as Normal-Group (NG) (*1/*1) or Risk-Group(RG) (carriers of *28 allele: *1/*28 or *28/*28). In the present analysis we present the data of the first patients included regarding dose reductions due to toxicity, severe adverse events (≥Grade(G)3; CTCAE v5.0), G2, treatment exposure (number of cycles) and Grow-Colony Stimulating Factor (G-CSF) use. Categorical variables were compared using Fisher's exact tests (two sides) and continuous variables using the Mann-Whitney U test (exact two-sided p value). Results: Since June 2025 till beginning January 2026, 17 patients were included (NG n=8; RG n=9). Median age was 48 and 55 years in NG and RG respectively, rest of baseline characteristics were broadly comparable between groups (Table). Dose reductions due to toxicity occurred more frequently in the RG 66.7% vs 37.5 in the NG. Treatment exposure was numerically lower among RG with mean rank number of cycles 6.81 vs 10.19 in the NG. Rates of any ≥G3 toxicity were 44.4% vs 28.6%, ≥G3 neutropenia 33.3% vs 28.6%, and any ≥G2 toxicity 44.4% vs 42.9% respectively for the RG and NG. High G-CSF use was observed in both cohorts (RG 88.9% and NG 83.3%). Conclusions: The presence of the UGT1A1*28 polymorphism in patients treated with SG in our population is associated with frequent toxicity-related dose reductions, lower treatment exposure, and higher rates of ≥G3 toxicities, including ≥G3 neutropenia (although a high use of G-CSF was observed). This study is ongoing, and additional patients are needed to clarify the clinical utility of proactive UGT1A1 genotyping for optimal SG management. Clinical characteristics and UGT polymorphism. UGT1A1 Normal (*1/*1) Risk (*28) p-value ECOG Asymptomatic (0) 7 (87.5%) 4 (44.4%) 0.131 Symptomatic (≥1) 1 (12.5%) 5 (55.6%) Hepatic Metastases No 2 (25.0%) 3 (33.3%) 1.000 Yes 6 (75.0%) 6 (66.7%) Tumoral Burden (n. of metastatic sites) < 3 metastatic sites 4 (50.0%) 5 (55.6%) 1.000 ≥ 3 metastatic sites 4 (50.0%) 4 (44.4%) SG* Line therapy Early (2nd-3rd line) 6 (75.0%) 7 (77.8%) 1.000 Late (≥4th line) 2 (25.0%) 2 (22.2%) HER2 Status HER2-0 (Neg) 3 (37.5%) 5 (55.6%) 0.637 HER2-Low 5 (62.5%) 4 (44.4%)

Evaluating satisfactory testing versus transcript grade performance between childhood cancer survivors and healthy controls.

10045 Background: Substantial evidence suggests that survivors of childhood cancer are at increased risk for poor academic performance including receiving poor or failing course grades. There is a paucity of primary data as many contributing studies have relied on parental reporting of school performance. In the state of Florida, a high school student graduating with a standard diploma must successfully pass required biology and math classes. These classes require taking a standardized state-wide test which constitutes 30% of their final course grade. Our team sought to evaluate the concordance of state testing and course grade performance between pediatric brain tumor survivors and matched healthy controls from Florida. Methods: Children who received radiotherapy for intracranial tumors between 2007-2020 who reside in Florida were recruited to this IRB-approved study (N=37). Electronic medical record data was linked to scholastic data provided by the Florida Department of Education. Scholastic data included state testing scores and grade transcripts. For every patient enrolled, the state provided scholastic data matched at a 3:1 ratio (healthy control to survivor), based on age, grade, school district, and eligibility for free or reduced lunch (ERFL). We used Fisher’s Exact test to perform an analysis of association of test scores and course grades between survivors and controls based on state-set pass/fail criteria. Results: Mean age of survivors was 14 years. Fifty-one percent of the survivors were female, 81% white, 8% Black, and 14% Hispanic. The majority received chemotherapy and were ERFL. Approximately 55% of survivors and controls received satisfactory math test scores (Table 1). However, survivors with unsatisfactory math scores were significantly more likely to pass their math class compared to controls (67% vs 51%; P<0.01). For biology, 79% of survivors vs 45% of controls had a satisfactory state test score; however, survivors with unsatisfactory biology scores were significantly more likely to pass their biology class compared to controls (80% vs 73%; P=0.007). Conclusions: We present the first US-based evaluation of primary evidence of childhood cancer survivors’ performance in schools looking at transcripts. Our results demonstrate a discordance that if a survivor or control performed unsatisfactorily on the state test, the survivor was significantly more likely to pass the actual course required for a standard diploma. Further work inviting stakeholder participation, including students, caregivers, and educators is needed. Comparison of standardized math test score and math course grades. State Test Number (%) P-value Unsatisfactory test Control (n=61) Survivor (n=21)  Passing course 31 (51) 14 (67) P<0.01  Failing course 30 (49) 7 (33) Satisfactory test Control (n=73) Survivor (n=26)  Passing course 71 (97) 26 (96)  Failing course 2 (3) 1 (4)

Phase II trial evaluating nivolumab in patients with recurrent IDH-mutant gliomas with and without hypermutation phenotype.

2064 Background: Tumor mutational burden (TMB) is an emerging biomarker for the prediction of immune therapy success in solid tumors. Response to immune checkpoint inhibitor (ICI) treatment in rare gliomas with biallelic mismatch repair deficiencies has been attributed to their hypermutation phenotype (HMP). This has not been tested in other gliomas. We developed a phase II clinical trial using nivolumab in recurrent IDH-mutant gliomas evaluating response in tumors with HMP (approximately 10% of cases) and in tumors with non-HMP (NHMP). Here we report the results of the analysis of the NHMP cohort. Methods: Adults with recurrent IDH-mutant glioma, KPS ≥ 60, normal organ function, with known somatic TMB (analyzed at NIH) were enrolled in a phase II trial. Nivolumab was given at 480mg IV every 28-day cycle with a maximum of 16 cycles. The primary endpoint is PFS rate at 6 months (PFS6) in both HMP and NHMP cohorts. Responses to treatment were evaluated by MRI every 2 cycles using iRANO criteria. Simon’s two-stage design was used to independently evaluate the HMP/NHMP cohort. For the NHMP cohort, the null and alternative hypotheses for PFS6 are 0.2 and 0.4, respectively. A total of 30 were planned to be accrued across stages I and II. If ≥10 patients are progression-free at 6 months, the null hypothesis will be rejected, indicating that the treatment is promising for patients with NHMP IDH-mutant gliomas. The design controls the type I error at 0.05 and yields a power of 0.8. Tumor samples and peripheral blood were collected for correlative studies. Patient-reported outcomes (PRO) were evaluated by longitudinal symptom burden analysis using Brain Tumor Module of the MD Anderson Symptom Inventory. Results: As of January 2026, thirty patients were enrolled and treated on the NHMP cohort (TMB˂5 mut/Mb). Among 30 evaluable patients, 20 were male, median age 44 and KPS 90. Histological diagnosis included 22 astrocytoma (grade 3, n=10; grade 4, n=12) and 8 oligodendroglioma (grade 2, n=1; grade 3, n=7). Median number of prior recurrences is 2, ranging from 1 to 5. At the time of analysis, all 30 evaluable patients were off study treatment: 7 completed all 16 cycles, 17 had disease progression, 3 withdrew to start other management. Three patients were off treatment due to treatment related grade 3 colitis, pneumonitis and dry mouth. Eleven and 8 out of 30 patients were progression free at 6 and 12 months, respectively. PRO and correlative studies are ongoing. Conclusions: Nivolumab is well tolerated and has shown efficacy in a cohort of patients with recurrent IDH-mutant gliomas with low TMB. Clinical benefit measured by objective response, PFS, OS and PRO, along with longitudinal immune monitoring, will help determine whether tumor TMB correlates with immunologic and clinical response to ICI therapy in IDH-mutant gliomas. Clinical trial information: NCT03718767 .