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Breast cancer incidence and mortality in LGBTQ+ populations compared with cisgender heterosexual individuals: A comparative epidemiologic synthesis.

1118 Background: Breast cancer incidence and mortality by sexual orientation and gender identity remain poorly characterized. We aimed to systematically review comparative studies in LGBTQ+ populations versus cisgender heterosexual comparators. Methods: We conducted a PRISMA 2020–guided systematic review evaluated breast cancer incidence and mortality in LGBTQ+ populations versus cisgender heterosexual comparators. PubMed, Embase, and Scopus were searched from inception to January 2026. Population-based cohort, registry, and health system studies reporting comparative incidence or mortality were eligible. Two reviewers independently screened records. Of 189 records, 105 were excluded at title/abstract, 84 underwent full-text review, and 8 studies were included. Due to heterogeneity in SOGI ascertainment, comparators, and effect measures, results were synthesized qualitatively. Results: Among transgender populations, breast cancer incidence varied by reference group. In a nationwide cohort, trans women had higher incidence vs cis men (SIR 46.7) but lower vs cis women (SIR 0.3), while trans men showed the inverse pattern (vs cis women SIR 0.2; vs cis men SIR 58.9). In a U.S. health system cohort, incidence was similar for FTM vs cis women (0.4% vs 0.5%) but higher for MTF vs cis men (0.2% vs 0.004%). Among sexual minority women, incidence did not differ from heterosexual women in UK Biobank (HR 0.63–0.93) or Nurses’ Health Study (aIRR 1.19; 95% CI, 0.92–1.53). Mortality data were sparse; one national linkage found higher breast cancer–specific mortality in same-sex partnered women (HR 3.24; 95% CI, 1.01–10.37). Conclusions: Breast cancer incidence in transgender populations is comparator-dependent: trans women have higher incidence vs cis men but lower vs cis women, with the inverse pattern in trans men; incidence among sexual minority women is similar to heterosexual women. Comparative studies. Study (Year) Data Source / Country SGM Population Comparator Outcome Key Estimate (95% CI) Yang 2025 UF Health IDR, USA FTM Cisgender women Incidence RR ≈ 0.72 (0.4% vs 0.5%) de Blok 2019 Nationwide registry, Netherlands Trans women Cisgender women Incidence SIR 0.30 (0.20–0.40) de Blok 2019 Nationwide registry, Netherlands Trans men Cisgender women Incidence SIR 0.20 (0.10–0.50) Brown 2014 VHA cohort, USA Transgender veterans Expected population Incidence SIR ~1 vs cis women; >1 vs cis men Underwood 2023 UK Biobank WSWM WSEM Incidence HR 0.93 (0.79–1.10) Underwood 2023 UK Biobank WSEW WSEM Incidence HR 0.63 (0.37–1.07) Huang 2024 Nurses’ Health Study, USA Lesbian women Heterosexual women Incidence aIRR 1.19 (0.92–1.53) Cochran 2012 NHIS mortality linkage, USA Same-sex partnered women Different-sex partnered Mortality HR 3.24 (1.01–10.37) Chan 2025 NCDB, USA TGD breast cancer cases Cisgender cases Overall survival 5-yr OS: 84.6% vs 91.7% (P=0.04)

Use of spatial multiomics to identify endosomal trafficking and S100A8/A9, and fibronectin-driven immune remodeling programs with T-DXd resistance in breast cancer brain metastases.

e15199 Background: Trastuzumab deruxtecan (T-DXd) has transformed the treatment of breast cancer brain metastases (BCBM). However, approximately half of patients exhibit acquired resistance, and no predictive biomarkers have been clinically established. Since antibody-drug conjugate (ADC) efficacy depends on the unique brain microenvironment and intracellular processing, we applied spatial multiomics to resolve tumor- and niche-specific resistance mechanisms. Methods: Pre-treatment BCBM specimens from T-DXd responders (R) and non-responders (NR) were profiled using Bruker GeoMX for spatial proteomics and whole transcriptome analysis (n = 2 R, 2 NR; 5-10 ROIs per specimen). Additionally, Bruker CosMX single-cell spatial transcriptomics was employed for pathway enrichment and cell crosstalk analyses (n = 3 R, 3 NR; 200 ROIs per specimen). Results: GeoMX analysis identified fibronectin as a potential spatial biomarker—the significantly stronger spatial correlation with T cell markers (CD3, CD4, CD8) in NR (p < 0.05), suggests a role in T cell exclusion. Both GeoMX and CosMX identified S100A8 and S100A9 as highly differentially regulated. Interestingly, their clinical significance was cell type-dependent: · Luminal A cancer cells in NR-enriched clusters exhibited S100A8/A9 upregulation (FDR q < 1 × 10⁻⁶), accompanied by increased phosphorylation of NF-κB pathway components. · In responders, S100A8/A9 expression was localized to monocyte-dominant clusters (FDR q < 1 × 10⁻⁶). Spatial Single Cell Crosstalk (S2C2) modeling predicted S100A8/A9-TLR4 interactions between monocytes and astrocytes, suggesting that innate immune–glial crosstalk may prime the niche for therapeutic sensitivity. Furthermore, responder HER2+ cancer cells were significantly enriched for ER-to-Golgi transport, vesicular trafficking pathways, and macroautophagy programs (NES > 3.4, FDR q < 0.01 for all). These findings are mechanistically consistent with the requirements of efficient intracellular processing and lysosomal cleavage for ADC payload release. Conclusions: To summarize, two plausible mechanisms of T-DXd resistance in BCBM were identified: 1) remodeling of the immune-glial niche associated with fibronectin and S100A8/9, and 2) impaired intracellular trafficking. Hence, the novelty of this research lies in uncovering potential biomarkers beyond the HER2 and topoisomerase I genes. Future work will explore these spatial signatures as high resolution biomarkers to stratify patients and nominate strategies to restore ADC efficacy in the CNS.

Features of gene copy number variation regulating mitochondrial function in endometrial cancer patients with type 2 diabetes mellitus.

e17630 Background: Endometrial cancer (EC) holds a leading position among oncogynecological diseases. Type 2 diabetes mellitus (T2DM) is detected in a significant proportion of patients with EC and is associated with an unfavorable prognosis. Mitochondrial dysfunction plays a key role in the pathogenesis of both conditions. An important mechanism influencing mitochondrial function through altered gene expression and protein dysfunction is copy number variation (CNV). The aim of this study was to conduct a comparative analysis of the relative gene copy number of genes regulating mitochondrial function in EC patients with and without T2DM. Methods: The study included 71 patients with morphologically verified adenocarcinoma of the endometrium, stage 1a-1b, stratified into groups by tumor grade: G1 (n=20), G2 (n=35), and G3 (n=16). The mean age of the patients was 58.3 ± 8.7 years. Within each grade group, subgroups with and without T2DM were identified. The relative copy number of 13 genes (MT-CO1, mtTFB, mtSSB, ATAD3, TFAM, POLG, POLRMT, TOP1MT, MGME1, TEFM, MT-RNR2, GCAT, NRF1) was determined in DNA samples from tumor tissue using real-time quantitative PCR. Control samples consisted of histologically normal endometrial tissue obtained from patients undergoing surgical treatment for uterine fibroids. The Mann-Whitney U test with Bonferroni correction for multiple comparisons was used to compare quantitative measures between groups. Differences were considered statistically significant at p < 0.05. Results: A significant decrease in mitochondrial gene CNV was observed in tumor tissue compared to normal tissue in EC patients, which was more pronounced in the presence of T2DM. The most significant changes were noted for the genes MT-CO1 (decrease of 16.7-55.6%), TFAM (decrease of 60.0-68.8%), and NRF1 (decrease of 60.0-62.5%). In the G1 group with T2DM, copy numbers decreased relative to conditionally normal tissue to 0.5 for MT-CO1, 0.4 for mtSSB, and 0.3 for MT-RNR2. In the G2 group with T2DM, decreases to 0.4 for MT-CO1, 0.3 for mtTFB, and 0.2 for NRF1 were observed. The G3 group with T2DM showed the most pronounced reductions: MGME1 copy number decreased 5.0-fold, mtSSB 5.0-fold, and mtTFB 3.3-fold. Conclusions: The presence of T2DM in EC patients is associated with a significant reduction in CNV for genes regulating mitochondrial functions. These alterations vary depending on tumor grade and are most pronounced in poorly differentiated tumors (G2-G3). The obtained data elucidate molecular mechanisms underlying the more aggressive course of EC in comorbid T2DM and justify the need for developing personalized therapeutic approaches that account for the patients' metabolic status.

Real-world evidence for comprehensive genomic profiling in myeloid malignancies: Changes in detection and clinical impact.

e18636 Background: Myeloid malignancies are characterized by marked genomic heterogeneity, where accurate and timely identification of pathogenic and actionable alterations is essential for diagnosis, prognostication, and therapeutic decision making. Targeted gene panels remain widely used but may miss clinically relevant variants. Comprehensive genomic profiling (CGP) offers broader molecular coverage, yet its real-world impact in myeloid disease is not well defined. Methods: In a retrospective study, molecular profiles of 6,481 patients were analyzed by integrating Neogenomics sequencing data (01/2025 – 12/2025) with standardized clinical data (cancer diagnoses, ICD-10 codes, medication records, molecular testing results) extracted from comprehensive electronic medical records using the xCures platform. Results: Pathogenic or likely pathogenic (P/LP) variants were detected in 2,763 of 5,610 patients with abnormal or detected results. The most tested assays included the NEO Comprehensive Myeloid (n=1,406) and NEO Comprehensive Heme (n=467) panels, as well as the NeoTYPE MDS/CMML Profile (n=698), NeoTYPE AML Prognostic Profile (n=76), and NEO AML Express (n=39). Medical record review of 1,066 patients with P/LP variants demonstrated that 199 received targeted therapy, with 50 initiating treatments within 30 days and 58 within 60 days of testing at Neogenomics. Targetable pathogenic variants (FLT3, IDH1, IDH2, and JAK2) were identified in 12 patients receiving targeted therapy (midostaurin, ivosidenib, enasidenib, ruxolitinib) within 60 days of Neo test results, 83% of whom were tested using the NEO Comprehensive Myeloid or Heme panels. Among 813 patients with initially unspecified diagnoses, 584 (72%) received definitive diagnoses within 30 days of CGP, and 74% of these were evaluated using the NEO Comprehensive panels. Conclusions: CGP markedly enhanced the detection of pathogenic and actionable variants beyond what targeted panels captured, translating into meaningful clinical impact. In this real-world cohort, CGP enabled definitive diagnoses in majority of previously unspecified cases. These findings demonstrate that broader molecular coverage not only improves diagnostic precision but also accelerates therapeutic decision-making, underscoring CGP as a critical tool for precision medicine in myeloid malignancies.

TRIDENT: A phase 2 study of relacorilant plus nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic ductal adenocarcinoma.

TPS4263 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a 5-year survival rate of < 5%. Approved treatment options are limited to combination cytotoxic chemotherapy such as mFOLFIRINOX or nab-paclitaxel + gemcitabine. Cortisol-mediated glucocorticoid receptor (GR) activation provides prosurvival signals to tumor cells that contribute to chemotherapy resistance. The addition of relacorilant, a selective GR antagonist, to paclitaxel + gemcitabine improved tumor growth inhibition over paclitaxel + gemcitabine alone in a PDAC xenograft model (Greenstein Oncotarget 2021). Moreover, in a phase 1 study of relacorilant and nab-paclitaxel, 2 durable confirmed partial responses were observed in patients with mPDAC (Munster Clin Cancer Res 2022). The combination of relacorilant and nab-paclitaxel prolonged progression-free survival (PFS) and overall survival (OS) in patients with platinum-resistant ovarian cancer in 2 randomized controlled trials, including the phase 3 ROSELLA study (Olawaiye Lancet 2025). The combination was well tolerated, with a safety profile that was consistent with nab-paclitaxel monotherapy. Therefore, the combination of relacorilant, nab-paclitaxel, and gemcitabine is deserving of further clinical study to improve outcomes in patients with mPDAC. Methods: TRIDENT is a phase 2, single-arm, open-label, multicenter study (NCT07259317) designed to evaluate the combination relacorilant + nab-paclitaxel + gemcitabine as a first-line treatment in mPDAC (target enrollment, N = 60). Key inclusion criteria are confirmed measurable metastatic disease (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), no prior systemic anticancer therapy to treat metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients will receive relacorilant 150 mg orally once daily for 3 consecutive days (day before, day of, and day after chemotherapy) in combination with nab-paclitaxel (100 mg/m 2 ) and gemcitabine (1000 mg/m 2 ) given on days 1, 8, and 15 of each 28-day cycle. Treatment will continue until disease progression or unmanageable toxicity. The primary endpoint is investigator-assessed PFS per RECIST version 1.1 and will be analyzed using Kaplan-Meier methods. Secondary endpoints are OS, best overall response, objective response rate, clinical benefit rate at 24 weeks, duration of response, cancer antigen 19-9 kinetics, and tolerability/safety. The study is currently enrolling. Clinical trial information: NCT07259317 .

Statin exposure and clinical outcomes in metastatic prostate cancer: A propensity-matched TriNetX cohort study.

e17087 Background: Statins have pleiotropic biologic effects and have been hypothesized to favorably influence prostate cancer outcomes. However, their association with outcomes during contemporary androgen-ablative systemic therapy in metastatic disease remains uncertain. Methods: We conducted a retrospective cohort study using the TriNetX Research Network (2014–2024). Men with metastatic prostate cancer initiating androgen deprivation therapy and/or androgen receptor pathway inhibitors were classified by baseline statin exposure (active statin use within 6 months before and on the index date) versus no statin use (none from 6 months before through 6 months after index). Cohorts were propensity score–matched 1:1 for demographics, metastatic sites, comorbidities, and baseline cardiometabolic/oncologic medications. Outcomes from day 1 post-index were overall survival (OS), treatment switching (docetaxel or lutetium Lu 177 vipivotide tetraxetan), skeletal-related events (SRE), and major adverse cardiovascular events (MACE) at 1 and 5 years using Kaplan–Meier analysis with log-rank testing. HRs with 95% CIs were generated by TriNetX. Results: Before matching, 5,071 statin users and 11,143 nonusers were identified; after propensity score matching, 3,565 patients were included per cohort. At 1 year, OS was similar (90.35% vs 89.24%; HR 0.887, 95% CI 0.762–1.032; log-rank p = 0.120). MACE was higher with statins (92.33% vs 93.76% event-free; HR 1.258, 95% CI 1.049–1.510; p = 0.015). At 5 years, statin exposure was associated with modestly higher OS (66.17% vs 63.48%; HR 0.903, 95% CI 0.821–0.994; p = 0.037), while MACE remained higher (79.85% vs 81.53% event-free; HR 1.154, 95% CI 1.010–1.318; p = 0.035). Conclusions: In this propensity-matched real-world cohort of men with metastatic prostate cancer receiving contemporary androgen-ablative therapy, baseline statin exposure was associated with a small OS advantage at 5 years but not at 1 year, without differences in treatment switching or skeletal events. Higher MACE rates suggest residual confounding by cardiovascular risk and emphasize cardio-oncology optimization. Prospective studies are needed to clarify causality. Outcomes comparing statin vs. no-statin groups. Outcome (Time Horizon) Statin KM % No-Statin KM % HR (95% CI) p (log-rank) OS (1 year) 90.35 89.24 0.887 (0.762–1.032) 0.120 Treatment switch (1 year) 91.78 92.38 1.085 (0.915–1.287) 0.347 SRE (1 year) 96.13 96.38 1.081 (0.842–1.388) 0.543 MACE (1 year) 92.33 93.76 1.258 (1.049–1.510) 0.015 OS (5 years) 66.17 63.48 0.903 (0.821–0.994) 0.037 Treatment switch (5 years) 84.34 84.25 1.011 (0.880–1.162) 0.875 SRE (5 years) 91.26 90.58 0.985 (0.816–1.189) 0.878 MACE (5 years) 79.85 81.53 1.154 (1.010–1.318) 0.035

Clinical outcomes of PD-1 versus PD-L1 inhibitors combined with chemotherapy as first-line treatment for extensive-stage small cell lung cancer: A propensity score–matched study.

e20132 Background: Small cell lung cancer (SCLC) is a highly aggressive malignancy, with approximately two-thirds of patients presenting with metastatic disease at initial diagnosis. Over the past decade, regimen combining platinum–etoposide with programmed cell death protein-1 (PD-1) or programmed cell death ligand-1 (PD-L1) inhibitors has become the standard first-line treatment for patients with extensive-stage SCLC (ES-SCLC). Although multiple phase III randomized trials have demonstrated survival benefits for both PD-1– and PD-L1–based regimens, direct comparative evidence between these two classes of immune checkpoint inhibitors remains limited. We therefore conducted a real-world analysis to compare clinical outcomes associated with PD-1 versus PD-L1 inhibitors combined with chemotherapy as first-line treatment for ES-SCLC. Methods: This study retrospectively analyzed 195 patients with ES-SCLC who received PD-1 inhibitors or PD-L1 inhibitors combined with chemotherapy as initial systemic treatment. The patients were divided into two groups: the PD-1 inhibitor plus chemotherapy group (PD-1 group) and the PD-L1 inhibitor plus chemotherapy group (PD-L1 group). Progression-free survival (PFS) and overall survival (OS) were compared and evaluated using the Kaplan-Meier method and Cox regression analysis. The bias between different groups was minimized using propensity score matching (PSM). Results: Among the included 195 patients, 82 (42.1%) received PD-1 inhibitors combined with chemotherapy and 113 (57.9%) received PD-L1 inhibitors combined with chemotherapy. Patients with ES-SCLC harboring liver metastasis were more likely to receive PD-L1 inhibitors combined with chemotherapy ( P < 0.001), but the baseline characteristics were remained balanced included 68 patients per groups after PSM. The results showed that the PFS and OS of patients in the PD-L1 group were significantly better than those in the PD-1 group before (PFS: 7.63 vs. 13.67 months, P < 0.001. OS: 13.33 vs. 23.17 months, P = 0.013) and after PSM (PFS: 7.40 vs. 16.37 months, P < 0.001. OS: 12.47 vs. 19.80 months, P = 0.020). After adjusting for confounders, regimen of PD-L1 inhibitors combined with chemotherapy was still a significant favorable factor for both PFS (HR = 0.43 [95%CI: 0.29-0.63], P < 0.001) and OS (HR = 0.64 [95%CI: 0.41-0.99], P = 0.043). Conclusions: In this retrospective real-world cohort of patients with extensive-stage small cell lung cancer, PD-L1 inhibitors combined with chemotherapy were associated with longer progression-free and overall survival compared with PD-1–based regimens. Given the retrospective design, these findings should be interpreted with caution and warrant further prospective validation.

Survival outcomes and subgroup efficacy analysis of Ga-68-NGUL and Lu-177-DGUL (pocuvotide satetraxetan) in patients with mCRPC: Results from a phase 1/2 study.

5117 Background: Ga-68-NGUL and Lu-177-DGUL (Pocuvotide Satetraxetan) is a novel PSMA-targeting radiopharmaceutical. This study reports the survival outcomes and identifies clinical factors associated with therapeutic response in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: In this phase 1/2 study (NCT05547061), mCRPC patients progressing after ARPI treatment received Lu-177-DGUL (200 mCi every 6 weeks, up to 6 cycles). Efficacy was evaluated using both RECIST v1.1 and PCWG3-modified RECIST v1.1. Key endpoints included ORR, overall survival (OS), and radiographic progression-free survival (rPFS). Results: A total of 91 patients were enrolled. Overall Survival: The median OS was 13.31 months (95% CI: 12.02–17.38). The median rPFS was 11.04 months (95% CI: 8.28–14.29) for the entire cohort. Subgroup Analysis by Metastatic Site: Significant differences in ORR were consistently observed across both criteria. Per RECIST v1.1, the ORR was significantly higher in patients with lung metastases (100% vs. 32.43%, p = 0.0144) and lymph node involvement (48.08% vs. 11.54%, p = 0.0015) compared to those without. These findings align with PCWG3-modified RECIST v1.1 results (Lung: 100% vs. 37.84%, p = 0.0252; LN: 51.92% vs. 19.23%, p = 0.0057). Furthermore, the presence of liver metastases was associated with significantly shorter rPFS compared to those without liver involvement, consistently across RECIST v1.1 (median 5.55 vs. 11.04 months; p = 0.0386) and PCWG3-modified criteria (median 2.76 vs. 8.38 months). Impact of Treatment Cycle on ORR and rPFS: Treatment intensity significantly influenced clinical outcomes across both evaluation criteria (all p < 0.0001). For ORR, under RECIST v1.1 criteria, the ORR was 0% for < 4 cycles, 30% for 4 cycles, and 59.46% for > 4 cycles. Similarly, per PCWG3-modified RECIST v1.1, the ORR improved with the number of cycles (0%, 35%, and 67.57%, respectively). For rPFS, under standard RECIST v1.1, the median rPFS increased with the number of cycles: 2.76 months (95% CI: 2.56–2.86), NE (95% CI: 5.55–NE), and 13.34 months (95% CI: 11.04–NE). Per PCWG3-modified RECIST v1.1, the median rPFS also increased consistently (2.66 months [95% CI: 2.56–2.76], 5.55 months [2.73–NE], and 11.04 months [10.18–14.29], respectively). Conclusions: Ga-68-NGUL and Lu-177-DGUL (Pocuvotide Satetraxetan) demonstrates promising survival benefits in mCRPC. The clinical response is particularly robust in patients with lung or lymph node metastases and those completing more treatment cycles. The significant difference in rPFS observed only under PCWG3-modified criteria highlights the importance of using PCWG3-specific assessments in bone-predominant mCRPC. Clinical trial information: NCT05547061 .

Tegavivint, a downstream Wnt/β-catenin inhibitor: Dose-finding results from a phase 1/2 trial in advanced hepatocellular carcinoma (aHCC).

4015 Background: Wnt/β-catenin pathway activation is a hallmark of many cancers, with Wnt pathway mutations (WPMs) present in ~40% of advanced HCC (aHCC). Tegavivint is a first-in-class small-molecule inhibitor of TBL1, a transcriptional co-factor required for nuclear β-catenin–dependent oncogenic gene expression. Binding of TBL1 by tegavivint disrupts the TBL1/β-catenin complex, resulting in selective degradation of nuclear β-catenin while preserving cytoplasmic and membrane-bound β-catenin functions associated with normal tissue homeostasis. This mechanism inhibits Wnt-driven oncogenicity while avoiding toxicities observed with upstream Wnt inhibitors. Here, we report dose-finding results from an ongoing phase 1/2 study of tegavivint in aHCC (NCT05797805). Methods: This multicenter, open-label phase 1/2 study employs a 3+3 dose-escalation design with backfill, followed by dose optimization. Eligible patients (pts) had aHCC previously treated with ≥1 systemic therapy, BCLC stage C or B disease not amenable to locoregional therapy, and Child-Pugh class A or B (score ≤ 7). WPM status was assessed by liquid biopsy. Tegavivint was administered intravenously once weekly. Primary objectives were safety and tolerability; secondary objectives included preliminary efficacy and PK/PD. Results: As of 21 Jan 2026, 39 pts were enrolled (median age 68 years [range 34–84]); 28 had WPMs, and the median number of prior systemic therapies was 2 (range 1–6). Pts were treated across four dose levels (3–8 mg/kg), demonstrating dose-proportional increases in exposure. At 8 mg/kg, 2 of 5 pts experienced Grade 3 anemia within the DLT window, establishing 3–6.5 mg/kg as the recommended dose range (RDR). Across all doses, the most common (all grade/grade ≥ 3; n/n) TRAEs were fatigue (9/0), hyperbilirubinemia (7/4; isolated, asymptomatic and reversible), anemia (5/5; reversible), myalgia (4/0), and decreased appetite (4/0). Among WPM pts evaluable for efficacy within the RDR (n = 18), those with ≤ 3 previous lines of therapy (n = 9) achieved an overall response rate (ORR) of 22%, disease control rate (DCR) of 89%, and median progression-free survival (mPFS) of 8 mo, compared with 0% ORR, 56% DCR, and 4 mo mPFS in pts treated in later lines (n = 9). No significant clinical benefit was observed in pts without WPMs. Pts remaining on treatment for ≥ 4 months (n = 9) demonstrated concordant improvements in liver enzymes, alpha-fetoprotein, platelet counts, and/or ctDNA variant allele frequency. Conclusions: Tegavivint is the first Wnt/β-catenin inhibitor to demonstrate monotherapy clinical activity and a manageable safety profile in heavily pretreated aHCC pts with WPMs. Observed partial responses, durable disease control, and on-target PD effects in 2L and 3L pts support further development of tegavivint as a monotherapy or in combination with other treatments for this population. Clinical trial information: NCT05797805 .

Trends and disparities in malignant neoplasms and Alzheimer's disease–related mortality in the United States, 1999-2023.

e23363 Background: Malignant neoplasms and Alzheimer’s disease contribute a major mortality burden in U.S. adults. The combined effects of tumor progression and neurodegeneration heighten risk and severity. This study aims to evaluate mortality trends in the United States from 1999 to 2023, stratified by various demographic and geographic factors. Methods: The mortality data from the CDC WONDER multiple cause of death files for adults aged ≥65 years were used to analyze age-adjusted and crude mortality rates (AAMRs and CMRs) per 100,000 through ICD-10 Codes: C00-C97 (malignant neoplasms) and ICD-10 Codes: G30.0, 30.1, 30.8 and 30.9 (Alzheimer’s disease), stratified by year, gender, race/ethnicity, place of death and geography. Joinpoint regression was used to estimate the average annual percent change (AAPC) and the annual percent change (APC) with 95% confidence intervals (CIs). Statistical significance was defined as p < 0.05. Results: From 1999 to 2023, a total of 142,770 deaths were reported among patients of malignant neoplasms and Alzheimer’s disease, most occurring in nursing homes or long-term care facilities. The overall AAMR declined from 13.9 in 1999 to 12.1 in 2023 (AAPC: -0.69; 95% CI: -1.37 to -0.01), with an initial increase until 2006 (APC: 1.50), a sharp decline through 2014 (APC: -4.57), and a subsequent rise in 2021 (APC: 2.81). Men had a higher AAMR (16.34 vs 11.84), but a more pronounced decline in mortality than women (AAPC: -1.12 vs -0.51). Adults aged 85+ years had the highest CMR (60.30). The highest AAMR was observed among non-Hispanic (NH) Blacks (14.39), while the lowest AAMR was noted in NH Asians (6.61). Geographic disparities were evident, with the West having the highest AAMR (16.11) and the Northeast having the lowest AAMR (10.47). Non-Metropolitan (15.51 vs 13.10) areas showed higher AAMR and a mortality decline less than that of metropolitan areas (AAPC: –0.38 vs –0.48). At the state level, North Dakota (24.27) and Oregon (29.40) ranked highest, placing in the top 90th percentile during 1999–2020 and 2021–2023, respectively. Conclusions: Mortality among patients of malignant neoplasms and Alzheimer’s disease has declined over the past two decades, with disproportionate effects observed in older men, NH Blacks, and those in non-metropolitan areas and the West region. These persistent disparities underscore the need for targeted prevention, early detection, and equitable, integrated care for vulnerable populations. Annual average percent change of AAMR for Malignant Neoplasms and Alzheimer's Disease in the United States, 1999 to 2023. Variable Deaths AAPC (95%CI) Overall 142,770 -0.69 (-1.37 to -0.01) Male 63,812 -1.12 (-2.05 to -0.18) Female 78,958 -0.51 (-1.16 to 0.15) Non-metropolitan areas 25,428 -0.38 (-1.07 to 0.32) Metropolitan areas 97,999 -0.48 (-1.01 to 0.06)

Trends and expenditure of cardioprotective drugs in cancer survivors: Medical Expenditure Panel Survey (2016-2023).

e23005 Background: Cardiovascular disease (CVD) is the leading non-cancer cause of death among cancer survivors. Managing this risk increasingly requires a transition from traditional generic therapies (e.g., statins, ACEi) to novel agents (e.g., SGLT2i, GLP-1RA). While these drugs are clinically recommended for survivors comorbidities, their population level economic impact has not been well defined. Methods: We analyzed the 2016–2023 Medical Expenditure Panel Survey (MEPS-HC) to identify U.S. adults with a history of cancer (n=5,165; weighted ~54.3M) and non-cancer controls (n=217,834). We evaluated utilization, total prescription expenditures, and out-of-pocket (OOP) costs across 10 cardioprotective drug classes: statins, ACE inhibitors, ARBs, aspirin, antiplatelets, ezetimibe, GLP-1RA, SGLT2i, PCSK9i, and colchicine. surgery-weighted Pearson chi-square tests and design-based F-statistics accounted for the complex sampling design. Results: Cancer survivors were older (mean age ~68 vs 46 years), with higher prevalence of hypertension (54.5% vs 31.5%), diabetes (18.7% vs 8.1%), and dyslipidemia (56.1% vs 23.1%) than controls (all p<0.001). Survivors more frequently used traditional cardioprotective therapies, including statins (43.7% vs 23.1%) and ACE/ARBs (35.8% vs 18.2%). Aspirin use remained common and stable with negligible expenditures and OOP costs, reflecting its role as a low-cost foundational therapy. Antiplatelet use was higher among survivors and associated with modest but persistent OOP spending. Between 2016 and 2023, mean annual per-patient statin expenditures declined by 65% ($177 to $61). In contrast, expenditures for novel agents increased substantially. Mean per-person SGLT2 inhibitor expenditures rose from $0.36 to $211.55, while GLP-1RA utilization increased from 2.0% to 20.5%. These shifts increased patient cost sharing: survivor OOP costs increased 40-fold for SGLT2 inhibitors ($0.35 to $13.91) and more than four-fold for GLP-1 receptor agonists ($3.69 to $15.83). Socioeconomic disparities were evident, with PCSK9 inhibitor users reporting higher family incomes than non-users ($123,069 vs $85,530), and ezetimibe utilization was higher among Black compared with White survivors (14.8% vs 9.5%; p<0.05). Conclusions: Among U.S. cancer survivors, declining costs of generic cardioprotective therapies have been fully offset by rising expenditures and OOP burdens from newer agents. Access to high-value therapies increasingly reflects socioeconomic disparities more than clinical risk alone. Reducing patient cost sharing will be essential to prevent financial barriers from worsening adherence and long-term cardiovascular outcomes in survivorship.

[211At]Astatine-Based Conditioning with a Humanized CD45 Antibody for Autologous Hematopoietic Stem Cell Gene Therapy

Successful transplantation of autologous gene-modified hematopoietic stem/progenitor cells (HSPCs) requires efficient ablation of resident hematopoietic stem cells. Since conventional myeloablative conditioning regimens are associated with non-hematologic toxicities, we evaluated CD45-directed radioimmunotherapy (RIT) using the a-emitter astatine-211 (211At) before transplantation of ex vivo gene-edited autologous HSPCs as an alternative in nonhuman primates. We humanized the CD45 antibody, BC8 (HuBC8), and labeled it with 211At. As a model, mobilized CD34+ HSPCs were multiplex gene-edited using an adenine base editor, modifying the HBG promoter to reactivate fetal hemoglobin (HbF) and deleting CD33. Two animals each received 300 or 400 µCi/kg of 211At. In contrast to historic controls conditioned with total body irradiation, CD45-RIT animals did not show any noticeable non-hematopoietic toxicities and were almost entirely transfusion independent with rapid recovery of neutrophils and platelets. 211At enabled dose-dependent engraftment of gene-edited cells. A new single cell sequencing assay revealed up to 70% combined mono- and bi-allelic gene-editing efficiency in the blood, consistent with complete replacement of the bone marrow stem cell compartment. Assessment by bulk analysis underestimated the frequency of gene-edited cells, highlighting the importance of a single cell readout. Single cell sequencing further confirmed stable and unbiased contribution of multiplex-edited HSPCs to all mature lineages in the blood, providing high-resolution data assuring successful replacement upon autologous HSPC gene therapy. Levels of edited cells remained stable for the entire follow-up of >18 months. Together, these studies identify 211At-CD45 RIT as a targeted alternative for myeloablative conditioning for autologous gene therapy.

Adsorption process of heavy metals from wastewater: A comprehensive review of adsorbents and process optimization

Submicron Perovskite Quantum Dot Glass Microspheres for Micro‐LED Displays

ABSTRACT Quantum‐dot (QD) color‐conversion technology is considered a promising strategy for constructing a full‐color micro‐LED display. Perovskite quantum dots (PQDs) are the preferred luminescent materials for constructing color‐conversion micro‐LED pixels, but their poor environmental stability severely limits their practical application in micro‐LED displays. Here, we design a novel submicron‐sized PQD glass microspheres (PQDGMS) with high quantum yield and excellent stability for color conversion micro‐LED displays. Kilogram scale (batch 2 kg) submicron‐sized PQDGMS was prepared by a top‐down strategy including melt‐quenching, secondary recrystallization, and optimized submicronization processes. Ultra‐stability of the PQDGMS was attributed to the passivation and self‐healing effects of PQDs by AgBr additive, and the protection effect of the glass matrix around PQDs. The prepared PQDGMS has excellent environmental stability, with PL intensity maintained over 95% after immersion in water for 10 000 h, over 82% at a temperature of 100°C, and over 86% under continuous blue light irradiation (800 W m −2 ) for 240 h. We prepared the PQDGMS color conversion pixels in a patterned through‐hole glass substrate via capillary filling assistance and constructed color conversion green and red micro‐LED chips with external quantum efficiency of 24.8% and 16.7%, respectively.

Beyond survival: Quality of life and symptoms burden among underprivileged breast cancer patients in Sirajganj, Bangladesh.

e24119 Background: While breast cancer survival has improved globally, post-treatment quality of life (QoL) remains inadequately studied in low-resource settings. This study evaluated QoL and symptom burden among socioeconomically underprivileged breast cancer survivors in rural Bangladesh. Methods: A cross-sectional descriptive study was conducted between May 2023 and October 2024 at Shaheed M. Monsur Ali Medical College Hospital, Sirajganj. One hundred histologically confirmed breast cancer survivors completed validated Bangla versions of the EORTC QLQ-C30 and QLQ-BR23 questionnaires. Descriptive statistics and multivariable regression analyses were used to identify predictors of impaired QoL. Results: The mean age was 42 ± 8 years; 48% had stage II and 42% stage III disease. Mean functional domain scores were modest: physical (64%), emotional (56%), cognitive (52%), role (49%), and social functioning (50%). The most burdensome symptoms were fatigue (66%), pain (63%), and financial difficulties (57%). On multivariable analysis, lower educational attainment (p < 0.01), unemployment (p < 0.05), and advanced disease stage (p < 0.05) were independently associated with poorer global QoL. Conclusions: Breast cancer survivors from underprivileged rural communities in Bangladesh experience substantial physical, psychosocial, and financial distress following treatment. Incorporating structured psychosocial support, financial counseling, and survivorship-focused interventions into routine cancer care is essential to improve holistic recovery in low-resource settings.

Patterns of poly(ADP-ribose) polymerase inhibitor use and overall survival in United States veterans with prostate cancer.

e17049 Background: PARP inhibitors (PARPi) are life-prolonging therapies for men with homologous recombination repair (HRR) deficient metastatic castration-resistant prostate cancer (mCRPC). While studies have reported improved clinical outcomes from PARPi, estimates of benefit in diverse patient populations are limited. Here we describe patterns of PARPi use and outcomes in mCRPC in the Veterans Health Administration (VA), which includes a high proportion of Black patients, otherwise significantly underrepresented in the published PARPi studies. Methods: This retrospective cohort included mCRPC patients prescribed a PARPi in the US national VA Healthcare System. Data collection included demographic, clinical, pathologic, and genomic data. Descriptive statistics and survival analyses were conducted, using inverse probability of treatment weighting (IPTW) to adjust for baseline differences by race (Gleason score, prior prostatectomy, stage IV at diagnosis, number of systemic therapies, age at diagnosis, PSA at diagnosis, and PSA at start of PARPi). The primary outcome was overall survival (OS), defined as time from PARPi initiation to death from any cause or censoring. Other outcomes included percent PSA change from baseline, time on PARPi, and genomics-stratified OS. Results: Among 597 Veterans, 79.4% were White and 20.6% Black. Compared to White men, Black men were younger (62 versus 68 yrs), had higher median PSA at diagnosis (19.0 versus 8.8 ng/mL), longer time from diagnosis to PARPi initiation (90.6 versus 69.4 mos), and were more commonly treated with PARPi as ≥4 th line therapy (43.9 versus 31.4%). Median OS from PARPi initiation was 13.7 months (95% CI 12.6-15.8), with no statistically significant difference between Black and White patients after IPTW (p = 0.95). In PSA responders, median time to best PSA response was 5.1 months (IQR 2.7-8.4). The most common HRR variants were BRCA2 , ATM , or CDK12 . In exploratory analyses, patients with BRCA alterations had longer OS than those without (median 15.9 vs 12.6 mos). Black patients with CDK12 alterations had longer OS than those without (median 21.4 vs 12.2 mos). Conclusions: In this real-world cohort of Veterans with mCRPC, Black patients were noted to have higher risk disease and received PARPi later in the course of their prostate cancer, pointing to the need to address equity in practice patterns. After adjustment for baseline differences, survival on PARPi was similar by race. Further research on CDK12 mutations and PARPi response, especially in Black patients, is warranted.

Integrated reflex molecular analysis to preserve clinically actionable targets in lung cancer regardless of specimen quality and panel coverage.

e20759 Background: Comprehensive molecular profiling is essential for precision treatment of lung cancer. However, in routine clinical practice, specimen-related limitations and restricted reportable gene lists may compromise detection of clinically actionable targets. We evaluated the clinical utility of an integrated reflex molecular analysis strategy based on extended re-analysis of next-generation sequencing (NGS) data in a real-world setting. Methods: We retrospectively reviewed consecutive lung cancer cases tested with ODxTT DNA/RNA NGS between 2021 and 2024. As part of institutional reflex molecular testing practice, concurrent single-gene assays included EGFR and KRAS RT-PCR (DNA-based) and ROS1 RT-PCR (RNA-based). All molecular assays were reported independently. ODxTT NGS data were routinely reviewed within the standard analytical environment and, in selected cases, underwent additional integrated molecular re-analysis of the same sequencing data to address specimen- or workflow-related limitations and/or to assess clinically important targets not included in the standard ODxTT reportable gene list. Clinically actionable alterations were identified through integrated pathologist review of all molecular test results generated for each case. Results: Among 465 lung cancer cases analyzed, additional integrated molecular re-analysis was performed in 33 cases (7.1%). Clinically actionable alterations were identified in 22 of these cases (66.7%), compared with 187 of 432 cases (43.3%) that did not require re-analysis (p = 0.0108). EGFR alterations remained a major actionable target, identified in 42.4% of cases undergoing re-analysis. Importantly, actionable alterations identified through extended re-analysis included clinically important targets not included in the standard ODxTT reportable gene list, such as ALK fusion events and NTRK family fusions, demonstrating preservation of clinically relevant targets despite specimen-related or reporting limitations. Conclusions: In a real-world clinical setting, integrated reflex molecular analysis incorporating extended re-analysis of NGS data within the standard analytical environment preserves clinically actionable targets despite suboptimal specimen quality and limited panel reporting. These findings support a pathologist-led, integrated molecular testing strategy to maximize therapeutic opportunities for patients with lung cancer.

Management strategies for PI3K/AKT inhibitor–induced hyperglycemia in HR+/HER2– metastatic breast cancer: A claims analysis.

e13048 Background: PI3K/AKT pathway inhibitors (PI3K/AKTi; alpelisib, inavolisib, and capivasertib) improve outcomes for patients with HR+/HER2– metastatic breast cancer (mBC) and managing potential hyperglycemia is critical to maintaining treatment adherence. Because PI3K/AKT inhibition directly affects insulin signaling, non-insulin antihyperglycemic (AHG) strategies are often preferred. This study describes real-world strategies for hyperglycemia management among patients receiving PI3K/AKTi. Methods: A retrospective cohort study was conducted using the IQVIA PharMetrics Plus database, including adults with mBC who initiated PI3K/AKTi between 05/01/2019 and 03/31/2025. The index date was defined as the first observed claim for a PI3K/AKTi. Patients were categorized by baseline glycemic status during the 6-month pre-index period using ICD-10 diagnosis codes for diabetes (DM), pre-diabetes (Pre-DM), or non-diabetes (Non-DM). DM patients were also required to have ≥1 pre-index AHG claim. Continuous health plan enrollment for ≥6 months prior to index was required; no continuous enrollment requirement was applied post-index. Patients were followed for up to 90 days post-index and censored at the end of the study period, or health plan disenrollment. AHG treatment use before and 90 days after PI3K/AKTi initiation was summarized descriptively, and the difference in % use for each drug class was reported. Results: Among 2,178 patients, 84.3% were Non-DM, 10.7% DM, and 5% Pre-DM at baseline. Prior to PI3K/AKTi initiation, AHG therapy was used by 7.7% of Non-DM and 21.1% of Pre-DM. Following treatment initiation, use of any AHG therapy increased among patients without baseline diabetes (30.2% Non-DM; 30.3% Pre-DM). Based on 90-day absolute percent-point changes from baseline, increases in AHG use among Non-DM patients were observed for biguanides (+26.1), insulin (+7.2), and sulfonylureas (+4.9), with corresponding increases among Pre-DM patients of +22.9, +13.6, and +9.5, respectively. Among patients with baseline diabetes, insulin use increased by 24.4% following initiation, accompanied by a decline in biguanide use (−11.1%) and a modest increase in DPP-4 inhibitor use (+3.9%). Conclusions: In real-world practice, AHG therapy use increased following initiation of PI3K/AKTi, including notable use of insulin among patients with and without baseline diabetes. These findings highlight variability in hyperglycemia management in clinical practice and underscore an opportunity to optimize supportive care during PI3K/AKTi therapy. Results should be interpreted in light of limitations inherent to claims-based analyses, including reliance on ICD-10 diagnosis codes to define diabetic status, which may result in misclassification, particularly among pre-DM patients.

GLP-1 receptor agonists for primary prevention of breast cancer in high-risk women: A real-world analysis of efficacy and safety.

10520 Background: Therapeutic options for breast cancer (BC) prevention for high-risk women remain limited, and not all eligible patients opt for endocrine therapy due to concerns related to adverse events (AEs). GLP1RAs are widely used for obesity and type 2 diabetes mellitus; their role in BC primary prevention (PP) in high-risk women with obesity has not been evaluated. Methods: Using the TriNetX Global Network (150 million patients, 108 organizations), we analyzed de-identified records of high-risk women aged 18–90 years with a BMI ≥ 30 who had health care encounters between January 1, 2000, and January 1, 2025, identified via ICD-10 codes. High risk was defined as at least one of the following: genetic predisposition to BC, family history of BC, atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, or dense breasts. Patients were grouped as having GLP1-RA use or no GLP-1RA use. Patients with a prior history of BC or use of endocrine therapy were excluded. GLP-1RA users were propensity score-matched 1:1 with non-users based on demographics, comorbidities, social determinants of health, lifestyle factors, BMI, HbA1c, and prior breast imaging. Incident BC served as the primary endpoint, with key AEs as secondary measures. Kaplan–Meier analysis and Cox proportional hazards models were utilized to assess outcomes, which were further validated through subgroup and sensitivity analyses. Results: Among 80,480 high-risk women with a BMI ≥ 30, 46,581 were assigned to each cohort. Baseline demographics were balanced between cohorts (mean age: 46 years, 70% White, 21% Black). Median follow-up was 2,790 vs 2,630 days for GLP-1RA users and non-users, respectively. BC incidence was 2.95% in GLP-1RA users (1,164/39,495 cases) vs 3.01% in non-users (1,200/39,057 cases) (3.27 vs. 3.57 cases per 1,000 person-years; HR 0.844; 95% CI, 0.779–0.915). GLP-1RA users exhibited an increased risk of endometrial cancer (HR 1.273; 95% CI, 1.088–1.491) and osteoporosis (HR 1.124; 95% CI, 1.054–1.199). No significant association was observed for venous thromboembolism. Gastrointestinal AEs were significantly higher in the GLP-1RA cohort. Conclusions: GLP-1RA use was associated with a modest reduction in BC incidence among high-risk women with obesity in this real-world study. Prospective randomized trials are needed to validate these associations.

Stage distribution, treatment patterns, and stage-specific survival in Merkel cell carcinoma before and after the immunotherapy era: A SEER analysis (2004–2022).

e21556 Background: Merkel cell carcinoma (MCC) survival has improved in recent years. Whether this reflects earlier diagnosis or better stage-specific treatment is unclear. Methods: We performed a retrospective cohort study of MCC in the SEER database (2004–2022). Eras were defined as pre-immunotherapy proxy (Pre-IO, 2004–2015) and IO-era proxy (2016–2022). Stage at diagnosis was categorized as localized, regional, distant, or unknown (Summary Stage). Overall survival (OS) was assessed using the Kaplan–Meier method and stage-specific Cox models, adjusted for age (<65, 65–79, ≥80), sex, and race/ethnicity. Local therapy patterns (surgery, radiation) for localized/regional cases were examined by era and age. Results: Among 5,969 MCC patients (3,313 Pre-IO; 2,656 IO-era), stage distribution was localized 54.7%, regional 26.9%, distant 9.8%, unknown 8.6%. Compared with Pre-IO, the IO-era showed more regional (24.3%→30.2%; +5.8 pp) and less localized disease (56.6%→52.3%; −4.3 pp); distant stage was stable. Stage-specific survival improved in the IO-era proxy. Distant: median OS 10→12 mo; 2-yr OS 24.2%→40.6%; 5-yr OS 14.0%→23.4%; adjusted HR 0.75 (p=0.004). Regional: median OS 30→64 mo; 2-yr OS 54.5%→69.6%; 5-yr OS 38.0%→51.0%; HR 0.71 (p<0.001). Localized: median OS 71 mo→NR; 2-yr OS 72.5%→76.6%; 5-yr OS 53.3%→58.1%; HR 0.91 (p=0.11). Decomposition of the overall 2-yr OS (61.8%→69.1%) showed a minimal stage-shift effect (−0.61 pp) and gains driven by within-stage survival (+7.97 pp). Treatment patterns indicated age-related de-intensification. In localized IO-era MCC, surgery + RT occurred in 49.4% (<65) vs 27.4% (≥80). In regional MCC ≥80, surgery+RT declined (53.0%→42.1%) while neither therapy increased (7.1%→14.5%). Conclusions: MCC stage distribution showed minimal stage migration, yet OS improved substantially after 2016—especially in Regional and Distant disease. Survival gains were driven primarily by within-stage improvements rather than stage migration. Persistent age-related differences in local therapy suggest undertreatment of older adults. OS Pre-IO proxy vs IO-era proxy by stage. Stage Median OS (mo) 2-yr OS % 5-yr OS % Adjusted HR P value Localized 71→NR 72.5→76.6 53.3→58.1 0.91 0.11 Regional 30→64 54.5→69.6 38.0→51.0 0.71 <0.001 Distant 10→12 24.2→40.6 14.0→23.4 0.75 0.004 Unknown 31→34 55.8→52.0 35.6→38.8 1.06 0.66