Browse Articles

Sex differences in thyroid cancer in Hanoi: Incidence trends and projections to 2045 from the Hanoi Cancer Registry.

e18080 Background: Thyroid cancer epidemiology has shown distinct sex-related differences, with women historically having higher incidence rates than men in many regions. However, data from low- and middle-income countries (LMICs) such as Vietnam are limited. The objective of this study was to project sex differences in Thyroid cancer incidence over the next two decades. Methods: Thyroid cancer data (ICD-10 code C73) from 1990 to 2020 were obtained from the Hanoi Cancer Registry, alongside population data from the Vietnam General Statistics Office. Age-standardized rates (ASR) were calculated using the WHO World Standard Population (2000). Poisson regression models were performed to project future incidence for men and women. Future incidence was projected under the assumption that the estimated Annual Percentage Change (APC) from the most recently identified trend segment would remain constant through 2045. Results: Sex differences in disease burden were observed throughout the study period. In 1990, the ASR was similarly low for both sexes (men: 0.3; women: 0.8 per 100,000) (Table 1). Between 1990 and 2020, ASR among women increased to nearly seven times that observed in men (57.7 vs. 8.2 per 100,000 person-years). The highest risk among women was observed in those 49 years and younger. From 2020 to 2045, the gap between women and men is projected to remain unchanged (57.7 vs. 8.2 per 100,000). Conclusions: Thyroid cancer in Hanoi is predominantly a women's phenomenon, driven by a disproportionate surge in cases among young and middle-aged women. The incidence gap in thyroid cancer between women and men significantly widened from 1991 to 2020 and is projected to remain unchanged over the next two decades. However, the magnitude of their differences may be overestimated due to potential overdiagnosis among women. Public health strategies in Vietnam and other LMICs with similar population characteristics and thyroid cancer burden should prioritize care and treatment for women to narrow the gap. Two-decade projection of age-standardized thyroid cancer incidence rates per 100,000 person-years in Hanoi, Vietnam. Women Men Year Cases ASR (95% CI) Cases ASR (95% CI) 1990 9 0.8 (0.3-1.3) 4 0.3 (0.0-0.6) 2000 47 3.6 (2.6-4.7) 17 1.5 (0.8-2.2) 2010 352 10.4 (9.3-11.5) 80 2.6 (2.0-3.2) 2020 2,523 57.7 (55.4-59.9) 343 8.2 (7.3-9.1) 2025 2,822 57.6 (55.5-59.8) 385 8.2 (7.4-9.0) 2030 3,079 57.7 (55.6-59.7) 412 8.2 (7.4-9.0) 2035 3,309 57.7 (55.7-59.7) 435 8.2 (7.4-9.0) 2040 3,494 57.7 (55.7-59.6) 468 8.2 (7.5-9.0) 2045 3,617 57.7 (55.7-59.6) 497 8.2 (7.5-9.0)

Farnesyl transferase inhibitor (FTI) darlifarnib (KO-2806) in combination with adagrasib in <i>KRAS</i> G12C mutated (mut) advanced solid tumors: Preliminary results from the FIT-001 phase 1 first-in-human trial.

3078 Background: Clinical response to RAS inhibitors (RASi) is often limited by inherent/adaptive resistance mediated by persistent mTORC1 signaling. RHEB is a farnesylation-dependent protein required for mTORC1 activation. Darlifarnib, a potent next-generation FTI, selectively inhibits mTORC1 pathway activation and demonstrates synergistic antitumor activity in combination with the KRAS G12C inhibitor adagrasib (ada) in preclinical models, supporting potential to improve clinical activity in KRAS G12C mut tumors. Methods: FIT-001 (NCT06026410) is an ongoing, multicenter, open-label Ph1 dose escalation/expansion study of darlifarnib in advanced solid tumors. Darlifarnib 3, 5 or 8 mg QD D1–7, D15–21 + ada 400 mg BID in 28d cycles was evaluated in heavily pretreated pts with KRAS G12C mut NSCLC, PDAC or CRC. Primary objectives: safety/tolerability; key secondary objective: antitumor activity. Results: Dose escalation resulted in candidate darlifarnib doses of 3 and 5 mg. As of 15 Dec 2025, 30 pts (median age 61y; 63% male; 83% White; 93% baseline [BL] Karnofsky performance status 80–100%) received ≥1 darlifarnib 3 (n=15) or 5 mg (n=15) + ada dose. Primary tumor types: 30% NSCLC, 20% PDAC, 50% CRC. Pts were heavily pretreated: 43% had ≥3 prior systemic therapies; 40% had prior KRASi. Both darlifarnib 3 and 5 mg + ada were well tolerated; most common (≥30%) any-grade (Gr) treatment-emergent AEs (TEAEs): 63% diarrhea, 57% nausea, 50% anemia, 43% vomiting, 40% neutropenia, 40% thrombocytopenia. Most common (≥15%) Gr ≥3 TEAEs: 30% neutropenia, 17% anemia. 1 dose limiting toxicity occurred (anemia, darlifarnib 5 mg + ada). Most common treatment (trx) discontinuation reason was progressive disease (n=10). With a median follow-up of 23 wks, 13 pts remained on trx. Preliminary results from 25 response-evaluable pts (≥1 darlifarnib dose + post BL scan) included confirmed + unconfirmed responses. Antitumor activity was observed in all tumor types. Across darlifarnib 3 and 5 mg + ada dose levels, ORRs (95% CI) were 67% (22.3–95.7) for NSCLC, 60% (14.7–94.7) for PDAC, 14% (1.8–42.8) for CRC (Table); DCRs (CR+PR+SD): 83% (35.9–99.6) for NSCLC, 100% (47.8–100) for PDAC, 71% (41.9–91.6) for CRC. Updated data across all doses to be presented. Conclusions: Darlifarnib 3 and 5 mg + ada were well tolerated with encouraging antitumor activity in heavily pretreated KRAS G12C mut NSCLC, PDAC and CRC. These preliminary data support further investigation of darlifarnib + KRASi, such as ada, to address mTORC1-mediated resistance and potentially improve clinical outcomes for pts. Clinical trial information: NCT06026410 . n (%) Darli 3 mg + ada Darli 5 mg + ada Total NSCLC 3 3 6 ORR a 1 (33) 3 (100) 4 (67) DCR 2 (67) 3 (100) 5 (83) PDAC 2 3 5 ORR a 2 (100) 1 (33) b 3 (60) b DCR 2 (100) 3 (100) 5 (100) CRC 6 8 14 ORR a 0 2 (25) 2 (14) DCR 3 (50) 7 (88) 10 (71) a Confirmed+unconfirmed responses. b 1 uPR post datacut.

The role of sarcopenia and adiposity in prognosis of pleural mesothelioma: A CT-based analysis.

8053 Background: Pleural mesothelioma (PM) is a rare malignancy associated with asbestos exposure and characterized by an aggressive clinical course and poor prognosis. Identifying clinical and biological prognostic markers is of significant clinical importance. Recently, computed tomography (CT) based body composition parameters have been investigated for their association with survival outcomes in cancer patients; however, their prognostic value in PM remains unclear. This study aimed to evaluate the impact of clinical characteristics and CT-derived body composition parameters on survival in patients with PM. Methods: This retrospective study included 73 patients diagnosed with pleural mesothelioma. CT images were used to calculate the subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), total abdominal adipose tissue index (TATI), skeletal muscle index (SMI), and psoas muscle index (PMI). Patients were classified as sarcopenic or non-sarcopenic based on SMI. Results: The median age was 60 years, and 57.5% of patients were male. Most patients had good performance status (ECOG 0–1), and the epithelioid subtype was the most common histology. Approximately one-third of patients had a history of smoking or prior surgery. In univariate analysis, age ≥60 years was significantly associated with increased mortality. In multivariate analysis, age ≥60 years (HR 2.45) and male sex (HR 2.13) were identified as independent poor prognostic factors. Non-sarcopenic patients had a significantly lower risk of mortality compared with sarcopenic patients (HR 0.37). Additionally, higher TATI values were associated with increased mortality risk (HR 2.26). Kaplan–Meier analysis demonstrated significantly shorter OS in patients aged ≥60 years (Table). Conclusions: In patients with pleural mesothelioma, advanced age and male sex are associated with poorer survival, whereas preserved skeletal muscle mass is associated with improved outcomes. Increased abdominal adiposity is linked to higher mortality risk. CT-based body composition parameters may provide useful prognostic information in patients with PM. Evaluation of the association between parameters and survival using univariate and multivariate analyses. Univariate analysis Multivariate analysis P value HR 95% CI P value HR 95% CI Age (&lt;60y / ≥60y) 0.005 2.27 1.27-4.05 0.005 2.45 1.31-4.61 Gender (female*/male) 0.06 1.65 0.96-2.83 0.011 2.13 1.19-3.81 ECOG PS (0-1*/2-3) 0.35 1.43 0.66-3.07 Histological subtypes (epithelioid / non-epithelioid) 0.26 1.42 0.76-2.66 Stage (I-III*/IV) 0.43 1.26 0.70-2.27 SMI cm 2 /m 2 (sarcopenia*/normal) 0.21 0.70 0.41-1.21 0.007 0.37 0.18-0.76 TATI cm 2 /m 2 (low*/high) 0.30 1.36 0.75-2.48 0.04 2.26 1.03-4.97

Patient reported outcomes (PRO) during and after multimodal treatment for resectable esophageal adenocarcinoma in the prospective, randomized, controlled, multicenter phase III ESOPEC trial.

105 Background: The ESOPEC trial showed that perioperative chemotherapy improved survival compared with preoperative chemoradiotherapy in pts with esophageal adenocarcinoma (EAC). Here we report on PRO which was a key secondary endpoint. Methods: Pts with cT1 cN+ cM0 or cT2-4a cNany cM0 EAC were randomized between perioperative chemotherapy with FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) or preoperative chemoradiotherapy with CROSS (41.4Gy/carboplatin/paclitaxel) both plus tumor resection. PRO was measured using the EORTC Quality of Life Questionnaire Core 30 (C30), Oesophageal Cancer Module (OES18) and Chemotherapy-Induced Peripheral Neuropathy Module (CIPN20) at baseline and during treatment and follow-up. The global health status / QOL (GH; C30), physical functioning (PF; C30), fatigue (FA; C30), dyspnoea (DY; C30), eating problems (EP; OES18), and sensory scale (SS; CIPN20) were chosen as primary outcomes. Predefined time points for comparison of PRO between treatment groups were directly before surgery, after discharge from surgery, and 6, 12, 24, and 36 months after start of treatment. Analyses were performed with mixed linear models for repeated measurements. Results: Of 438 randomized patients, 401 (197 FLOT, 204 CROSS) were included in the PRO analysis. Differences between The FLOT and CROSS groups are shown in the table. Before, surgery, GH and PF were higher in the FLOT group, while FA, DY, and EP were less pronounced in the FLOT as compared to CROSS group. At discharge from surgery and at follow-up, no significant differences in GH, PF, FA, DY, and EP were measured. Results in SS were worse in FLOT as compared to CROSS at all timepoints. Conclusions: Patients treated with FLOT as compared to CROSS reported better PRO results following neoadjuvant therapy and before surgery. In contrast, sensory problems were higher in FLOT versus CROSS over the whole treatment trajectory and follow-up. Clinical trial information: NCT02509286 . Adjusted mean difference in points (FLOT minus CROSS)with 95%-CI and two-sided p-value Preoperatively Discharge 6 months 36 months Global health status / QOL* 6.3 (1.1,11.5)p=0.019 0.6 (-4.9,6.1)p=0.83 -4.3 (-9.6,1.0)p=0.11 2.7 (-3.4,8.8)p=0.38 Physical functioning* 7.7 (3.1,12.4)p=0.001 5.3 (-0.6,11.1)p=0.076 -3.1 (-9.0,2.7)p=0.29 2.8 (-3.5,9.1)p=0.39 Fatigue** -8.6 (-14.2,-3.0)p=0.003 -2.7 (-9.1,3.7)p=0.41 5.2 (-1.5,11.8)p=0.13 -4.8 (-12.3,2.6)p=0.20 Dyspnoea** -10.9 (-17.1,-4.7)p&lt;0.001 -1.8 (-10.5,6.8)p=0.68 1.5 (-7.5,10.4)p=0.75 0.7 (-8.9,10.2)p=0.89 Eating problems** -12.7 (-18.9,-6.4)p&lt;0.001 -2.9 (-10.1,4.3)p=0.43 -0.0 (-7.3,7.3)p=1.00 -5.3 (-13.5,3.0)p=0.21 Sensory scale** 14.8 (11.6,18.0)p&lt;0.001 4.8 (1.7,8.0)p=0.003 14.6 (10.7,18.5)p&lt;0.001 7.1 (1.1,13.0)p=0.020 *Higher scores indicate better QOL/function. **Higher scores indicate more symptoms.

TROPION-Urothelial03: A phase 2/3 study of datopotamab deruxtecan (Dato-DXd) + platinum chemotherapy (CT) vs gemcitabine + platinum CT in participants with locally advanced or metastatic urothelial carcinoma (la/mUC) with progression on or after enfortumab vedotin (EV) + pembrolizumab.

TPS4642 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a Phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, Phase 2/3 trial. In Part A (Phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In Part B (Phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended Phase 3 dose (determined using Part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in Part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in Part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab (&lt;6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of Part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of Part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (Part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (Part B). In Part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In Part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

FLT3 inhibitors in acute myeloid leukemia: A network meta-analysis of phase III trials.

e18505 Background: FLT3 inhibitors improve outcomes in FLT3-mutated acute myeloid leukemia (AML); however, no head-to-head phase III comparisons exist among available agents. Updated randomized data from RATIFY (midostaurin), QUANTUM-First (quizartinib), and ADMIRAL (gilteritinib) enable indirect comparative effectiveness assessment of FLT3-directed therapy across treatment settings. Methods: A frequentist network meta-analysis was performed using phase III randomized trials enrolling FLT3-mutated AML patients. Reported hazard ratios (HRs) for overall survival (OS) and event-free survival (EFS) were extracted. Random-effects network models estimated treatment effects versus chemotherapy and ranking probabilities (P-scores). The evidence network was anchored through shared chemotherapy control arms. Frontline survival comparisons included RATIFY and QUANTUM-First; ADMIRAL was analyzed separately due to relapse/refractory (R/R) population differences. Results: Across five comparisons (~1,600 patients), midostaurin (HR 0.78; 95% CI 0.63–0.96) and quizartinib (HR 0.78; 95% CI 0.62–0.98) each significantly reduced mortality versus placebo in frontline AML. Indirect comparison demonstrated no detectable difference between the two agents (HR 1.00; 95% CI 0.73–1.36). Ranking analysis assigned near-identical P-scores to midostaurin and quizartinib (0.74 vs 0.74), supporting equivalent likelihood of benefit in the frontline setting. In the R/R population, gilteritinib significantly improved survival compared with salvage chemotherapy (HR 0.64; 95% CI 0.49–0.83). Conclusions: Midostaurin and quizartinib demonstrate equivalent survival probability in frontline FLT3-mutated AML based on current randomized evidence, challenging assumptions of superiority among FLT3 inhibitors. Gilteritinib remains an effective salvage option in relapsed disease but reflects a distinct treatment setting rather than comparative frontline potency. Interpretation is limited by cross-trial differences in age eligibility, FLT3 subtype inclusion, chemotherapy backbones, and trial era, which may affect transitivity assumptions in this network meta-analysis. This frequentist network meta-analysis incorporates mature survival updates from RATIFY and QUANTUM-First and demonstrates near-identical ranking probabilities (P-scores 0.74 vs 0.74), supporting equivalent frontline survival benefit of midostaurin and quizartinib. Future head-to-head trials incorporating MRD response and transplant-adjusted outcomes are warranted to refine sequencing strategies for FLT3-directed therapy.

Distinct genomic and microenvironmental profiles of brain metastases in renal cell carcinoma: Insights into hypoxia-driven adaptation and therapeutic vulnerabilities.

2033 Background: Brain metastases (BM) in renal cell carcinoma (RCC) are associated with poor prognosis and may exhibit unique genomic alterations influenced by the tumor microenvironment (TME), differing from primary tumors or extracranial metastases (ECM). This study aimed to characterize these differences to identify potential therapeutic targets. Methods: 3,913 RCC samples underwent NGS of DNA and RNA at Caris Life Sciences (Phoenix, AZ) and were linked to corresponding insurance claims data. Real-world overall survival (rwOS) was calculated from the date of sample collection to last contact using Cox PH model and log-rank testing. Genomic alterations were compared at an adjusted significance level of 0.05 using Fisher’s exact test. TME differences between the primary RCC, BM and ECM were assessed by therapeutic target gene expression using Mann-Whitney U test, gene set enrichment analysis (GSEA) by normalized enrichment scores (NES) and false discovery rates (FDR), and a gene expression-based score reflecting HIF1-associated metabolic and stress-response pathways. Results: The cohort consisted of 1,775 primary, 138 BM, and 2,000 ECM. Median age was different in BM vs ECM vs primary (64 vs 66 vs 63 y, p&lt;0.0001). Approximately 75% of BM patients had not received any systemic or radiation therapy prior to tissue collection. The rwOS was 49.4 months for primary, and 30.3 months for both BM and ECM (BM vs. ECM: HR=0.96, 95%CI: 0.76-1.22, p=0.796). Genomic profiling revealed, in BM compared with primary tumors, CDKN2B deletions (41% vs. 18.1%, p&lt;0.0001), as well as PTEN (22.5% vs 6.7%, p&lt;0.0001), and TP53 mutations (22.7% vs 11%, p=0.0088). Gene expression analysis demonstrated no significant differences in the expression of RCC novel therapeutic targets, including CD70 , ENPP3 , CA9 , HLA-G , CDH6 and FOLH1 , between BM and primary (p&gt;0.05). Compared to primary, GSEA revealed BM were enriched in pathways including epithelial-mesenchymal transition (NES=3.41, FDR&lt;0.001), mTORC1 signaling (NES=3.05, FDR=0.002), hypoxia (NES=2.68, FDR=0.009), and others. Compared to ECM, BM showed hypoxia enrichment (NES=2.90, FDR=0.023), while ECM was enriched in mitotic spindle (NES=-3.84, FDR&lt;0.0001) and G2M checkpoints (NES=-3.32, FDR&lt;0.0001). The HIF1-associated hypoxia score was significantly higher in BM vs primary (p&lt;0.01). Conclusions: Conserved expression of multiple actionable RCC therapeutic targets across primary and BM sites supports the biological feasibility of emerging targeted and immune-based therapies in CNS disease. The findings provide a biologic framework for understanding RCC BM and highlight hypoxia-associated pathways. Key limitations include the use of tissue-based rather than clinically adjudicated BM definitions, and the lack of cancer stage information.

Divergent transcriptomic signatures and microenvironmental markers of <i>KRAS</i> and <i>BRAF</i> mutations in colorectal cancer: A multi-omics integrative analysis.

3668 Background: KRAS and BRAF mutations are critical drivers in colorectal cancer (CRC), acting as key nodes in the MAPK signaling pathway. While their genomic prevalence is well-documented, the specific transcriptomic programs they trigger and how these programs differ between KRAS and BRAF variants remain a subject of intense translational interest. This study utilizes a multi-omics approach to define mutation-specific signatures that could inform personalized therapeutic strategies. Methods: We performed an integrated analysis of SNV/Indel data and gene expression profiles from 192 CRC patients. Patients were stratified into BRAF -mutant (n=20), KRAS -mutant (n=102), and MAPK-wild-type (WT, n=64) groups. Frequency was calculated as the percentage of unique samples mutated per gene. Differential expression analysis (DEA) was utilized to identify significant (p &lt; 0.05) gene expression changes specific to each driver mutation. Results: The most frequently mutated genes were TP53 (79.2%), APC (56.8%), and KRAS (53.1%). BRAF mutations were identified in 10.4% of the cohort. KRAS -mutant tumors exhibited a specific upregulation of SPP1 (osteopontin) and TGFBI . These markers are associated with extracellular matrix remodeling and TGF-β signaling, suggesting that KRAS mutations may actively contribute to an immune-excluded tumor phenotype. BRAF -mutant CRC was characterized by a distinct signature involving ABI3BP upregulation and a profound downregulation of CTNNBL1 (p &lt; 0.00001). Additionally, a cluster of small nucleolar RNAs ( SNORA2B , SNORA9 ) was significantly elevated, pointing toward altered ribosome biogenesis or non-coding RNA regulation unique to the BRAF -mutant subset. While both mutations activate the MAPK pathway, the downstream transcriptomic output is significantly divergent, with KRAS favoring myeloid-recruiting signals ( SPP1 ) and BRAF favoring structural and RNA-processing alterations. Conclusions: Our multi-omics integration reveals that KRAS and BRAF mutations in CRC are not transcriptomically redundant. The discovery of SPP1 as a KRAS -associated marker and CTNNBL1 as a BRAF -linked marker provides novel avenues for targeted therapy and patient stratification. Specifically, KRAS -mutant patients might benefit from therapies targeting the SPP1 -TGF-β axis in combination with standard care.

Trends and disparities in esophageal cancer mortality in the United States, 1999-2023.

e16102 Background: Esophageal cancer remains a significant cause of cancer mortality in the United States. While overall trends have been reported, less is known regarding contemporary long-term patterns and specific disparities across demographic and geographic strata. We aimed to characterize esophageal cancer mortality trajectories and identify populations with divergent outcomes by age, race/ethnicity, geographic region, and urbanization status. Methods: We analyzed esophageal cancer mortality data from 1999 to 2023 using the Centers for Disease Control and Prevention (CDC) WONDER database. Age-adjusted mortality rates (AAMRs) were standardized to the 2000 U.S. standard population. Joinpoint regression analysis was utilized to estimate the annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CIs). Analyses were stratified by age, sex, race/ethnicity, census region, state, and urbanization level. Results: Overall esophageal cancer mortality in the U.S. declined significantly from 1999 to 2023 (AAPC, -0.81%; 95% CI, -0.97% to -0.65%; P &lt; 0.001). Declines were observed across most age groups, with the steepest reductions among adults aged 45-54 years (AAPC, -1.68%; 95% CI, -2.01% to -1.35%) and 55-64 years (AAPC, -1.25%; 95% CI, -1.51% to -0.99%). Marked racial and ethnic disparities were identified. Non-Hispanic (NH) Black individuals experienced the most rapid decline (AAPC, -4.07%; 95% CI, -4.42% to -3.72%). Conversely, trends among NH White individuals remained stable overall (AAPC, -0.05%; P = 0.59), characterized by an initial increase from 1999 to 2005 (APC, 1.14%; P = 0.002) followed by a modest decline from 2005 to 2023 (APC, -0.44%; P &lt; 0.001). Regionally, the West demonstrated the largest decline (AAPC, -1.13%; 95% CI, -1.26% to -0.99%), followed by the Northeast (AAPC, -1.05%). West Virginia was the only state to exhibit a significant increase in mortality (AAPC, 1.01%; 95% CI, 0.38% to 1.64%; P = 0.003). Mortality declined significantly in metropolitan areas (AAPC, -1.09%; P &lt; 0.001), while trends in nonmetropolitan areas remained stagnant (AAPC, 0.48%; P = 0.12). Conclusions: Despite a national decline in esophageal cancer mortality, substantial disparities persist across racial, geographic, and urbanization groups. The dramatic improvement among NH Black populations contrasts with the relative stability in NH White populations and the lack of progress in nonmetropolitan areas. The significant rise in mortality in West Virginia warrants targeted investigation. These findings underscore the critical need for population-tailored strategies to ensure equitable progress in cancer prevention and care.

ETCTN 10302: A randomized phase II trial of radium-223 dichloride in combination with paclitaxel in patients with bone metastatic breast cancer.

3096 Background: Radium-223 dichloride is an alpha particle emitting radiopharmaceutical that mimics calcium and localizes bone metastases inducing double-strand DNA breaks. Tumor cells in M-phase cell cycle arrest from paclitaxel are highly sensitive to alpha-emitting radionuclides. ETCTN 10302 tested the hypothesis that addition of radium-223 to paclitaxel will improve outcomes for bone-dominant metastatic breast cancer. Methods: ETCTN 10302 was a randomized, two-arm, multicenter, open-label phase II trial. Patients (pts) were randomized to receive either radium-223 (1.49 microcurie/kg iv day 1 x 6 doses) and paclitaxel (80 mg/kg iv on days 1,8 and 15) of each 28-day cycle (Arm A) or paclitaxel alone (Arm B). Inclusion criteria included HER2-negative metastatic breast cancer with ≥2 bone lesions and limited visceral metastases (five or less and ≤4 cm in size). Primary endpoint was median progression-free survival (PFS). Exploratory analyses included whole exome sequencing and serum alkaline phosphatase dynamics. Results: 70 pts were randomized from August 2020 to May 2024. Median age was 58.5 years, 100% were female, 60% were non-Hispanic whites, 14% had triple negative breast cancer, 37% had bone only disease. In the intent-to-treat analysis (37 Arm A, 33 Arm B), there was no significant difference in median PFS (5.8 vs 5.6 months; HR 0.92 p=0.80) but there was a numeric improvement in median OS in radium-223 plus paclitaxel arm (20.2 vs 16.6 months; HR 0.74 p=0.40). Overall response rate (ORR) was 5% in Arm A vs 9% in Arm B. There was no difference in median OS and PFS when analysis was limited to efficacy evaluable pts who completed at least one cycle (37 Arm A, 24 Arm B). Common treatment-related adverse events (TRAE) with the combination of radium-223 plus paclitaxel vs paclitaxel were anemia (78% vs 54%), neutropenia (76% vs 45%), fatigue (49% vs 50%), nausea/vomiting (46% vs 21%), diarrhea (32% vs 25%), peripheral sensory neuropathy (33% vs 30%) and increased ALT (22% vs 4%). Most common ≥grade 3 TRAE was neutropenia in Arm A (43% vs 8% in Arm B). Treatment discontinuation rate due to TRAE was 3%. Conclusions: Combination of radium-223 and paclitaxel can be administered safely as most adverse events observed were grade 1 to 2 except for higher incidence of ≥ grade 3 neutropenia. The trial did not meet the primary PFS endpoint but there was a numerical improvement observed in median OS with the combination. Clinical trial information: NCT04090398 .

Phase 1, multi-center clinical trial evaluating the safety, pharmacokinetics, pharmacodynamics and anti-cancer activity of PQ203, a first-in-class peptide drug conjugate targeting SORT1 in patients with advanced solid tumor malignancies (NCT07190469).

TPS3171 Background: Antibody–drug conjugates (ADCs) have improved outcomes in several refractory cancers by enabling the targeted delivery of potent cytotoxins but their use is limited by suboptimal payload release, off-target and immune-related toxicities, poor tumor penetration and complex manufacturing. Peptide drug conjugates (PDCs) offer potential advantages over ADCs including smaller size, increased tumor penetration, more rapid systemic clearance and decreased immunogenicity. PQ203 is a first in class, AI-designed PDC comprised of a 17 amino acid peptide targeting sortilin (SORT1) conjugated to the cytotoxin monomethyl auristatin E (MMAE) via a para-amino-benzyl-valine-citrulline (PAB-VC) cleavable linker. SORT1, a receptor of the Vps10p family involved in protein trafficking, is overexpressed across multiple tumor types and associated with tumor invasiveness. Preclinical breast cancer models, including patient-derived xenografts, show that PQ203 can overcome resistance to commonly used TOP1-based ADCs. Methods: This first-in-human, multi-country Phase 1A/B dose-escalation, expansion and optimization clinical trial is designed to assess the safety, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary anti-tumor activity of PQ203. Treatment consists of once weekly IV infusion × 4 weeks (Q1Wx4) and continues until the occurrence of disease progression or dose-limiting toxicity. In Part 1 of the study, up to 7 dose cohorts are anticipated (commencing at 0.02 mg/kg) in a backfill Bayesian optimization (BF-BOIN) dose escalation design with a target toxicity rate of 27.5%. Upon satisfaction of pre-defined safety criteria for particular dosing cohorts, up to 9 additional patients (pts.) in pre-defined settings of biologic and clinical interest may be enrolled to backfill expansion of that dose level. Upon identification of one or more recommended doses for expansion, up to 50 pts. across 1-3 tumor types of particular clinical interest, including pts. with triple negative breast cancer, will be enrolled in the expansion and dose optimization phases of the study. Alternative dosing schedule(s) with reduced frequency may additionally be explored based on emerging PK and safety data. At the time of submission, cohorts 1 and 2 were completed without DLTs and enrollment of Cohort 3 was initiated in January, 2026. Clinical trial information: NCT07190469 .

Global evolution of HER2-targeted clinical trials across solid tumors: Shifts in tumor representation, biomarker definitions, therapeutic modalities, and geographic leadership.

e23085 Background: HER2 has expanded from a breast-restricted biomarker to a pan-tumor therapeutic target, driven by advances in antibody–drug conjugates, next-generation TKIs, refined HER2-low assays, and recognition of HER2 mutations. Despite this rapid evolution, the global landscape of HER2-directed clinical trials spanning tumor types, biomarker categories, therapeutic modalities, and geographic trends remains undefined. A comprehensive mapping is needed to clarify these shifts and guide next-generation HER2-targeted development and global trial design. Methods: A landscape analysis of interventional HER2-targeted trials was performed using ClinicalTrials.gov harmonized with AACT (cutoff December 2024). Trials were identified using HER2/ERBB2 terms, HER2-low and HER2-mutant criteria, and HER2-directed agents (trastuzumab, pertuzumab, T-DM1, T-DXd, tucatinib, neratinib, lapatinib, pyrotinib, poziotinib). Extracted variables included tumor type, phase, biomarker definitions, therapeutic modality, sponsor, design architecture, and geographic distribution. Temporal trends from 2005–2024 were assessed. Results: Across 1,327 HER2-targeted trials, early development was dominated by breast cancer (&gt; 50% before 2015). After 2020, breast trials fell to 28%, while studies in other tumors expanded sharply gastric (14%), lung (12%), colorectal (11%), biliary (6%), and gynecologic (5%). HER2-mutant trials increased from &lt; 1% to 17%, driven by mutation-focused TKIs. HER2-low trials rose to 22% after the success of T-DXd. Therapeutically, ADCs showed the fastest growth, increasing from 6% of trials in 2010 to 41% in 2024. Monoclonal antibody regimens decreased from 48% to 19%. TKI development concentrated heavily in Asia, which now conducts 63% of global TKI trials. Randomized trials increased from 12% to 31%, and HER2–immunotherapy combinations from 2% to 18%. Industry sponsored 59% of trials, academic groups 31%, and government programs 10%. Global activity expanded from 17 countries pre-2010 to 59 countries by 2024. Conclusions: The global HER2-targeted trial landscape has shifted dramatically from a breast-focused, monoclonal-antibody era to a broad, biomarker-driven, and therapeutically diverse ecosystem across many solid tumors. Three major trends stand out: (1) rapid growth of HER2-low and HER2-mutant trial programs(2) ADCs becoming the dominant driver of HER2 drug development (3) Asia emerging as the global leader in TKI innovation. These shifts highlight the need for clearer biomarker standards, especially for HER2-low, and for coordinated development of pan-tumor HER2-directed strategies. This comprehensive mapping helps define priorities for the next generation of HER2-targeted therapies and reflects the rapidly evolving global geography of HER2 innovation.

Racial disparities in in-hospital outcomes among patients with lung cancer receiving immune checkpoint inhibitors: A National Inpatient Sample analysis.

e23072 Background: Lung cancer is the second most common cancer and the leading cause of cancer-related mortality in the United States. Immune checkpoint inhibitors (ICI) are increasingly used in first line therapy in selected patients, with demonstrated improvements in survival. Despite advances in systemic therapy, inpatient hospitalizations due to ICI complications remain common. Prior studies have shown that African Americans experience worse cancer-related outcomes, in part due to social determinants of health. However, data evaluating race-based differences in inpatient outcomes among hospitalized patients with lung cancer receiving ICI are limited. This study examines racial differences in in-hospital outcomes among patients with lung cancer treated with ICI. Methods: We conducted a retrospective cohort study using the National Inpatient Sample database from 2015 to 2022. Patients with lung cancer of any stage who were hospitalized for ICI-related complications were identified. Inpatient outcomes were compared across racial groups. Multivariable logistic regression models adjusted for patient demographics, hospital-level factors, and comorbidity burden using the Elixhauser Comorbidity Index. Primary endpoint was in-hospital mortality. Secondary outcomes included ICI-associated complications and intensive care unit (ICU)-level therapies. Statistical significance was defined as a p &lt; 0.001. Results: A total of 5,574 hospitalizations were studied. After multivariable adjustment, African American patients had higher in-hospital mortality than White patients (OR 1.1, CI 1.1 - 1.17). African Americans were associated with increased odds of admissions for ICI-related complications, including pneumonitis (OR 2.2, CI 2.0 - 2.04), colitis (OR 1.8, CI 1.6 - 2.0), carditis (OR 2.5, CI 2.2 - 2.8), transaminitis (OR 1.8, CI 1.7 - 2.0), anemia (OR 1.8, CI 1.7 - 1.8), acute kidney injury (OR 1.2, CI 1.1 - 1.8), and arrhythmias (OR 1.2, CI 1.1 - 1.2). African Americans were more likely to experience ICU-level therapies, including shock (OR 1.1, CI 1.0 - 1.2), vasopressors (OR 1.1, CI 1.1 - 1.2), mechanical ventilation (OR 1.1, CI 1.1 - 1.2), and continuous renal replacement therapy (CRRT) (OR 1.2, CI 1.1 - 1.2). (all p &lt; 0.001). Conclusions: In this cohort study, African American patients hospitalized with lung cancer receiving ICIs experienced significantly worse in-hospital outcomes than White patients. These findings highlight persistent racial disparities in inpatient clinical outcomes despite advances in treatment and ICI management. Further, these results underscore the need for targeted interventions, improved risk stratification, and investigation into the structural and clinical factors contributing to these disparities. Future work should focus on identifying actionable drivers to improve equity in outcomes.

Therapy-related myeloid neoplasms after radioligand therapy in neuroendocrine tumors: A multicenter real-world analysis.

4181 Background: Therapy-related myeloid neoplasms (t-MNs), including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), represent a rare but serious long-term hematological toxicity associated with radioligand therapy (RLT). Real-world data on the incidence of t-MNs and associated risk factors following RLT in are limited. We sought to investigate the incidence and risk factors of t-MN in patients with NETs treated with 177Lu-Dotatate. Methods: We conducted a multicenter retrospective cohort study using the TriNetX research network. Adult patients with NETs who received 177Lu-Dotatate were identified, with first administration defined as the index date. The primary outcome was development of t-MNs (incident MDS or AML) with a 12-month latency period after target treatment. Incidence was calculated and Cox proportional hazards models were used to evaluate associations between baseline covariates and t-MN risk. Covariates included age, sex, race, primary tumor site (small bowel, colon, pancreas, lung), liver and bone metastases, prior alkylating chemotherapy (temozolomide exposure), chronic kidney disease (CKD), and nicotine or alcohol dependence. Treatment pathways were assessed for 177Lu-Dotatate re-treatment and temozolomide. Results: A total of 1,811 patients met inclusion criteria. Mean age at index was 65.4 ± 10.9 years; 977 (54.0%) were male, and 1,503 (83.0%) were White. Median follow-up duration was 20.5 months. Following 177Lu-Dotatate, 37 of 1,807 patients (2.05%) developed MDS, and 15 of 1,804 patients (0.83%) developed AML, with an overall incidence of t-MNs 2.88% (52/1,804). At baseline, mean age (67.1 ± 9.3 vs 65.4 ± 11.0 years, p=0.27) and sex (males 42.0% vs 54.2%, p=0.14) were comparable between patients who did and did not develop t-MNs. On multivariable Cox proportional analysis, higher age at index (HR 1.03; 95% CI 1.01–1.07; p=0.048) and baseline CKD (HR 2.69; 95% CI 1.32–5.49; p=0.006) were independently associated with increased risk of t-MNs. Sex, race, primary tumor site, presence of liver or bone metastases, alkylating chemotherapy exposure, and nicotine or alcohol dependence were not significantly associated with t-MN risk. Evaluation of treatment pathways demonstrated similar 177Lu-Dotatate re-treatment rates (2.33% vs 2.77%, p=1.0), and comparable receipt of temozolomide for ≥12 months (18.6% vs 16.4%, p=0.66) between groups that did and did not develop t-MNs, respectively. Conclusions: In this large real-world cohort of NET patients treated with 177Lu-Dotatate, t-MNs were uncommon but clinically significant. Older age and CKD were associated with increased risk, whereas repeat 177Lu-Dotatate and alkylating chemotherapy exposure were not associated with increased t-MN incidence. These findings may inform risk stratification, patient counseling, and long-term hematologic surveillance following 177Lu-Dotatate.

Breaking barriers: Evaluation of a low-threshold community-based HPV vaccination model for gender minorities and sex workers in Milan.

1542 Background: Human Papillomavirus (HPV) is the primary etiological factor for anogenital and oropharyngeal cancers. Sexual and gender minorities (SGM) and sex workers (SW) face an increased risk of HPV-related diseases but encounter significant barriers to vaccination, including stigma, discrimination in healthcare settings, and low risk perception. "VaccinaMILAN*" is a community-based initiative designed to enhance vaccine accessibility by offering the first dose of the 9-valent vaccine in safe and inclusive environments, such as Milan's "rainbow" districts during weekend evening hours. This study assessed the demographic characteristics, risk factors, and barriers within this hard-to-reach population. Methods: An anonymous paper-based questionnaire was administered to participants vaccinated during the May and October 2024 editions of VaccinaMILAN*. The survey evaluated demographics, gender identity, sexual behaviors, HPV knowledge, vaccination barriers, and satisfaction with the community approach. Categorical variables were described using frequencies and percentages; data were analyzed using Chi-square tests (two-tailed p-value &lt; 0.05). Results: 320 questionnaires were collected (response rate: 76.2%). Most respondents were under 35 years old (68.7%) and held a university degree (65.9%). The sample primarily consisted of cisgender MSM (76.9%), followed by cisgender female SWs (13.4%) and gender minorities (9.8%). Despite a high prevalence of receptive anal intercourse (61.7%), 95.4% had never undergone anal cancer screening. HPV knowledge was significantly higher among younger participants (p = 0.0063) and university graduates (p = 0.0169). Reported barriers included: 45.7% did not know how to access vaccination; 25.4% did not perceive themselves at risk; approximately 20% had previously experienced vaccination refusal in traditional healthcare settings. Overall, 99.7% expressed satisfaction with the initiative. Conclusions: The VaccinaMILAN* project demonstrates the effectiveness of a multidisciplinary community-based approach in improving vaccine equity for marginalized populations. The findings highlight the urgent need for targeted awareness campaigns and specific training for healthcare providers regarding HPV vaccination and anal cancer screening recommendations for these populations.

Iterative Synthesis of Pentacene Derivatives with Continuous Boron–Oxygen Bonds

ABSTRACT Iterative syntheses—repeating sequences of the same reactions to construct complex molecules—can facilitate the synthesis of specific classes of small molecules with structural redundancies, including acenes. Despite the prevalence of zigzag edges in the structures of acenes, few examples that effectively manipulate the edge configurations of acenes exist. In this study, the rationally designed iterative synthesis of three pentacene derivatives with continuous boron–oxygen bonds at the zigzag edges is reported. The simple and efficient two‐step iteration employed ipso iodination with a trimethylsilyl group as the directing group and Suzuki cross‐coupling/condensation reactions. Because of the fundamental role of pentacene derivatives in a broad spectrum of electronic applications, these findings are valuable across a diverse range of chemical and physical disciplines.

Dose-finding and optimization in drug development for rare diseases

Recent Advances and Prospects in Skin‐Integrated Electronics: Flexible Sensing Systems for Robotics, Human‐Machine Interaction, and Health Monitoring

ABSTRACT Biological skin is among the most sophisticated organs and mediates essential sensory function. Inspired by its structure and function, skin‐integrated flexible sensing systems have developed rapidly and demonstrated significant utility in applications such as closed‐loop robotic control, human‐machine interaction, and health monitoring. These systems typically comprise sensing components and electrodes/circuits for signal acquisition, transmission, and processing, that can provide direct feedback to users or support control signals to actuators. A central objective in this field is the integration of appropriate flexible materials to fabricate functional units that optimally balance response sensitivity and mechanical compliance for special scenarios. This review systematically summarizes sensing components for mechanical stimuli (pressing, stretching, bending, and twisting) and evaluates material selection and optimization strategies according to distinct transduction mechanisms, including capacitive, piezoelectric, resistive, triboelectric effects, etc. Besides, the review investigates the design and layout of flexible signal‐acquisition electrodes and processing circuits, and surveys recent progress in deformation‐invariant high‐conductivity materials. Specific applications in electrophysiological monitoring and physicochemical sensing of biological fluids are discussed in detail. Finally, the review highlights current challenges and future perspectives to guide material development, optimization, and applications of next‐generation intelligent electronic skins.

Learning from the literature: An AI-assisted Bayesian framework for evidence-driven oncology trial design.

e23010 Background: Designing modern oncology trials requires synthesizing prior evidence to inform hypotheses and sample size estimation. Incomplete or imprecise literature summaries can lead to mis-specified hypotheses and underpowered studies. To address this gap, we developed LEAD-ONC (Literature to Evidence for Analytics &amp; Design in Oncology), an AI-assisted platform that extracts trial data from published studies and performs Bayesian evidence synthesis to support evidence-driven trial design. Methods: Using expert-curated publications meeting prespecified criteria, LEAD-ONC applies large language models to extract baseline characteristics from published tables and reconstruct individual-patient data (IPD) from Kaplan–Meier curves. Trials are clustered by similarity in baseline characteristics to define comparable populations, including cohorts enrolling multiple histologies (i.e., trials enrolling both squamous and non-squamous disease). Within each cluster, Bayesian hierarchical models are fitted to reconstructed IPD to generate predictive survival distributions for new trials enrolling similar populations. Results: IPD were reconstructed from five completed phase III non–small-cell lung cancer trials evaluating chemo-immunotherapy versus intensified immunotherapy strategies involving PD-1/PD-L1 inhibitors with or without CTLA-4 inhibition. LEAD-ONC identified three population groupings: non-squamous (KEYNOTE-189), squamous (KEYNOTE-407), and multi-histology trial populations (POSEIDON, CheckMate-227, CheckMate-9LA). For a hypothetical randomized trial enrolling a multi-histology population, comparing standard chemo-immunotherapy with intensified regimens incorporating dual immune checkpoint blockade (± chemotherapy), the predicted median overall survival difference was 2.8 months (95% CI, −1.8 to 7.6), with a 0.45 probability of achieving a ≥3-month OS benefit. Conclusions: Integrating AI-based data extraction with Bayesian hierarchical modeling enables scalable learning from published trials and provides an evidence-driven framework for oncology trial design. Projected overall survival by immunotherapy strategy in multi-histology NSCLC trials. Time OS (Mono-ICI) OS (Dual-ICIs) OS Differences Mean 2.5% CI 97.5% CI Mean 2.5% CI 97.5% CI Mean 2.5% CI 97.5% CI 12 0.54 0.48 0.59 0.58 0.52 0.63 0.04 -0.04 0.12 24 0.35 0.30 0.41 0.41 0.36 0.46 0.06 -0.02 0.13 36 0.24 0.20 0.29 0.30 0.25 0.36 0.06 -0.01 0.13 48 0.17 0.13 0.22 0.23 0.19 0.28 0.06 -0.01 0.12 60 0.13 0.09 0.17 0.18 0.14 0.23 0.05 -0.01 0.12 72 0.09 0.06 0.13 0.14 0.10 0.19 0.05 -0.01 0.10

Clinicopathological profile of gastric cancer in a Bolivian cohort: A retrospective analysis from the Instituto Gastroenterológico Boliviano Japonés (2020–2025).

e16022 Background: Gastric cancer remains a leading cause of cancer-related mortality worldwide, particularly in low- and middle-income countries. Regional epidemiological data are critical to inform public health strategies and clinical decision-making. Methods: We conducted a retrospective review of the clinical records of patients admitted with clinically suspected gastric malignancy based on symptoms or findings during endoscopy at the Instituto Gastroenterológico Boliviano Japones (La Paz, Bolivia) between 2020 and 2025. Of 106 initially identified cases, 3 were excluded due to confirmed benign disease, leaving 103 patients for analysis. Histopathological confirmation was available in 80 cases (77.7%); the remaining 23 cases were clinically or endoscopically highly suspicious for malignancy but lacked histopathological confirmation. Demographic, clinical, endoscopic, pathological, and treatment-related variables were extracted and analyzed descriptively. Results: Of the 80 patients included, the median age at diagnosis was 55 years (range: 21–83), with 17.7% (n = 11) of patients under 40 years. Female patients comprised 53.2% (n = 33) of the cohort. Notably, no patient reported tobacco use, while 16.7% (n = 10) consumed alcohol and 6.5% (n = 4) had a family history of gastric cancer. Helicobacter pylori was detected in 69% (29/42) of tested patients. The most common occupations were housewives (21.7%), technical workers (20%), and farmers (15%). Among the 40 patients with documented timelines, the median symptom-to-diagnosis interval was 116 days (range: 2–461). Endoscopically, 83.6% of lesions were proximal. Histologically, 77.5% (n = 62) had adenocarcinoma, 17.5% (n = 14) gastric lymphoma, and 5% (n = 4) GIST. The majority (61.3%, n = 38) had poorly or undifferentiated tumors, and 37.1% (n = 23) presented with signet-ring cell histology. At diagnosis, 61% (n = 36) were stage IV, and 49.2% (n = 30) had carcinomatosis. Only 13.1% (n = 8) underwent curative-intent surgery (total or partial gastrectomy); 18% (n = 11) received palliative surgery or laparoscopy, and 65% (n = 39) were managed with palliative intent. In-hospital mortality was 11.3% (n = 7). Conclusions: This is the first data collected in Bolivia about gastric cancer. This cohort reflects a pattern of late diagnosis, aggressive histology, and limited access to curative therapy, despite a complete absence of tobacco use—a notable finding in global gastric cancer epidemiology. The high prevalence of H. pylori , prolonged symptom-to-diagnosis interval, and predominance of proximal, poorly differentiated tumors underscore the need for region-specific prevention programs, including H. pylori eradication and early endoscopic screening in high-risk populations. Keywords: gastric cancer, epidemiology, Bolivia, Helicobacter pylori , ASCO Global Health.