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Achieving Zero Phase Transition in P2‐Type Layered Oxides via Targeted Chemical Design for Zero‐Strain Sodium Storage
ABSTRACT P2‐type layered oxide cathodes dominate sodium‐ion batteries (SIBs) due to exceptional sodium ion kinetics. However, longstanding phase transitions (e.g., P2‐to‐O2) not only compromise this inherent kinetic advantage but also cause severe stress strain undermining structural stability. Here, we propose a stage‐specific chemical design that targetly addresses de‐sodiated interlayer O 2− repulsion, the structural origin of phase transitions in P2 cathodes. The designed Na 0.67 Ni 0.05 Fe 0.05 Ti 0.05 Cu 0.2 Mn 0.65 O 2 (NFTCM) cathode shows a record Na‐layer spacing (3.67 Å) with reduced negative charge on oxygen ions, maximally lowering O 2− –O 2− repulsion during the entire desodiation process. As evidenced by in situ X‐ray diffraction, the NFTCM cathode shows a true zero‐phase‐transition behavior with a record‐low volume variation of 0.062% upon cycling. This stable, zero‐strain Na ions storage behavior contributes to exceptional rate capability (121 mA h/g at 10C) and remarkably stable cycling, retaining 93.7% capacity after 600 cycles. Furthermore, operando neutron diffraction data indicate that the eliminated phase transition also enables a robust oxygen framework, a crucial factor in stabilizing the ion storage process of layered oxides.
Timing of statin initiation for primary atherosclerotic cardiovascular disease (ASCVD) prevention following lung cancer screening in Missouri: A retrospective cohort study.
e22537 Background: Individuals undergoing lung cancer screening (LCS) represent a population at elevated risk for Atherosclerotic Cardiovascular Disease (ASCVD) due to overlapping risk factors like smoking. Although statin therapy is recommended for many individuals undergoing LCS, little is known about the timing of statin initiation in relation to LCS, particularly among statin-naïve individuals. We examined time to statin initiation following LCS and factors associated with earlier prescribing. Methods: We conducted a retrospective cohort study using electronic health record data from Barnes Jewish healthcare system in Missouri. Adults aged 50–80 years who underwent LCS between 2022–2023, were statin-naïve, and met 2019 ACC/AHA criteria for primary prevention were included. The primary outcome was time from LCS to statin initiation. Kaplan–Meier methods described statin uptake over time, and multivariable Cox proportional hazards models estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for predictors of statin initiation. Results: Among 3,223 statin-eligible individuals (mean age 64.9±6.4 years; 48.7% female; 24.4% Black), only 33.6% (n = 1,082) were prescribed a statin within one year following LCS. Cumulative statin initiation remained low over time, with 2.9% by 90 days, 5.7% by 180 days, and 11.2% by 360 days post-LCS. Median time to statin initiation was not reached due to high censoring (66.4%). In adjusted analyses, earlier statin initiation was associated with diabetes (HR 1.36, 95% CI 1.18–1.57), hypertension (HR 1.44, 95% CI 1.24–1.67), chronic kidney disease (HR 1.21, 95% CI 1.01–1.44), and a cardiology visit in the year preceding LCS (HR 1.25, 95% CI 1.07–1.45). Former smokers were more likely to initiate statins than current smokers (HR 1.16, 95% CI 1.01–1.34). Increasing age was modestly associated with lower likelihood of initiation (HR per year 0.98, 95% CI 0.97–0.99). ASCVD risk category was not independently associated with time to statin initiation when compared with low risk (high risk HR 1.45, 95% CI 0.84–2.50). Race, sex, insurance type, and area deprivation index were not significantly associated with statin initiation. Conclusions: Among statin-eligible patients with no prior statin use before lung cancer screening, statin initiation was uncommon and substantially delayed. Prescribing was driven by comorbid conditions and specialty care rather than calculated ASCVD risk. Integrating cardiovascular risk assessment and preventive decision support into LCS workflows may reduce missed opportunities for ASCVD prevention in this high-risk population.
Clinical outcomes from a multi-institution precision oncology tumor board: The PROMOTE study update.
e23355 Background: The role of next generation sequencing to identify unique genetic makeup of a tumor has become monumental in cancer care. The implementation of molecular tumor boards (MTB) provides a multidisciplinary approach to guide individualized treatment options for each patient. Since 2022, the University of Illinois Cancer Center has adapted monthly Precision Oncology Tumor Board (POTB) discussions for this purpose. Since the establishment of the POTB, the program has expanded to include other institutions in the Chicago and surrounding area. We aim to analyze the impact of POTB recommendations on PFS for patients across all types of cancer. Methods: We investigated patients presented at POTB between September 2022 to May 2025 and gathered data through retrospective chart review. Patient demographics including age, sex, race, ethnicity, insurance, cancer type, cancer stage, time from diagnosis, and recommendation category were obtained. We defined PFS1 as the line of therapy prior to initiation of POTB recommended therapy and PFS2 as the POTB recommended therapy started as a subsequent line of therapy. The PFS2/PFS1 ratio was calculated to determine significant clinical benefit from POTB recommendations. Results: A total of 100 patients were included in the analysis and of these, 28 patients received POTB recommendations that led to change in therapy. In our POTB group (n = 28), 82% of patients were older than 64 years of age and 78% of patients were receiving Medicare or Medicaid. The study population comprised patients who were Asian (14%), Black (39%), and White (39%). At presentation, 75% of patients had stage IV disease, with lung cancer being the most common malignancy (36%). About 50% of patients were presented at POTB at >1 year after diagnosis and targeted therapy was recommended in 57% of patients, while immunotherapy in 21% and chemotherapy in 7%. PFS1 was found to be 6.9 months versus 5.2 months for PFS2 with a p-value of 0.5379. The PFS2/PFS1 ratio is 0.75. Conclusions: The advancement of precision oncology has allowed an increase in treatment options for patients with advanced cancers. Our cohort represents a small proportion of patients but supports a trend towards improved PFS in patients when tumor molecular profiling is used to guide care. Qualitatively, MTBs also expand patient care by offering improved access to clinical trials and re-evaluation of precision oncology strategies by the MTB. Our study represents one of the most racially and ethnically diverse groups of patients to be presented in a molecular tumor board cohort. As MTBs continue to be integrated into cancer care, additional data is needed to quantify their clinical impact.
Real-world pharmacovigilance analysis for antibody drug conjugates (ADCs) in treatment of solid tumor malignancies.
e20503 Background: Despite their efficacy in targeted cancer therapy, antibody-drug conjugates (ADCs) come with unique toxicity profiles that may be incompletely captured in their trials for FDA approval. We sought to define real-world toxicity phenotypes across FDA-approved ADCs and to evaluate the effect of payload class, linker chemistry, and target expression on patterns of toxicity with the goal of informing clinically actionable monitoring strategies. Methods: We conducted a disproportionality analysis of FDA Adverse Event Reporting System (FAERS) pharmacovigilance data (Q1 2021–Q1 2024) for six FDA-approved ADCs: trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), enfortumab vedotin (EV), mirvetuximab soravtansine (MIRV), tisotumab vedotin (TV), and trastuzumab emtansine (T-DM1). We then calculated reporting odds ratios (RORs) and proportional reporting ratios at the MedDRA preferred-term level using primary suspect reports. Safety signals were then interpreted in the context of payload pharmacology and linker stability. Results: Distinct and reproducible toxicity phenotypes were observed across ADC classes. Among topoisomerase I inhibitor (TOPO1) - based ADCs with cleavable linkers, divergent systemic toxicity profiles emerged. T-DXd (n = 4,845) demonstrated a strong pulmonary toxicity signal, including interstitial lung disease and pneumonitis (ROR = 34.6), and was additionally associated with hematologic toxicity, including neutrophil count decrease (ROR = 9.9) and haematotoxicity (ROR = 8.4). In contrast, SG (n = 2,100) was primarily associated with neutropenic colitis (ROR = 108.0), neutropenia (ROR = 55.7), and neutropenic sepsis (ROR = 404.0). Among MMAE-based ADCs studied, toxicity profiles aligned with target organ expression. EV (n = 2,206) showed disproportionately high rates of cutaneous toxicity (ROR = 55.4) and peripheral neuropathy (ROR = 74.3), while TV (n = 389) exhibited marked ocular surface toxicity (ROR = 470.0). Within the maytansinoid class, class- and linker-specific toxicities were evident. MIRV (n = 474) was associated with significant ocular toxicity (ROR = 466.0), whereas T-DM1 (n = 1,479) showed hepatic microvascular injury, including nodular regenerative hyperplasia (ROR = 267.5) and portal hypertension (ROR = 82.4). Conclusions: ADC toxicity is not class-wide but is instead affected by payload, linker, and target. TOPO1 inhibitor ADCs showed divergent toxicity profiles despite payloads, while MMAE ADCs have toxicities related to target expression in normal tissues. Maytansinoid ADC toxicities were distinct, reflecting both payload-dependent effects (DM4 vs DM1) and target-dependent effects (T-DM1). These findings highlight the need for mechanism-informed toxicity monitoring and tailored supportive care strategies to optimize the therapeutic index of ADCs in oncology practice.
Association of immunoglobulin replacement with infection and mortality outcomes in multiple myeloma patients receiving bispecific antibodies: A TriNetX analysis.
e19526 Background: Bispecific antibodies have transformed the treatment landscape for relapsed or refractory multiple myeloma (MM) but are associated with high rates of serious infections. Immunoglobulin replacement therapy is variably used in clinical practice, and its impact on infectious outcomes in this setting remains incompletely characterized. We evaluated the association of early immunoglobulin replacement and infection and mortality outcomes in MM patients treated with bispecific antibodies. Methods: Using TriNetX, a federated network of de-identified electronic health records from participating healthcare organizations, we identified adults aged ≥18 years with MM who initiated bispecific antibody therapy (teclistamab, elranatamab, or talquetamab). Patients receiving immunoglobulin replacement within one month of bispecific initiation were compared with those who did not receive immunoglobulin replacement. Cohorts were propensity score–matched 1:1 on demographic factors, comorbidities, and prior myeloma therapies. The primary outcome was serious infection within 90 days. Ninety-day all-cause mortality was assessed as a secondary outcome. Results: After matching, 858 patients were included (429 per cohort). Serious infections occurred in 13.3% of patients receiving immunoglobulin replacement compared with 19.3% of those who did not (p = 0.016). Ninety-day mortality was 9.1% in the immunoglobulin group and 19.8% in the no-immunoglobulin group (p < 0.001). Conclusions: In this real-world cohort of MM patients treated with bispecific antibodies, early immunoglobulin replacement was associated with lower risks of serious infection and early mortality. These findings suggest a potential role for immunoglobulin replacement in reducing early infectious risk among patients receiving bispecific antibodies and support further prospective evaluation.
Clinical outcomes of immune checkpoint inhibitors in combination with tyrosine kinase inhibitors in metastatic MSS/pMMR colorectal cancer: A systematic review and meta-analysis.
e15593 Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in microsatellite-stable or mismatch repair-proficient (MSS/pMMR) metastatic colorectal cancer (CRC). Aberrant angiogenesis and an immunosuppressive tumor microenvironment contribute to resistance to immunotherapy in this population. Tyrosine kinase inhibitors (TKIs) may enhance antitumor immunity, providing a rationale for combination with ICIs. We conducted a systematic review & meta-analysis to evaluate efficacy and safety of TKI-ICI combinations in patients with MSS/pMMR metastatic CRC. Methods: A systematic search of PubMed, Embase, and Cochrane databases was done through December 2025 to identify studies reporting outcomes of ICI + TKI in CRC. Objective response rate (ORR) was defined as a combination of complete response and partial response, while disease control rate (DCR) was defined as a combination of ORR and stable disease. ORR, DCR, ≥ grade 3 treatment-associated adverse event rates (TRAEs), and median progression-free survival (PFS) were pooled using the random-effects model and inverse-variance methods to report effect size with its 95% CI. Results: A total of 13 clinical trials, comprising 1183 patients with metastatic MSS/pMMR CRC treated with ICI + TKI, were included. The mean age of the patients was 58.1 years, and 41% were women. ECOG performance status of 0 was present in 44.4% of the patients, and 65% of them had BRAF and/or RAS mutations. The pooled ORR was 11.6% (95% CI, 6.6-17.7) with substantial heterogeneity (I² = 84.4%). The pooled DCR was 62.8% (95% CI, 53-72.2), also with high heterogeneity (I² = 85.3%). Median PFS pooled across 13 studies was 3.45 months (95% CI, 2.78-4.13). Pooled rate of ≥ grade 3 TRAEs was 30.8%. Subgroup analysis by the type of TKI showed that studies using regorafenib had lower DCR and ORR (51.52% & 9.93%) when compared to studies using cabozantinib (87.07% & 26.01%) (p < 0.001). Meta-regression analyses, including ECOG 0 status, age, female sex, BRAF/RAS mutation, or presence of right-sided CRC, were not significantly associated with ORR or DCR. Conclusions: In this meta-analysis, outcomes with ICI+TKI in MSS/pMMR metastatic colorectal cancer were associated with modest objective responses and short median PFS, but a relatively high disease control rate. Cabozantinib+ICI showed better ORR and DCR when compared with regorafenib + ICI, although patient numbers were much lower in studies of the former. ORR & DCR stratified by the type of TKI administered. TKIs No. of Trials Total No. of MSS/pMMR participants ORR DCR Fruquintinib 2 118 15.4 [7.7 - 25.1] 80.8 [64.5 - 94.1] Zanzalitinib 1 451 3.5 [1.7 - 5.4] 53.7 [48.9 - 58.4] Regorafenib 7 327 9.9 [3.0 - 19.7] 51.5 [40.5 - 62.5] Cabozantinib 2 46 26.0 [13.9 - 40.1] 87.1 [75.2 - 95.8] Lenvatinib 1 241 10.4 [6.0 -14.3] - Overall 13 1183 11.62 [6.6 - 17.7] 62.8 [53.1 - 72.2]
WhatsApp-based behavioral intervention and adherence to adjuvant endocrine therapy in early breast cancer: Real-world data from Brazil.
e13706 Background: Adjuvant endocrine therapy significantly reduces recurrence and mortality in patients with early-stage estrogen receptor–positive breast cancer. Despite its proven benefit, long-term adherence remains suboptimal, mainly due to treatment-related adverse effects and unintentional non-adherence. Digital behavioral interventions may represent a scalable strategy to improve adherence in real-world settings. Methods: In this randomized study, 143 post-surgical patients with luminal breast cancer were assigned to two cohorts. Cohort A received standard adjuvant endocrine therapy (tamoxifen or anastrozole) plus weekly automated WhatsApp reminders reinforcing the importance of daily medication adherence for one year (June 2024–May 2025). Cohort B received standard of care without behavioral intervention. Adherence was assessed every three months based on patient-reported missed doses and pill counts, with remaining tablets used to estimate non-adherent days. Adherence outcomes between groups were compared using the Mann–Whitney U test, a non-parametric statistical test used to compare paired or independent samples when the data do not follow a normal distribution. Results: Most patients were women aged 45–60 years, predominantly married or partnered, with secondary-level education. Over one year of follow-up, Cohort A reported a higher number of leftover tablets compared with Cohort B. Although no statistically significant differences in adherence were observed between groups across quarterly assessments (p = 1.00, 0.67, and 0.27 for the second, third, and fourth quarters, respectively), a trend toward improved adherence over time was noted in the intervention group, suggesting that the effect of the behavioral intervention may increase with longer follow-up. Patients receiving WhatsApp reminders may have developed greater awareness of their treatment routines, resulting in more accurate reporting of missed doses, while higher non-response rates in the control group may have underestimated true non-adherence. Conclusions: In this real-world randomized study, a WhatsApp-based behavioral intervention did not achieve statistical significance in improving adherence to adjuvant endocrine therapy over one year. However, the observed trend suggests that longer follow-up and larger sample sizes may allow detection of clinically meaningful differences. These findings support continued investigation of digital behavioral strategies to optimize adherence to endocrine therapy in early breast cancer. Clinical trial information: 79420124.1.0000.5071.
Association between gabapentinoid exposure and chemotherapy-associated peripheral neuropathy among adults starting new neurotoxic chemotherapy in a multi-hospital health system.
e24202 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity of taxane, platinum, and vinca alkaloid chemotherapy. While duloxetine is recommended for painful CIPN, preventive pharmacologic strategies are limited. Gabapentinoids are frequently used in clinical practice despite minimal evidence of preventive benefit. We evaluated the association between gabapentinoid exposure during chemotherapy and documented drug induced polyneuropathy in a real world cohort. Methods: We conducted a retrospective cohort study using electronic health record data from a multi-hospital health system. Adults receiving neurotoxic chemotherapy (paclitaxel, docetaxel, oxaliplatin, cisplatin, or vincristine) between July 2025 and January 2026 were included. Exposure was defined as receipt of any gabapentin or pregabalin during chemotherapy. The primary outcome was documentation of chemotherapy-associated peripheral neuropathy, defined by ICD-10-CM code G62.0 and/or chemotherapy adverse-effect codes (T45.1X5A, T45.1X5D, T88.7XXS) after chemotherapy initiation. Rates were compared between exposed and unexposed patients and stratified by taxane and platinum regimens. Secondary analyses evaluated G62.0 alone with gabapentinoid exposure. Results: Among 565 patients, the mean age was 66, and 26% were female; 130 (23.0%) had documented neuropathy. Gabapentinoid exposure was present in 182 (32.2%). Neuropathy occurred in 66/182 exposed patients (36.3%) versus 64/383 unexposed patients (16.7%) (RR 2.17, 95% CI 1.60–2.95). Among taxane-treated patients, neuropathy occurred in 49/116 exposed (42.2%) versus 31/200 unexposed (15.5%) (RR 2.72, 95% CI 1.86–3.98). Among platinum-treated patients, neuropathy occurred in 20/65 exposed (30.8%) versus 33/162 unexposed (20.4%) (RR 1.51, 95% CI 0.92–2.48). In secondary analyses limited to G62.0, neuropathy occurred in 64/182 exposed patients (35.2%) versus 59/383 unexposed patients (15.4%) (RR 2.29, 95% CI 1.71–3.07). Conclusions: Gabapentinoid exposure at initiation and or during neurotoxic chemotherapy was associated with higher rates of documented chemotherapy-associated peripheral neuropathy, particularly among taxane-treated patients. Secondary analyses also showed higher neuropathy rates among gabapentinoid-exposed patients. Because the timing of gabapentinoid initiation relative to neuropathy onset cannot be determined, causal inference is limited. Prospective studies are needed to assess preventive or disease-modifying effects. Cohort Gabapentinoid Exposed n/N (%) Unexposed n/N (%) Relative Risk (95% CI) Overall 66 / 182 (36.3%) 64 / 383 (16.7%) 2.17 (1.60–2.95) Taxane-based 49 / 116 (42.2%) 31 / 200 (15.5%) 2.72 (1.86–3.98) Platinum-based 20 / 65 (30.8%) 33 / 162 (20.4%) 1.51 (0.92–2.48)
Effect of type and location of <i>BRCA2</i> deleterious variant on prognosis and survival in metastatic prostate cancer: A longitudinal, international, cohort study from hormone-sensitive to castration-resistant settings.
10503 Background: Emerging evidence suggests that BRCA -altered prostate cancer (PC) is not a unique molecular subtype. However, the prognostic and therapeutic relevance of specific pathogenic/likely pathogenic variant (PV) in metastatic PC (mPC) remains poorly defined. We investigated the impact of BRCA2 PV type and position on clinical outcomes across across different metastatic settings. Methods: This international, hospital-based cohort study (Jan 2020–Apr 2025) included mPC patients (pts) across 29 centers who underwent germline, somatic, and/or ctDNA BRCA testing. Analysis included three settings: 1) mHSPC (ADT+docetaxel vs. ADT+ARPi); 2) mCRPC (ARPi vs. taxanes); 3) mCRPC treated with PARP inhibitors (PARPi). Outcomes [Time on Treatment (ToT); Overall Survival (OS)] were analyzed by PV type (frameshift, missense, nonsense, splicing; indels, SNV, CNV) and position: 1) Functional Domains (FDs) (RAD51-BD [AA 900-2000] vs. DBD [AA 2459-3190] vs. Others); 2) The recently identified Prostate Cancer Cluster Regions (PCCR) (c.756-c.1000 and 3' of c.7914 vs. Others). Results: Of 2.119 pts included, 401 harbored Homologous Recombination Repair PVs. In the cohort of 1.411 mHSPC pts, BRCA2 -mutated (n = 201) showed significantly shorter OS vs. wild-type (mOS 63 vs 76 months; HR 1.2, p = 0.02), regardless of first-line therapy. Contrary to previous reports, BRCA2 -mutated mHSPC pts had superior ToT from ADT+ARPi vs. ADT+docetaxel (55 vs 15 mos; HR 3.5, p < 0.001). Within the BRCA2 subgroup, PV location was highly prognostic for OS. In mHSPC, PCCR-outside variants (c.756-c.1000/3'of c.7914) and non-FD variants (RAD51-BD/DBD-outside) were associated with shorter OS (PCCR: 57 vs 97 mos, HR 4.0, p = 0.006; FD: 47 vs 88 mos, HR 3.0, p < 0.001). Similar prognostic impacts were confirmed in 684 mCRPC pts (PCCR: 78.0 vs 38.0 mos, HR 3.3, p = 0.01; FD: 64.0 vs 34.0 mos, HR 2.7; p = 0.009). Among 201 pts treated with olaparib, those with RAD51-BD PVs achieved significantly longer ToT (20.0 vs 7.0 mos; p = 0.01) and longer OS. Furthermore, frameshift deletions were associated with shorter OS compared to other PV types (15.9 vs 26.0 mos; p = 0.04). Conclusions: This is the largest longitudinal study to demonstrate that BRCA2 PV type and location are critical determinants of survival and treatment response in mPC. Our findings identify a "high-risk" molecular subgroup (PCCR and RAD51-BD/DBD-outside and frameshift deletions) with significantly poorer outcomes. These results provide a rationale for refined risk-stratification and personalized treatment selection, including early PARPi integration, in BRCA2 -mutated patients.
Neurocognitive outcomes after proton versus photon radiotherapy in pediatric CNS tumors: Systematic review and meta-analysis.
e22007 Background: Long-term neurocognitive impairment is a major source of disability in survivors of pediatric CNS tumors. Proton radiotherapy may reduce dose to developing brain structures, potentially preserving cognition compared with conventional photon therapy. Methods: We performed a systematic review and meta-analysis of MEDLINE, Embase, PsycINFO, and CENTRAL. Eligible studies included pediatric CNS tumor patients treated with proton or photon radiotherapy reporting neurocognitive outcomes (full-scale IQ, attention, processing speed, executive function) over time. Standardized mean differences (SMD) were pooled using random-effects models, and slope analyses assessed longitudinal IQ change. Subgroups included age at radiotherapy, craniospinal vs focal fields, tumor type, chemotherapy exposure, and follow-up duration. Certainty of evidence was graded using GRADE. Results: Eleven studies encompassing 624 patients were included. Proton therapy was associated with significantly less decline in full-scale IQ compared with photon therapy (SMD 0.43, 95% CI 0.21–0.65, p < 0.001). Domain-specific analyses showed preservation of attention (SMD 0.36, 95% CI 0.10–0.61) and processing speed (SMD 0.41, 95% CI 0.18–0.64). Longitudinal slope analysis indicated an average IQ decline of 0.7 points/year after proton therapy versus 2.4 points/year after photon therapy. Benefits were greatest in younger children (<8 years) and those receiving craniospinal irradiation. Attrition and missing data were similar across groups. Conclusions: Proton radiotherapy in pediatric CNS tumors is associated with clinically meaningful preservation of neurocognitive function compared with photon therapy, particularly in younger patients and those receiving extensive fields. Clinical Takeaway: When available, proton therapy should be considered for children at high risk of cognitive decline to optimize long-term functional outcomes.
A phase Ib study of osimertinib and tegavivint as first-line therapy in patients with metastatic <i>EGFR</i> -mutated non–small cell lung cancer (NSCLC).
8648 Background: EGFR TKIs improve clinical outcomes for patients with EGFR-mutated NSCLC. However, they are not curative even when combined with chemotherapy or antibody-based therapies because of slow-cycling, drug-tolerant cells that persist due to transcriptional reprogramming. This inevitably leads to tumor resistance and disease progression. Our preclinical studies showed that EGFR-mutated NSCLC cells enter a persistent state in response to TKIs due to increased transcriptional activity of β-catenin. Treatment of mice bearing EGFR-mutated NSCLC xenografts with an EGFR TKI and a β-catenin inhibitor caused a greater depth and duration of response than treatment with an EGFR TKI alone, which improved overall survival (OS). We also observed that patients with EGFR-mutated NSCLC who had the greatest increase in serum levels of the secreted β-catenin transcriptional target PAI-1 following treatment with a TKI had significantly worse progression free survival (PFS). These data led us to conduct a single-arm phase Ib clinical trial (NCT04780568) that investigated osimertinib in combination with tegavivint, an inhibitor of β-catenin transcriptional activity. Methods: Patients with metastatic EGFR-mutated (exon 19 deletion or L858R) NSCLC who had not received prior treatment with an EGFR TKI were eligible. All participants received osimertinib 80mg daily and were enrolled to escalating dose levels of tegavivint, which was administered weekly IV for 16 weeks. The primary objectives were to assess the safety and tolerability of the combination and to determine the recommended phase 2 dose (RP2D) of tegavivint. Secondary objectives measured the objective response rate (ORR), median PFS, and OS. Results: Fifteen evaluable patients received treatment on the dose escalation portion of this study, including six patients at the highest dose level of tegavivint (8 mg/kg), which was determined to be the RP2D. No dose limiting toxicities nor drug-related serious adverse events occurred. The adverse events that were observed included hematologic, skin, and GI toxicities, consistent with the known osimertinib toxicity profile. Pharmacokinetic analysis showed a dose-dependent increase in the C max and AUC of tegavivint, and plasma levels of osimertinib were comparable to those seen historically when administered as a single agent. The ORR was 73% with 2 of 15 patients (13%) achieving a complete response. Median PFS was 20.6 months (95% CI: 7-32 months). OS data is still maturing. Conclusions: NCT04780568 showed that the combination of osimertinib and tegavivint was safe and tolerable as first-line therapy in patients with metastatic EGFR-mutated NSCLC. This novel combination has the potential to improve the depth and durability of response to EGFR TKIs, without significantly increasing toxicity, by targeting drug-tolerant persistence. Clinical trial information: NCT04780568 .
DISCO update: Diagnostic performance of <sup>64</sup> Cu-SARTATE compared to <sup>68</sup> Ga-DOTATATE in patients with known or suspected neuroendocrine tumors.
4174 Background: Diagnostic imaging is critical in the management of neuroendocrine tumors (NETs). 64 Cu-SARTATE may provide advantages over existing imaging agents due to its longer half-life and sarcophagine chelator, with a potential to accurately detect additional disease in NETs. Methods: This multi-center Phase II study assessed the safety and efficacy of 64 Cu-SARTATE (200 MBq) in participants with known or suspected gastroenteropancreatic (GEP)-NETs (NCT04438304). (SARTATE; at 4 ± 1 h and 20 ± 4 h post-injection) were assessed by two independent blinded central readers, and . Discordant lesions (only present on either DOTATATE or SARTATE PET/CT) were subsequently evaluated by an independent assessor against a standard of truth (SOT; biopsy and/or follow-up conventional imaging). The per-lesion sensitivity (SE) for discordant lesions was calculated for both SARTATE and DOTATATE (SE=proportion of true positive foci / [true positive foci + false negative foci]). Lesion detection rate (DR) was calculated for a composite (best-case scenario) lesion detection across both SARTATE time points and for DOTATATE (DR= total number of lesions detected on scan / total number of lesions on scan pair). Values express the averages across readers and both PET/CT time points (for SARTATE). Results: 45 participants were enrolled and received SARTATE (41 known and 4 suspected NETs). Most had stage 3 or 4 disease. The mean number of foci detected by SARTATE was 441 vs. 227 by DOTATATE. A total of 238 discordant foci were identified in 34 participants; 223 of these were detected by SARTATE alone and 15 by DOTATATE alone. For the 122 discordant foci with evaluable SOT, the difference in SE for SARTATE vs. DOTATATE was statistically significant 94.7% [95% CI 65.1, 99.5] for SARTATE vs. 5.4% [95% CI 0.5, 34.9] for DOTATATE; p<0.001). The lesion DR was 97.2% [95% CI 75.9, 99.5] for SARTATE and 44.4% [95% CI 32.3, 57.5] for DOTATATE. The liver had the highest number of foci detected by both tracers (352 foci on SARTATE vs. 180 on DOTATATE) among all regions. Seven (15.6%) participants experienced 9 SARTATE-related AEs; 8 were Grade 1 and one was Grade 2, with most resolving within 2 days. Conclusions: 64 Cu-SARTATE was found to be safe and well-tolerated in patients with GEP-NETs. SARTATE lesion detection was higher than that of DOTATATE, with the liver having the highest number of lesions identified. SARTATE was able to detect additional true positive lesions compared to DOTATATE. The enhanced diagnostic performance offered by SARTATE, especially in key organs affected by GEP-NETs, may have important clinical implications to inform treatment decisions. A phase III study of 64 Cu-SARTATE in NETs is being planned. Clinical trial information: NCT04438304 .
Burden of mortality due to brain metastases secondary to lung cancer in the United States: A population-based study.
2021 Background: Brain metastasis is a common and severe complication in lung cancer, contributing significantly to morbidity and mortality. Despite therapeutic advances, the burden remains substantial. This study examines mortality trends, disparities, and geographic variation using CDC WONDER data in the United States. Methods: We accessed the CDC WONDER Multiple Cause of Death database (1999–2023) to identify individuals who died of brain metastasis (ICD-10: C79.3) among lung cancer patients (ICD-10: C34.0–C34.9). Mortality disparities were examined by year, sex, race/ethnicity, and geography. Age-adjusted mortality rate (AAMR) per 100,000 was calculated. Joinpoint regression was used to estimate the average annual percentage change (AAPC) and annual percentage change (APC), with 95% confidence intervals (CIs). Results: The total of 207,151 deaths related to brain metastasis among lung cancer patients. Overall, the AAMR slightly decreased from 4.95 (95% CI: 4.85-5.05) in 1999 to 3.62 (95% CI: 3.55-3.69) in 2023 (AAPC: -1.40; 95% CI: -1.82 to -0.99, p < 0.000001). The trend initially declined, followed by an upward trajectory between 2013 and 2017 (APC: 3.03; 95% CI: 1.00 to 5.10), after which it remained relatively stable till the end of the study period (APC: 0.33; 95% CI: -0.29 to 0.95). The decrease in mortality was slightly more pronounced in men than in women (AAPC: -2.03 vs -0.74). The highest incidence rates were noted among non-Hispanic (NH) Whites, followed by NH Blacks or African Americans and NH Asians and Pacific Islanders. Geographic disparities were apparent, with the South experiencing the greatest impact, while the Northeast was the least affected. Rural regions consistently showed higher AAMR compared to urban areas, while urban locations experienced a steeper decline between the two (AAPC: -1.95 vs -0.92). Conclusions: Mortality from brain metastasis in lung cancer patients has slightly declined over the past two decades, with greater reductions observed in men. However, persistent disparities across race, geography, and rural–urban populations underscore the urgent need for targeted interventions and equitable healthcare strategies to achieve favorable outcomes. Deaths and AAMR per 1,000,000 for trends related to lung cancer with brain metastasis, 1999 to 2023. Variable Deaths AAMR (95%CI)1999 AAMR (95% CI)2023 Overall 207,151 4.95 (4.85 to 5.05) 3.65(3.55 to 3.69) Male 108,179 6.25 (6.07 to 6.42) 3.85 (3.74 to 3.96) Female 98,972 3.98(3.85 to 4.10) 3.41(3.32 to 3.50) NH White 176,368 5.17(5.06 to 5.29) 4.05(3.96 to 4.14) NH Black 22,609 6.10(5.71 to 6.48) 3.63(3.41 to 3.85) NH Asians 5,762 2.29(1.84 to 2.73) 2.68(2.42 to 2.94) South 88,589 5.40(5.22 to 5.59) 3.94(3.82 to 4.06) Northeast 30,890 4.60(4.38 to 4.82) 2.64(2.49 to 2.78) Metro 120,044 1.51 (1.44 to 1.57) (2020)5.33(5.23 to 5.42) Non metro 27,540 1.39(1.27 to 1.52) 6.17(5.94 to 6.41)
A phase 1b/2 study of JK06, a 5T4-targeted antibody-drug conjugate (ADC), in patients with unresectable locally advanced or metastatic cancer.
3038 Background: 5T4, a Type I transmembrane glycoprotein, is over expressed in a broad spectrum of solid tumors. It modulates the CXCR4 & WNT signaling pathways contributing to epithelial to mesenchymal transition contributing to metastatic progression & correlates with poor clinical outcomes among a range of cancers, such as NSCLC, CRC & ovarian. JK06 is a tetravalent, biparatopic DAR2 MMAE ADC targeting 5T4, providing picomolar affinity & enhanced internalization to compensate for generally lower 5T4 expression levels & poor intrinsic internalization kinetics. Methods: Pts with advanced relapsed/refractory solid tumors, unselected for 5T4 expression, receive IV JK06 monotherapy once every 3 wks. Dose escalation has been completed, and the study is currently enrolling multiple tumor-specific cohort expansions with randomization across two doses of JK06 to identify an RP2D in NSCLC & breast cancer. Fresh & archival tumor biopsies are being collected for retrospective correlation of 5T4 expression to efficacy & safety. Responses are assessed every 9 wks per RECIST v1.1. Exploratory evaluations of changes in quality of life after JK06 treatment are included in cohort expansions. Results: To date, 80 refractory metastatic solid tumor pts (n = 39 in dose esc; n = 41 in cohort expansions) have been treated, median age of 60 yrs, >70% treated with ≥ 3 prior lines of therapy, including >75% of treated pts with prior taxane exposure. Treatment has been well-tolerated with predominantly low-grade treatment-related adverse events (TRAEs) (Gr 1 & 2), such as fatigue (35%), alopecia (18%), decreased appetite (18%), dry eye (10%) & peripheral sensory neuropathy (PSN) (9%). Among 70 pts have sustained JK06-related Gr 3 adverse events (AEs): fatigue, malaise, gait disturbance, keratitis, vomiting, corneal ulcer, & PSN, that resolved, with two continuing treatment with dose reduction; no Gr 4 JK06-related AEs have been observed to date. Four pts underwent dose reductions, and five additional pts were discontinued due to TRAEs. Among 19 response-evaluable NSCLC pts to date, a 32% ORR has been observed, with 1 confirmed complete response (cCR), 4 confirmed partial responses (cPR) (one with CNS response) & 1 with unconfirmed partial responses (uPR), with the longest continuing therapy for 51 wks. Responses have been observed in adenomatous, squamous & EGFR mutant NSCLC pts. One of seven evaluable breast cancer pts (14% ORR) achieved a cPR and remained on treatment for >27 wks. Conclusions: To date, JK06 demonstrates promising emerging clinical activity in refractory NSCLC & breast cancer at multiple dose levels while being well tolerated without significant drug-related toxicities. Updated safety & clinical activity data from both dose escalation & expansion cohorts, including the initial assessment of dose randomization, will be presented. Clinical trial information: NCT06667960 .
Pan-cancer long mononucleotide repeat microsatellite instability testing for detection and immunotherapy selection.
2648 Background: Microsatellite instability (MSI) and mismatch repair deficiency (dMMR) are crucial biomarkers to inform potential for hereditary risk and eligibility for immunotherapy across multiple cancers. While current standard of care testing can identify most MSI-high (MSI-H)/dMMR patients, improved testing sensitivity for MSI-H status could identify more patients who may benefit from immunotherapy. Recent studies have indicated potential for more sensitive testing using a long mononucleotide repeat (LMR)-based multiplex MSI-detection assay. Methods: Patients were identified and consented as part of an IRB-approved protocol (UW15068) based on MSI status, MMR gene variants, or high tumor mutation burden (TMB). Patient tissues, normal and tumor, were formalin-fixed and slides were prepared for pathologist annotation and immunohistochemistry (IHC) for CD8. CD8+ tumor infiltrating lymphocytes (TILs) were quantified/high powered field (HPF). Slides were scraped for DNA isolation. MSI testing was performed on the resultant DNA using the LMR MSI Analysis System (Promega, Madison, WI) and the OncoMate MSI Dx Analysis system (OM, Promega) per manufacturer protocols. LMR MSI status and score were compared with other testing methods, TMB, CD8+ TILs/HPF, immunotherapy response, progression-free survival (PFS), and overall survival (OS). Results: A cohort of 202 patients (median age: 64 (range: 24-80+)) with 20+ different cancer types (lung 27.2%, colorectal 18.8%, skin 9%, esophageal 5.9%, uterine 5.9%) and across disease stages, mutation profiles, and immunotherapy treatment regimens were consented. At least one test identified a case as dMMR/MSI-H in 31.6% of cases. In 9.4% of cases, a discrepancy between testing methods was observed. LMR detected 9 cases as MSI-H that were not detected by clinical NGS or OM. 4 cases were detected as MSI-H by LMR and OM alone, one case by OM alone, and one case by LMR and clinical NGS alone. Additionally, 2 cases were dMMR by IHC but not LMR, OM, or clinical NGS and 2 cases were dMMR by IHC and MSI-H by clinical NGS, but not LMR or OM. LMR score positively correlated with TMB (r 2 = 0.57) for MSI-H, but not MSS patients (r 2 = 0.002). LMR score weakly correlated with CD8+ TILs/HPF (r 2 = 0.16) in MSI-H, but not MSS cases (r 2 <0.001). LMR MSI-H cases have a 52.6% complete response rate compared to 6.12% of LMR MSS subjects (p<0.001). Patients identified as MSI-H by LMR testing had an increased PFS (median PFS (days) MSI-H: 711, MSS: 178; hazard ratio (HR) 0.25 [95% CI 0.13-0.50; p<0.001]) and OS (median OS (days) MSI-H: 926, MSS: 402; HR 0.43 [95% CI 0.22-0.82; p=0.015]) compared to LMR MSS patients. Conclusions: Variability can be observed between dMMR/MSI testing methods indicating that multiple methods should be considered for each patient. LMR testing demonstrates promising sensitivity and correlation with immunotherapy efficacy.
Telehealth and the patient experience in rural America.
e13708 Background: Rural populations face systemic barriers to healthcare, including specialty scarcity, travel burden, and limited local infrastructure. While telehealth has emerged as a potential tool to bridge geographic divides, its equitable adoption remains unclear. This study seeks to evaluate telehealth use and quality, with a focus on rural cancer survivors. Methods: Nationally representative Health Information National Trends Survey data from 2022 and 2024 were analyzed; 2013 RUCA (1-3: urban, 4-9: rural) defined rurality. Any telehealth in the past 12 months was considered “use”. Patient-reported quality measures were dichotomized; telehealth was “as good as a regular in-person visit” (agree, disagree), internet connection satisfaction (satisfied, not satisfied), and health communication (always occurred vs any other response). Analysis in STATA used sampling and jackknife weights (50 replicates) to produce national representation. Design-based F test assessed for associations; survey weighted logistic regression was used when estimates were not calculable due to structural zero. Statistical significance was p < 0.05. Results: 13,530 were included (urban 87.4%, 12.6% rural). Rural participants were older (mean: 52.5 yrs rural, 48.4 urban), had lower income ( < $50k: 48.7% rural vs 36.2% urban) and were more commonly cancer survivors (12.0% rural, 8.9% urban) (p < 0.05 for comparisons). Most were insured (88.6% urban, 89.5% rural). Telehealth use declined from 33.5% in 2022 to 29.7% in 2024 (p < 0.01), with rural participants overall less likely to use (31.5% vs 36.4% urban, p < 0.01). Rural participants were less likely to be satisfied with their internet connection (56.8% vs 70.1% urban, p < 0.01). Reasons for telehealth use differed, with rural participants more frequently using it for chronic diseases (24.6% vs 17.5% urban) and less for acute/minor illness (20.3% vs 27.7% urban) (p < 0.05 both). Most agreed telehealth was as good as in-person care (77.6% rural, 77.4% urban), that providers explained things clearly (56.8% rural, 57.2% urban) and that they had a chance to ask questions (58.3% rural vs 56.8% urban). Telehealth was not associated with providers spending enough time (38.6% telehealth vs 41.2% no telehealth; 42.5% rural vs 38.1% urban) (p = NS for all comparisons). Cancer survivors had higher telehealth use (42.5% vs 35.1% without cancer, p < 0.01), driven by urban survivors (43.5% vs 35.8% without cancer, p < 0.01). Rural survivors did not have statistically different use (37.0% vs 30.7% without cancer, p = 0.12). Conclusions: Telehealth has declined slightly over time, with ongoing barriers seen in rural populations, especially with internet connectivity. Given no differences in perceived quality and communication, differential telehealth use appears driven by structural factors rather than patient-provider relationships. Expanding reliable telemedicine access to rural cancer survivors may improve survivorship care.
Health-related quality of life with low-dose pembrolizumab plus chemotherapy in early triple-negative breast cancer: Findings from the PLANeT trial.
607 Background: The PLANeT trial randomized stage II–III TNBC patients to neoadjuvant chemotherapy with or without low-dose pembrolizumab. Primary efficacy end point results were presented at ESMO Congress 2025. QoL was assessed at baseline, mid-treatment, and end-treatment using the EORTC QLQ-C30 across seven domains. Longitudinal changes were analyzed using mixed-effects models with LS-mean estimates and change from baseline at each timepoint. Methods: Stage II–III TNBC patients were randomized in a 1:1 ratio to receive standard NACT with or without pembrolizumab (50 mg Q6W ×3 cycles) prior to surgery. QoL was assessed at baseline, mid-NACT (after 4 cycles), and at the end of NACT (after 8 cycles) using the EORTC QLQ-C30 questionnaire. Seven key QoL domains were analyzed: global health status/QoL (GHS), physical, role, emotional, cognitive, social functioning, and pain. Longitudinal QoL changes were compared between arms using mixed-effects models (MMRM) adjusted for nodal status. Least-squares (LS) mean scores and changes from baseline were estimated for each timepoint. Results: Among 157 patients (median age 49), baseline QoL was high and comparable between arms. QoL declined during neoadjuvant therapy in both groups, with the greatest burden mid-treatment and partial recovery by cycle 8. LS-mean global QoL fell by 14 points in each arm, with no meaningful separation between treatments across any functioning domain. Pain increased in both groups, and financial difficulty peaked mid-treatment before improving by cycle 8. Overall, low-dose pembrolizumab did not compromise QoL compared with chemotherapy alone. Conclusions: Adding low-dose pembrolizumab to neoadjuvant chemotherapy in TNBC did not worsen patient quality of life. The trajectory of functioning and symptom scores was nearly identical to chemotherapy alone, indicating that incorporating reduced-dose immunotherapy does not add to the treatment burden from the patient’s perspective. Clinical trial information: CTRI/2024/01/062088 . Least-squares mean (LS-mean) scores at cycle 8 and changes from baseline for all EORTC QLQ-C30 domains, comparing pembrolizumab + chemotherapy vs chemotherapy alone in the PLANeT trial. Domain Pembro + Chemo (C8 LS-mean) Change Chemo Alone (C8 LS-mean) Change Between-Arm Δ (Change) Global QoL 39.61 −14.19 41.27 −13.61 −0.58 Physical Functioning 73.09 −19.92 74.49 −18.14 −1.78 Role Functioning 85.68 −10.90 85.65 −12.66 +1.76 Emotional Functioning 78.31 −11.11 77.00 −10.34 −0.77 Cognitive Functioning 88.03 −5.99 83.97 −8.44 +2.45 Social Functioning 83.33 −13.04 82.07 −12.87 −0.17 Pain 67.31 +20.73 52.11 +12.45 +8.28
Consensus molecular subtypes, mutational features, and circulating tumor DNA dynamics in colorectal cancer: A real-world clinico-genomic analysis.
3652 Background: Consensus molecular subtypes (CMS) define biologically distinct colorectal cancer (CRC) groups with differences in tumor microenvironment, genomic features, and prognosis. While CMS classification is well established in tissue-based transcriptomic studies, its relationship with circulating tumor DNA (ctDNA) dynamics and molecular features in real-world clinical practice remains incompletely characterized. We evaluated CMS subtype distribution, mutational characteristics, and ctDNA detection patterns in a large real-world CRC cohort. Methods: Patients with CRC who underwent whole-transcriptome sequencing via Altera (Natera, Inc.) testing were identified from Natera’s real-world clinico-genomic database. CMS subtype assignment was based on the whole-transcriptome sequencing, and then correlated with Signatera results, a personalized, tumor-informed ctDNA assay. In patients with stage II–III CRC, ctDNA positivity was assessed during the MRD window (1–10 weeks post-surgery) and during post-MRD surveillance (>10 weeks post-surgery). Overall survival (OS) was estimated using the mortality database (Veritas Data Research, Fact of Death Mortality Data Index). Results: Among 8,456 CRC cases with available molecular data, CMS distribution was 10% CMS1, 26% CMS2, 12% CMS3, 22% CMS4, and 29% inconclusive. While canonical anatomic patterns were recapitulated (CMS1 right-sided, CMS2 left-sided, CMS3 rectal), CMS4 tumors were enriched in advanced-stage disease. CMS1 demonstrated high MSI-H prevalence (53%), frequent BRAF V600E (35%) and KMT2D (44%) alterations, and enrichment of MMR deficiency and APOBEC and POLE mutational signatures. CMS2 tumors were almost exclusively microsatellite stable (99.7%) and enriched for APC (84%) and TP53 (80%) mutations, whereas CMS3 showed intermediate MSI-H prevalence (10%) with frequent APC (74%) and KRAS (61%) alterations. CMS4 tumors exhibited low MSI-H prevalence (2%) but frequent TP53 (60%) and APC (59%) mutations. Among patients with stage II–III CRC, ctDNA positivity during the early post-operative MRD window was not associated with CMS subtype. In contrast, during later surveillance, ctDNA positivity was more frequent in CMS4 tumors compared with CMS1–CMS2 (36.8% vs 28.1%). Among MRD-positives, CMS1 was associated with the shortest OS, whereas CMS2 demonstrated the longest OS. No difference in OS was noted in MRD-negative patients. Conclusions: In this large real-world cohort, CMS subtypes were recapitulated with expected clinicogenomic and mutational associations and demonstrated distinct ctDNA detection patterns during surveillance. Integration of CMS biology, mutational features, and longitudinal ctDNA dynamics provides insights into residual disease and recurrence risk beyond static tissue-based classification.
Predictors of response and safety profile of axatilimab in chronic GVHD: Pooled analysis of 384 patients.
e18564 Background: Chronic graft-versus-host disease (cGVHD) remains a significant complication following allogeneic hematopoietic cell transplantation, impacting more than half of HCT recipients. Monocytes and macrophages dependent on colony-stimulating factor 1 receptor (CSF1R) play a crucial role as mediators in chronic GVHD. Axatilimab, a humanized monoclonal antibody, blocks CSF-1R signaling to inhibit macrophage development and has demonstrated promising clinical benefits in chronic GVHD. We conducted a systematic review and meta-analysis to synthesize the available clinical evidence on axatilimab’s efficacy and safety in cGVHD. Methods: We followed PRISMA guidelines to search major databases until December 2025 for studies on axatilimab in chronic graft-versus-host disease (cGVHD), including clinical trials and cohorts. Two reviewers independently screened studies, extracted data, and assessed bias using the ROBINS-I, RoB 2.0, and NOS tools. Pooled proportions were calculated with random-effects models in R (R Foundation for Statistical Computing, Vienna, Austria) using the meta package. A p-value of less than 0.05 was considered statistically significant. Results: A total of five studies comprising 384 patients were included in the meta-analysis. Using a random-effects model, the pooled overall response rate across all studies was 73% (95% CI: 60%–82%) (p<0.05). Organ-specific analyses demonstrated variable clinically significant response rates. The pooled response rate was 19% (95% CI: 4%–54%) for ocular involvement, 25% (95% CI: 6%–63%) for pulmonary involvement, 52% (95% CI: 33%–71%) for oral cavity involvement, and 42% (95% CI: 8%–86%) for joint/fascial involvement. Higher response rates were observed in gastrointestinal manifestations (p>0.05), with pooled estimates of 79% (95% CI: 7%–99%) for esophageal involvement, 99% (95% CI: 1%–100%) for lower gastrointestinal involvement, and 97% (95% CI: 0%–100%) for upper gastrointestinal involvement. It was noted that any grade treatment-related adverse events occurred in 96% of participants (95% CI: 39%–100%). The wide confidence intervals reflect the limited sample size of the studies. Conclusions: In conclusion, axatilimab demonstrates promising efficacy in treating chronic graft-versus-host disease (cGVHD), achieving an overall response rate of 73%. Response rates varied by organ involvement, with particularly high rates in gastrointestinal manifestations. However, treatment-related adverse events were noted in 96% of patients, emphasizing the need for careful monitoring. Due to the limited sample sizes and wide confidence intervals, further research is warranted to better understand the risk-benefit profile of axatilimab for the management of cGVHD.
GGPP as a driver of esophageal squamous cell carcinoma progression via protein prenylation: Therapeutic potential of zoledronic acid repurposing.
e16104 Background: Esophageal cancer is a prevalent malignant tumor of the digestive system, with its development closely related to metabolic reprogramming. Emerging evidence implicates dysregulated cholesterol biosynthesis in ESCC pathogenesis, yet the specific role of geranylgeranyl pyrophosphate (GGPP), a critical intermediate metabolite, remains poorly defined. This study investigates how GGPP drives ESCC progression through protein prenylation-dependent mitochondrial reprogramming and evaluates the therapeutic potential of targeting GGPP synthesis using zoledronic acid (ZA), a clinically approved bisphosphonate for osteoporosis. Methods: The oncogenic role of GGPP was systematically investigated through genetic manipulation of GGPS1 (the rate-limiting enzyme for GGPP synthesis) and pharmacological inhibition with ZA. Transcriptomic profiling and immunohistochemistry were performed on ESCC patient tissues. Functional assays including CCK-8, colony formation, nude mouse xenograft models and seahorse metabolic analysis assessed the impact of GGPP depletion on cell proliferation and mitochondrial oxidative phosphorylation (OXPHOS). GGPP rescue experiments validated metabolite-specific effects. Candidate prenylated proteins were identified through LC-MS and validated by Western blotting. The therapeutic efficacy of ZA was assessed in xenograft-bearing nude mice via tail vein injection, with tumor growth monitored by caliper measurements and endpoint analyses including tumor weight and immunohistochemistry. Results: Transcriptomic analysis revealed significant upregulation of cholesterol biosynthesis genes in ESCC tissues, with GGPS1 expression positively correlating with disease progression. GGPS1 knockdown markedly suppressed ESCC cell proliferation and tumor growth in xenograft models, accompanied by reduced Ki67 expression. Mechanistically, GGPP depletion disrupted protein prenylation, leading to impaired mitochondrial OXPHOS and fatty acid oxidation. Exogenous GGPP supplementation fully rescued the proliferative defects caused by GGPS1 knockdown, confirming GGPP as the critical effector metabolite. Importantly, pharmacological inhibition of GGPP synthesis with ZA significantly inhibited tumor growth in xenograft models, with no apparent toxicity. Conclusions: This study identifies GGPP as a pivotal oncometabolite driving ESCC progression through prenylation-dependent maintenance of mitochondrial OXPHOS. Targeting the GGPP synthesis pathway represents a promising therapeutic strategy for ESCC. The demonstrated preclinical efficacy of zoledronic acid provides strong rationale for clinical repurposing of this FDA-approved drug in ESCC patients, offering a readily translatable therapeutic approach for this aggressive malignancy.