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Preclinical evaluation of intrathecal TRP1-targeted CAR T cells: Effects on durable antitumor immunity in melanoma leptomeningeal disease.
2086 Background: Melanoma leptomeningeal disease (LMD) is fatal, with median survival under 3 months and no effective immune-based therapies. Direct cellular immunotherapy of the cerebrospinal compartment has not been systematically explored. Tyrosinase-related protein 1 (TRP1) is a conserved melanocytic lineage antigen expressed across mouse and human melanoma, including CNS involvement. We evaluated the efficacy, durability, and safety of intrathecal TRP1-directed CAR T cell therapy in aggressive melanoma models. Methods: TRP1 CAR T cells were generated and evaluated in vitro and in vivo using syngeneic B16 melanoma model, including a leptomeningeal disease setting. CAR T cells were administered intrathecally. Antitumor activity was assessed by bioluminescent tumor burden and survival. Durability of response was evaluated by secondary tumor rechallenge. Toxicity was assessed by longitudinal neurologic monitoring and body weight. Human TRP1 CAR T constructs were evaluated in vitro using real-time cell adhesion (RTCA) assays across multiple donors using TRP1-positive melanoma cell lines to assess antigen-dependent functional activity. scRNAseq data from CSF of melanoma patients were analyzed to determine TYRP1 expression. Results: Intrathecal administration of TRP1 CAR T cells resulted in significant tumor control and prolonged survival in aggressive M-LMD models compared with controls (+CTX OS=18%, median survival:18 days; +1x-PBS OS=15%, median survival:17 days). Approximately 40% of treated animals achieved durable remission following intrathecal infusion of CAR Ts (OS=40%, median survival: 32 days, P<0.0001). Long-term survivors (eg. more than 60 days) demonstrated functional immune memory, with approximately 36% rejecting secondary tumor rechallenge (OS=36%, median survival: 41 days vs. naïve control OS=17%, median survival: 15 days, P<0.0001). Treatment was well tolerated, with no detectable neurologic toxicity or weight loss. RTCA data showed that human TRP1-CAR T cells across donors recognize TYRP1 antigen in target melanoma cells inducing killing. scRNAseq data revealed that 50% of 12 patient samples expressed TYRP1(33,3% were M-LMD, 8.3% were primary intradural spinal melanoma, and 8.3% from 1 autopsy). Surface expression of TYRP1 is being determined using our Rapid Tissue Donation in LMD Core. Together, our data supports translational relevance. Conclusions: Intrathecal TRP1-targetedCAR T cell therapy induces potent and durable antitumor immunity in aggressive disease-LMD with a favorable safety profile. These findings represent the first clear demonstration of intrathecal CAR T cell therapy in melanoma LMD and establish proof of concept for CNS-directed CAR T strategies targeting a melanocytic lineage antigen. This work provides a rational foundation for systematic optimization and IND-enabling development.
Neoadjuvant chemotherapy combined with toripalimab for triple-negative breast cancer: A prospective, single-arm, multi-center study (NEOTORCH-BREAST02).
595 Background: Neoadjuvant de-escalation chemo-immunotherapy with abbreviated cycles remains unclear. We aimed to assess the efficacy and safety of toripalimab, a novel PD-1 antibody, combined with an abbreviated course of epirubicin–cyclophosphamide (2 cycles) followed by nab-paclitaxel (2 cycles), as a neoadjuvant regimen for early-stage TNBC patients. Methods: This phase II trial, conducted from 2024 to 2025, involved stage II–III TNBC. The neoadjuvant regimen included epirubicin, cyclophosphamide, and toripalimab for 2 cycles, followed by nab-paclitaxel and toripalimab for another 2 cycles. Patients achieving a pathological complete response (pCR) received up to 13 cycles of adjuvant toripalimab, while those with residual disease received additional chemotherapy and toripalimab. Whole-exome sequencing (WES) and circulating tumor DNA (ctDNA) monitoring were also performed. The primary endpoint was the total pCR (tpCR) rate (ypT0/is ypN0). Secondary endpoints included breast pCR (bpCR; ypT0/is), residual cancer burden (RCB 0–1), objective response rate (ORR), and event-free survival. This trial was registered with ClinicalTrials.gov (NCT06682195). Results: As of January 20, 2026, 48 patients were enrolled, and 40 underwent surgery (median age: 48 years; 87.5% stage II). WES analysis in 37 patients identified BRCA1 mutations in 12 (32.4%). Baseline ctDNA was positive in 32 of 34 (94.1%) patients, and 24 (75%) achieved ctDNA negativity after neoadjuvant therapy. Among 40 surgical patients, tpCR, bpCR, RCB 0-I, and ORR rates were 55%, 60%, 70, and 92.5%, respectively. Subgroup analyses showed tpCR rates of 25% for CPS <1, 58.3% for CPS ≥1, 72.7% for CPS ≥10, and 80% for CPS ≥20. For TILs <10, tpCR was 25%, increasing to 66.6% for TILs ≥10, 82.3% for TILs ≥30, and 85.7% for TILs ≥50. Among BRCA1 mutation carriers, 75% achieved tpCR, and 62.5% of patients with ctDNA negativity also achieved tpCR. Grade ≥3 AEs occurred in 6 (15%) patients, most commonly vomiting (7.5%) and leukopenia (7.5%). Hypothyroidism was the most frequent immune-related AE (17.5%, all grade 1–2). Conclusions: Preliminary findings indicate that this 4 cycles de-escalation neoadjuvant strategy is effective and safe for early-stage TNBC, warranting further investigation in randomized trials. Clinical trial information: NCT06682195 . Response endpoints for the entire cohort (N = 40). Efficacy endpoint N (%) 95% CI(%) tpCR(ypT0/is, ypN0) 22(55.0) 38.5–70.4 bpCR(ypT0/is) 24(60.0) 43.3–75.0 Miller–Payne (MP) grades MP score 1 2 (5.0) 0.6-23.2 MP score 2 3 (7.5) 1.6-27.3 MP score 3 7 (17.5) 7.3-34.7 MP score 4 4 (10.0) 2.8-23.7 MP score 5 24 (60.0) 43.3.-75.0 Residual cancer burden (RCB) class RCB class 0–I 28(70.0) 53.3–83.4 RCB class II 6 (15.0) 5.7-31.9 RCB class III 6 (15.0) 5.7-31.9 Abbreviations: tpCR, total pathological complete response; bpCR, breast pathological complete response; CI, confidence interval.
The SWOG Mentoring Advanced Practice Providers (MAPP) program.
e21005 Background: Oncology Advanced Practice Providers (APPs), which include Nurse Practitioners (NPs) and Physician Associates (PAs), are highly trained health care providers who are instrumental in delivering high-quality cancer care. The number of APPs has grown considerably in recent years. These clinicians provide much of the clinical care for cancer patients, with expertise in symptom management and care coordination; however, their role in clinical research has been limited. The SWOG Cancer Research Network has been engaging APPs since 2022 with the support of the Hope Foundation. In 2025, SWOG launched the Mentor APP (MAPP) Program, which aimed to examine a formalized mentorship intervention to integrate APPs into SWOG and increase involvement of APPs in clinical research practice. The primary objective of the program was to improve research self-efficacy (RSE) among participants and secondary objectives included increasing clinical research involvement and acceptability and feasibility of the intervention. Methods: Over a one-year period, 6 participants were mentored by 2 APP mentors and 2 program leads. Mentees were selected based on institutional involvement with SWOG, geographic location, and potential impact of their participation. Two PAs and 4 NPs were selected for participation. Five formal mentorship meetings occurred between mentors and mentees after an initial kick-off meeting conducted by the program leads. The meetings were a mixture of in-person at SWOG meetings and Zoom. Initial mentor-mentee meetings were 1:1, while the others were learning collaboratives at the SWOG Meetings. Mentees were able to request additional 1:1 meeting with their mentors if desired. The Mentees completed pre/post program questionnaires, which measured APP demographics (pre-only), APP RSE, & APP Clinical Research Involvement. Feasibility/acceptability and appropriateness were assessed through informal interviews and discussions with program participants. Results: Among the 6 APPs mentored, RSE improved in all 22 measured items (ranked 0-5), with mean scores ranging from 2.5-4.33 on pre-MAPP APP RSE and 3.8-5.0 on post-MAPP APP RSE scores. Greatest positive mean differences were how to enroll/refer a patient for a study (+2.3), investigator roles (+1.7, 1.9), understanding of regulatory process and inclusion of women and minorities (+2.03, 1.84), accessing APP resources (+1.5), grading CTCAE (+1.67), and confirming eligibility (+1.7). Meaningful improvements were noted for clinical research involvement and overall understanding of the National Clinical Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP). All mentees reported the intervention as feasible, acceptable, and appropriate. Conclusions: Formal APP mentorship through the NCTN/NCORP improves APP RSE, clinical research activity, and involvement within the research base and within APP practice.
<i>TP53</i> status and licensing complex/IFNγ transcriptional profiles to stratify endocrine-related outcomes with CDK4/6i exposure in 10,833 real-world ER+/HER2- breast cancers and a treatment-naïve subset.
1032 Background: Endocrine therapy (ET) durability for ER+/HER2- breast cancer (BC) with CDK4/6 inhibitor (CDK4/6i) exposure is vastly heterogeneous. Aberrant activation of CDK4/6-Rb axis is mechanistically linked to DNA replication origin licensing programs, and IFNγ-mediated signaling has been observed at onset of CDK4/6i resistance (PMID 33536276). We previously reported licensing complex (LC) mRNA to be predictive of ET benefit in primary ER+/HER2- BC (SABCS24-P1-03-20). Here we assessed these findings in a large, real-world cohort of primary and metastatic ET±CDK4/6i-treated tumors. Methods: ER+/HER2- BC biopsies (N=10833 all-comers and a treatment-naïve subset of N=1960) with DNA- and RNA-seq profiling from Caris Life Sciences were reviewed. LC score was calculated as a mean z-score across 14 LC genes; IFNγ score of PMID 28650338 was used. Groupings of Q1 (low) and Q4 (high) LC and IFNγ score quartiles were compared (i.e., Q1/Q1, Q4/Q4, Q1/Q4, Q4/Q1). Endpoints inferred from claims data were time on 1 st ET (To1) and cumulative time on ET (start of 1 st ET to end of last ET; ToT). Logrank p-values and HRs were derived from Cox proportional hazard models. Immune microenvironment (TME) proportions were estimated via quanTIseq deconvolution. Corrected q-values were calculated for quanTIseq and genomic analyses. Results: For all-comers, LC score Q4 vs Q1 predicted shorter ToT for ET with or without CDK4/6i exposure (HR 1.27 [p<0.0001]; 1.13 [p=0.0019]). LC-Q1~IFNγ-Q1 tumors demonstrated longer ToT (ET HR 1.76 [p=0.0015]; ET+CDK4/6i HR 1.32 [p=0.022]) relative to Q4/Q4 when TP53 was not mutated ( mut ). In the treatment-naïve subset, the distribution of LC and IFNγ scores, PAM50 luminal subtype, and TP53 mut appeared similar to all-comers. IFNγ-Q4 vs Q1 predicted shorter To1 with CDK4/6i exposure (14.4 vs 19.9 months, HR 1.28 [p=0.0074]). LC/IFNγ profiles significantly stratified both To1 and ToT only with CDK4/6i exposure. Relative to Q1/Q1, all other quartile groups had shorter To1 (HR 1.53 [p=0.071], 1.88*, and 2.15* [*p<0.01]) and shorter ToT (HR 1.89, 2.33, and 1.98; all p<0.05). Relative to Q1/Q1, the Q4/Q4 cohort was enriched for TP53 mut (44.2% vs 12.5% [q=0.002]). In TP53 WT tumors, Q4~Q4 trended toward shorter ToT than Q1~Q1 (42.7 vs 26.5 months, HR 1.67 [p=0.075]). Finally, LC-Q4/IFNγ-Q4 vs Q1/Q1 tumors exhibited a more inflamed TME with higher M2 macrophages, myeloid DCs, and Tregs (all q≤0.01). Conclusions: Real-world validation confirms the LC and IFNγ-stimulated transcriptional state jointly stratify outcomes in the CDK4/6i-treated setting, predicting shorter time on ET. Though enriched for TP53 mut , convergence of LC/IFNγ may hold potential predictive value in TP53 WT disease. The LC-Q1/IFNγ-Q1 CDK4/6i response predictor in the TP53 WT setting remains to be validated prospectively.
A study of the safety, efficacy, and pharmacokinetics of SPJ-101CA as maintenance therapy for newly diagnosed high-risk neuroblastoma.
10038 Background: Isotretinoin (ISO), an oral vitamin A derivative, induces differentiation of neuroblastoma (NB) cells and is used as maintenance therapy. SPJ-101CA (Sun Pharma Ltd.), a novel ISO formulation developed with microparticle technology to enhance absorption, is designed to achieve adequate systemic exposure at 80% of the conventional dose. As ISO is an off-label treatment for NB worldwide, the present, registration-directed clinical trial was conducted to evaluate the safety, efficacy, and pharmacokinetics (PK) of SPJ-101CA in pediatric patients. Methods: This open-label, multicenter phase 2 trial enrolled 16 patients aged 1-18 years with newly diagnosed, high-risk NB who had completed the standard, multidisciplinary therapy without progression. Eligibility required an ECOG performance status of 0-2 and adequate organ function. The exclusion criteria were other active malignancies, gelatin allergy, pregnancy or breastfeeding, psychiatric disorder, and intolerance to the study treatment. Written informed consent was obtained from the patients’ legal guardians, and assent was provided by the patients when appropriate. The patients received oral SPJ-101CA 64 mg/m² twice daily for 14 days in each, 28-day course for a total of six courses. Dinutuximab was permitted only before or after, but not during, SPJ-101CA administration. The primary endpoint was the incidence of serious adverse events (AEs). The secondary endpoints included 1-year event-free and overall survival, the AE incidence, and PK properties. Blood samples were collected on day 14 of the first course at predefined intervals to measure the plasma concentration of ISO and 4-oxo-isotretinoin, and the standard PK parameters were evaluated. Results: All 16 patients were included in the full analysis and per-protocol sets. Three serious AEs related to SPJ-101CA occurred in three patients (two and one case of hypertriglyceridemia and hypercalcemia, respectively), for a total incidence of 18.8%. Common, non-serious AEs included upper respiratory inflammation (75.0%), dry skin (62.5%), hypercalcemia (56.3%), eczema (50.0%), hypertriglyceridemia (43.8%), cheilitis (37.5%), pruritus (31.3%), and neutropenia (31.3%). The 1-year event-free survival rate was 93.8%, and the overall survival rate was 100%. PK analysis of 15 patients found that the mean T max of ISO was 3.9 hours and that the 4-oxo-isotretinoin level remained constant and exhibited no distinct peak. The mean ISO C max was approximately 2.3 µg/mL, with a half-life of about 5 hours; 4-oxo-ISO had a higher C max and longer half-life. Conclusions: SPJ-101CA was well-tolerated and effective as maintenance therapy following multidisciplinary treatment for high-risk NB. The PK findings were consistent with the known profile of ISO and indicated good absorption of the formulation. Clinical trial information: jRCT2031220687.
Real-world outcomes of daratumumab in light-chain amyloidosis patients with advanced renal failure: A TriNetX network study.
e19517 Background: Light-chain (AL) amyloidosis frequently involves the renal and cardiac systems and is associated with high mortality and morbidity, particularly in patients with advanced renal dysfunction. Daratumumab is now the standard therapy for the treatment of AL-amyloidosis, and the data on the real-world use of daratumumab in this high-risk population remain limited. Methods: We conducted a retrospective cohort study using the TriNetX global research network. Adults (≥18 years) with AL amyloidosis and advanced renal disease (chronic kidney disease stage 4–5, end-stage renal disease, or dialysis dependence) diagnosed between January 1, 2020, and December 31, 2025, were included. Outcomes in patients treated with daratumumab were compared with those not receiving daratumumab. Propensity score matching (1:1) was performed to balance baseline characteristics, which were assessed 365 days prior to the index date. Clinical outcomes included all-cause mortality, cardiomyopathy, heart failure, atrial fibrillation, and neuropathy. Laboratory outcomes included hematologic abnormalities. Survival was assessed using Kaplan–Meier analysis and Cox proportional hazards models. Results: After propensity score matching, 179 patients were included in each cohort, with a median follow-up of 365 days. All-cause mortality occurred more frequently in the daratumumab cohort (21.2% vs 8.9%), with a hazard ratio for mortality of 2.60 (95% CI, 1.45–4.67; p = 0.001). Daratumumab-treated patients demonstrated lower risks of cardiomyopathy (11.2% vs 17.9%, RR 0.625), heart failure (31.3% vs 45.3%, RR 0.691, p=0.007), and atrial fibrillation (25.1% vs 36.3%, RR 0.692, p = 0.022), while neuropathy (26.3% vs 11.2%, RR 2.35, p<0.0001) was more commonly observed. Daratumumab exposure was associated with a significantly higher incidence of laboratory abnormalities compared with non-daratumumab therapy, with a median follow-up of 180 days. Patients receiving daratumumab had significantly increased risks of anemia (21.8% vs 7.3%; risk ratio [RR] 3.00, p<0.0001), thrombocytopenia (42.5% vs 9.5%; RR 4.47, p<0.0001), leukopenia (55.9% vs 13.4%; RR 4.17, p<0.0001), neutropenia (34.1% vs 5.6%; RR 6.10, p<0.0001), and lymphopenia (41.9% vs 8.4%; RR 5.00) (all p<0.001). No significant differences were observed in NT-proBNP levels (14.5% vs 16.2%) or proteinuria (8.9% vs 6.1%). Conclusions: In this real-world analysis of AL amyloidosis patients with advanced renal dysfunction, daratumumab exposure was associated with differences in survival and cardiac outcomes, as well as an increased burden of hematologic abnormalities. These findings highlight the need for careful patient selection and close monitoring and support further prospective evaluation of daratumumab in renally impaired AL amyloidosis populations.
Exploration of biomarkers for TRUCE-01: Development of a urine-based efficacy prediction model.
4622 Background: Preliminary results from the TRUCE-01 phase II trial (NCT04730219) indicate encouraging antitumor activity and a manageable safety profile for the combination of the immune checkpoint inhibitor tislelizumab and nab-paclitaxel in patients with T2-4a N0/X M0 muscle-invasive bladder cancer (MIBC) of predominant urothelial carcinoma histology. To identify patient subgroups that may derive particular benefit, we conducted a comprehensive biomarker analysis. Methods: We performed whole-exome sequencing (WES) on baseline tumor tissue from 44 patients. Concomitantly, urine samples were collected during treatment. Baseline urine from 44 patients was subjected to 808-panel circulating tumor DNA (ctDNA) detection, and low-depth whole-genome sequencing (WGS) was performed across three time points (pre-treatment, during treatment, and post-treatment) for 47 patients. Results: The classic biomarker PD-L1 expression failed to predict complete response (CR) Urine-derived biomarkers showed high concordance with tissue-based mutation profiles. Specifically, urinary mutations in RB1, ERCC2, and AR were associated with CR, while mutations in ELF3, KDM6A, and TP53 were linked to non-clinical response (NCR). Baseline ctDNA levels (p=0.016) and baseline (p=0.011)/post-treatment (p=0.0011) WGS scores were significantly higher in the NCR versus CR group, potentially reflecting higher tumor burden. Interestingly, only two patients who achieved CR later experienced disease progression; both showed a rising trend in WGS scores during treatment, suggesting that CR does not ensure long-term favorable prognosis and that dynamic urine monitoring may be crucial during treatment. Finally, we developed a predictive model integrating urinary WGS scores, ctDNA scores, and efficacy-associated mutation genes. This integrated model achieved an area under the curve (AUC) of 0.930, significantly outperforming models based on WGS score alone (AUC=0.695) or ctDNA score alone (AUC=0.749). Conclusions: Urine-based biomarker assays show promise for predicting response to chemo-immunotherapy in MIBC. Further studies with expanded sample sizes and multi-center validation are warranted to confirm these findings and assess their clinical utility in broader patient cohorts. Clinical trial information: NCT04730219 .
Development of an electronic patient navigation platform to enhance adjuvant therapy coordination after cancer surgery.
e13685 Background: For many solid tumors, adjuvant therapy (AT) after curative surgery can reduce recurrence risk and improve survival and is supported by practice guidelines. Implementation of guideline-based care faces several challenges, including comprehensive and efficient identification of patients who may be candidates for AT to optimize care coordination. This study assessed the feasibility and accuracy of an electronic patient navigation platform that identifies patients eligible for AT. Methods: In a single health system, this platform was piloted for renal cell carcinoma and urothelial carcinoma. Clinical databases were searched for required criteria, and sources of inaccuracies were documented. Initially, the EHR was used to identify patients by querying for surgery codes, but it couldn’t filter for cancer cases or specific pathologic data because relevant variables were in unstructured text. The laboratory information system (LIS), in contrast, stored structured data for cancer specimens using the College of American Pathologists (CAP) Cancer Protocol templates, so an LIS report was generated by selecting templates, querying pathologic features, and calculating AT eligibility using rule-based logic. To validate, an EHR report was created by querying the EHR for surgery codes, focusing on cases from 9/2025 to 11/2025, and a genitourinary oncologist manually verified eligibility for AT per established guidelines and whether the patient was appropriately referred to a medical oncologist. The LIS report was compared with the EHR validation report to determine accuracy. Results: The LIS report identified 127 surgical pathology reports, of which 117 were for cancers and 19 were flagged as requiring AT using rule-based logic. The EHR report identified 262 surgical cases. Manul review verified that 123 were for cancers and 18 met criteria for AT (of which 6 were not appropriately referred). The LIS report missed 7 cancers from the EHR report because a CAP template was not used; all were early-stage and did not meet criteria for AT. The EHR report missed 4 cancers in the LIS report, one of which met criteria for AT, due to inefficiencies in surgical coding. For determining AT eligibility, using denominators of patients identified in either report, the rule-based logic had 95% sensitivity and 99% specificity, with 1 false-positive (metastatic cancer not eligible for AT protocol) and 1 false-negative (histology type in the CAP template was incorrect). Conclusions: A report querying CAP Cancer Protocols enabled automated determination of AT eligibility. However, clinical documentation errors can lead to inaccurate reporting. In the next phase, a large language model (LLM) approach will be used to refine the report. For implementation, a coordinator will review the report monthly and facilitate referrals. The program's success will be determined by adherence to AT guidelines.
Temporal trends in gastric cancer incidence by age and sex in the United States.
e16130 Background: The overall incidence of gastric cancer has declined in the United States over recent decades. However, emerging evidence suggests that these aggregate trends may obscure important demographic heterogeneity. Rising incidence among younger adults has been reported, but the magnitude, direction, and demographic specificity of these changes remain incompletely characterized. A comprehensive evaluation of long-term incidence trends across age, sex, and race is needed to identify subpopulations with disproportionate increases in gastric cancer incidence and to inform future etiologic and prevention-focused research. Methods: We conducted a population-based trend analysis using SEER data from 2000–2022. Cases of microscopically confirmed malignant gastric cancers were included with no histological restrictions. Age-adjusted incidence rates (per 100,000) were standardized to the 2000 U.S. standard population. Temporal trends were quantified using annual percent change (APC) with robust 95% confidence intervals (CI). Age-stratified analyses compared younger adults (20–49 years) with older adults (≥50 years). Interaction tests assessed heterogeneity in temporal trends by age group, sex, and race. Analyses were performed using SEER*Stat and R (v4.5.2). Results: 142,606 total gastric cancer cases were identified. Overall incidence declined significantly over the study period (APC −0.59%; 95% CI −0.78 to −0.40; p = 1.6×10⁻⁹). Incidence among adults aged ≥50 years (n = 126,495) declined significantly (APC −0.79%/; 95% CI −1.25 to −0.32; p = 0.0009). In contrast, among adults aged 20–49 years (n = 15,967), incidence increased from 1.78 to 2.22 per 100,000 (+24.7%), corresponding to an APC of +1.01% (95% CI +0.55 to +1.48; p = 1.6×10⁻⁵) with strong evidence of divergence between age groups (interaction p = 7.06×10⁻⁸). Further sex-stratified analyses in the young adult group demonstrated that incidence among females aged 20-49 increased significantly (APC +2.29% per year; 95% CI 1.75 to 2.83; p = 3.65×10⁻¹⁷), whereas no significant change was observed among males aged 20-49 (APC −0.06%; 95% CI −0.49 to 0.38; p = 0.795), with significant sex-based heterogeneity (interaction p = 2.61×10⁻¹¹). Conclusions: Despite an overall decline in gastric cancer incidence, the rates are increasing among younger adults, mostly driven by increasing incidence in young females based on our study. These divergent trends suggest distinct and evolving risk profiles in early-onset gastric cancer that are not captured by aggregate population statistics. Further research into age-specific etiologic factors and targeted prevention strategies is warranted. Group N APC (% per yr) 95% CI p-value Overall 142,606 −0.59 −0.78 to −0.40 1.6×10⁻⁹ Age ≥50 126,495 −0.79 −1.25 to −0.32 9.0×10⁻ 4 Age 20–49 15,967 +1.01 +0.55 to +1.48 1.6×10⁻⁵ Male, 20–49 8,570 −0.06 −0.49 to +0.38 0.795 Female, 20–49 7,316 +2.29 +1.75 to +2.83 3.65×10⁻¹⁷
Antitumor efficacy of 2-(1,1-Dimethyl-1H-Benzo[e]Indol-2-yl)-5,6,7-trichloro-1,3-tropolone on various models of hepatocellular carcinoma.
e16265 Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer, for which multikinase inhibitors are often used in treatment. However, the rapid development of tumor cell resistance to these drugs dictates an urgent need for testing new molecules. Therefore, the aim of this work was to investigate the effect of the pharmacological compound 2-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-5,6,7-trichloro-1,3-tropolone on tumor growth in subcutaneous and orthotopic models of the experimental transplantable Hep G2 HCC in mice. Methods: Hep G2 cells were implanted subcutaneously into donor mice, followed by subsequent passage into recipient mice via subcutaneous and intrahepatic implantation. Micro-CT with contrast enhancement was used to measure intrahepatic tumor nodules. Compounds were administered orally daily after tumor nodules reached 50-60 mm³ for 3 weeks. The concentration of 2-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-5,6,7-trichloro-1,3-tropolone was 60 mg/kg. Sorafenib (20 mg/kg) was used for comparison, and saline solution served as the control. The combination therapy group received both the tropolone and sorafenib at the same concentrations and schedule. Results: At the end of the experiment, the mean volume of subcutaneous and orthotopic tumor nodules was: 804.13 ± 40.56 mm³ and 910.66 ± 51.45 mm³ in the control group; 250.23 ± 18.28 mm³ and 184.26 ± 13.24 mm³ in the combination therapy group; 502.14 ± 31.06 mm³ and 390.14 ± 22.23 mm³ in the tropolone monotherapy group; 295.03 ± 24.99 mm³ and 310.29 ± 14.57 mm³ in the sorafenib monotherapy group, respectively. Tumor Growth Inhibition (TGI) by tropolone monotherapy was more effective in orthotopic models than in subcutaneous ones (57.16% vs. 37.55%), whereas sorafenib did not demonstrate such selectivity (65.93% vs. 63.31%). The highest TGI was observed with combination therapy (68.88% and 79.77% for subcutaneous and orthotopic models, respectively). Although tropolone monotherapy did not demonstrate higher efficacy compared to sorafenib, no body weight loss was observed in animals treated with tropolone, which may indicate its lower toxicity. Conclusions: The antitumor effect of 2-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-5,6,7-trichloro-1,3-tropolone in combination with sorafenib suggests potential synergy or an additive effect between the investigated compounds. The absence of signs of toxic impact from the tropolone could be utilized for developing effective strategies for the compound's application in clinical practice.
Outcomes of robot-assisted interval debulking surgery in older women with advanced ovarian cancer unfit for laparotomy: A real-world study.
e17600 Background: Older women with advanced epithelial ovarian cancer frequently have comorbidities and frailty that limit suitability for open interval debulking surgery (IDS) after neoadjuvant chemotherapy (NACT). Evidence on robot-assisted IDS (RA-IDS) in this population remains limited. We compared perioperative and early oncologic outcomes of RA-IDS offered to patients deemed unfit for open cytoreduction with contemporaneous open IDS in older women. Methods: We conducted a single-centre retrospective real-world study of women aged 65 years or older who underwent IDS following NACT between January 2025 and October 2025. RA-IDS was offered only to patients considered unsuitable for open IDS by multidisciplinary assessment. Perioperative and early oncologic outcomes were compared with women aged 65 years or older undergoing open IDS during the same period. Analyses were unadjusted. Results: RA-IDS was offered to 15 women deemed unfit for open cytoreductive surgery; 10 (66.7%) accepted and underwent RA-IDS. During the same period, 16 women aged 65 years or older underwent open IDS. Patients treated with RA-IDS were older (median age 72 years [IQR 68–76] vs 68 years [65–72]) and had a higher comorbidity burden (median Charlson Comorbidity Index 7 [6–10] vs 5 [4–7]). The majority had FIGO stage IIIC disease (80% vs 87.5%). Median Peritoneal Carcinomatosis Index was comparable (16 [11–26] vs 18 [11–28]). BRCA mutation or homologous recombination deficiency was present in 40% of RA-IDS and 50% of open IDS patients. Among patients selected for RA-IDS, reasons for unsuitability included ongoing antiplatelet or anticoagulant therapy for recent cardiac or thromboembolic disease (60%), frailty with poor nutritional status (20%), and severe renal disease (20%). Conversion to laparotomy occurred in 1 patient (10%) due to extensive diaphragmatic disease. Major postoperative complications (Clavien-Dindo grade ≥3) occurred in 10% of RA-IDS patients compared with 69% of open IDS patients. There was no 30-day mortality. Complete gross resection was achieved in 80% of RA-IDS and 81% of open IDS cases. Median length of hospital stay was shorter following RA-IDS (3 days [2–5] vs 8 days [6–11]), with lower estimated blood loss (60 mL [50–100] vs 300 mL [100–500]) and earlier initiation of adjuvant chemotherapy (23 days [21–30] vs 27 days [27–40]). Six-month progression-free survival was comparable between groups (80% vs 81%). Conclusions: In a real-world cohort of older ovarian cancer patients with higher comorbidity burden deemed unsuitable for open IDS, RA-IDS had lower major morbidity, faster recovery, and preserved early oncologic outcomes. These findings support prospective evaluation of RA-IDS as a risk-mitigation strategy to enable cytoreductive surgery in selected older and frail ovarian cancer patients otherwise excluded from surgical management.
Long term functional survivorship in oral cavity cancer: Quality of life (QOL) outcomes by return to work (RTW) status.
6107 Background: Long-term survivors of oral cavity cancer (OCC) often experience persistent physical, functional, and psychosocial impairments despite disease control. Return to work (RTW) reflects real-world functional recovery and social reintegration. We evaluated whether health-related quality of life (QOL) differs between OCC survivors who returned to work and those who did not. Methods: This prospective cohort study included OCC survivors ≤65 years who underwent definitive surgery between 2016 and 2023 and were disease-free for ≥2 years. Health-related QOL was assessed using EORTC QLQ-C30, EORTC QLQ-HN43, and UW-QOL questionnaires. QOL domains were compared between survivors who returned to work and those who did not. Results: Three hundred OCC survivors were evaluated at a median of 28.5 months after treatment. Survivors who returned to work demonstrated significantly higher global health status and superior physical, role, emotional, cognitive, and social functioning on EORTC QLQ-C30 compared with non-working survivors (all p<0.0001). Non-working survivors had substantially greater head-and-neck–specific symptom burden on EORTC QLQ-HN43, including swallowing difficulty, speech problems, shoulder dysfunction, pain, dry mouth, body-image disturbance, social eating limitations, and fear of progression (all p<0.0001). UW-QOL confirmed significantly worse pain, activity, recreation, swallowing, chewing, speech, shoulder function, mood, anxiety, and overall health-related QOL in survivors who did not return to work (all p<0.0001). Conclusions: Return to work is strongly associated with superior multidimensional quality of life in oral cavity cancer survivors. Survivors who do not resume work experience profound physical, functional, and psychosocial impairment, highlighting the need for rehabilitation-centered survivorship care to restore meaningful functional recovery beyond oncologic cure. Quality of life scores for European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 43 (EORTC QLQ HN 43). EORTC QLQ HN 43 Total patients (Overall population ) Returned to work at the time of survey (Mean + SD) Did not return to work at the time of survey (Mean + SD) P Value Pain in the mouth 34.2 + 15.8 10.3+ 13.2 33.2 + 13.5 p<0.0001 Swallowing issue 10.8 + 12.5 7.8 + 8.7 25.5 + 16.9 p<0.0001 Problems with teeth 17.8 + 19.2 14.1 + 17.2 35.7 + 18.6 p<0.0001 Dry mouth and sticky saliva 23.4 + 21.9 19.5 + 19.1 42.8 + 24.3 p<0.0001 Problems with senses 18.1 + 18.9 14.2 + 16.6 36.9 + 18.0 p<0.0001 Speech issues 15.9 + 18.8 11.6 + 15.4 44.9 + 17.2 p<0.0001 Body image issues 18.0 + 19.7 12.5 + 15.2 41.3 + 20.1 p<0.0001 Social eating issues 17.0 + 19.9 12.0 + 15.7 47.1 + 22.5 p<0.0001 Sexuality problem 18.1 + 22.7 12.2 + 17.6 46.4 + 18.3 p<0.0001 Problems with shoulder 18.6 + 22.0 12.9 + 17.9 46.4 + 18.3 p<0.0001 Skin Problems 13.5 + 18.5 9.0 + 14.7 35.7 + 19.4 p<0.0001
Concordance of measurable residual disease (MRD) rates in the peripheral blood and bone marrow after first-line treatment for CLL with targeted agents: A systematic review and meta-analysis.
e19023 Background: Undetectable measurable residual disease (uMRD) is associated with prolonged progression free survival in patients with chronic lymphocytic leukemia (CLL) (Rios-Olais et al., 2024). Peripheral blood (PB) MRD testing is less invasive and allows more frequent MRD monitoring than bone marrow (BM) MRD testing. As MRD testing and MRD-guided time-limited therapies become more common, there is a need to determine the concordance between rates of uMRD in the PB and BM. Methods: We performed a systematic review and meta-analysis of studies in CLL to determine the concordance between rates of uMRD in the PB and BM. Prospective clinical trials evaluating first-line, time-limited treatment of CLL with targeted agents or anti-CD20 monoclonal antibodies (mAbs) were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception until December 15 th , 2025. Studies were included if they reported rates of BM and PB uMRD at the same timepoint using the same method of MRD testing. Study arms evaluating chemotherapy, single-agent targeted therapy or single-agent anti-CD20 mAbs were excluded. Study sample size, number of patients receiving MRD testing, rates of uMRD in PB and BM, time and method of MRD testing, depth of MRD testing, and treatment arm were extracted. The agreement of uMRD rates between PB and BM was assessed using intraclass correlation coefficients (ICC). Results: 3128 studies were identified on initial search. After study selection criteria were applied, 24 timepoints across 12 prospective clinical trials were analyzed. Across all timepoints, 3121 PB and 2782 BM MRD measurements were included. All timepoints defined uMRD at a depth of under 0.01% CLL cells (10^-4). 20/24 timepoints utilized flow cytometry for MRD testing, 3 utilized allele-specific oligonucleotide PCR (ASO-PCR), and one utilized next-generation sequencing (NGS). 8 timepoints evaluated patients treated with a BTK inhibitor + venetoclax, 10 evaluated patients treated with venetoclax + an anti-CD20 mAb, and 6 evaluated patients treated with triplet therapy. The ICC between rates of uMRD in PB and BM was 0.925 (95% CI: 0.89, 0.95), indicating an excellent degree of agreement between the two methods of testing.(Koo & Li, 2016) The mean uMRD rates in PB and BM were 70.1% and 64.3%, respectively. The mean rate of uMRD in the PB was 5.87% (95% CI: -7.05, 18.80%) higher than in the BM; indicating a consistent slight bias of higher PB uMRD rates compared to BM across timepoints. Conclusions: Overall, we demonstrate that in patients with CLL treated with modern, time-limited therapy, there is high concordance in uMRD rates between PB and BM. Rates of uMRD in the PB are typically slightly higher than in BM.
Variability in higher-education support for adolescents and young adults with active cancer: A cross-sectional survey study.
e23279 Background: Adolescents and young adults (AYA) with cancer frequently face disruptions to educational trajectories, yet limited data exist on how higher-education institutions accommodate students undergoing active cancer treatment. Understanding institutional support mechanisms is critical to improving academic continuity and psychosocial outcomes for this vulnerable population. Methods: We conducted a cross-sectional, survey-based study of undergraduate students aged 18–25 years enrolled in four-year U.S. colleges or universities who carried an active cancer diagnosis requiring ≥3 outpatient oncology visits within a 12-month period. Participants were recruited through online cancer advocacy networks on social media. The survey assessed institutional accommodations including exam rescheduling, assignment flexibility, attendance leniency, access to disability services, and administrative communication. Perceived institutional support was measured using a 5-point Likert scale. Outcomes were compared between public and private institutions using chi-square tests and multivariable logistic regression adjusting for cancer type, treatment intensity, and academic year. Results: A total of 122 students completed the survey (public institutions: 42%; private institutions: 58%). Overall, 62% reported needing to miss ≥2 weeks of coursework due to cancer-related care. Exam rescheduling was permitted in 42% of cases, while 58% were allowed assignment extensions without penalty or needing to repeat a module or semester. Students at private institutions reported higher rates of proactive administrative outreach (63% vs 37%, p < 0.05) and greater flexibility in exam rescheduling (82% vs 18%, p < 0.05) compared with public institutions. After adjustment, enrollment at a private institution was independently associated with higher perceived institutional support (adjusted OR 3.4, 95% CI 1.5–7.7). Inadequate academic accommodations were associated with consideration or initiation of withdrawal or leave of absence in 92% of respondents. Conclusions: Significant variability exists in institutional support for undergraduate students undergoing active cancer treatment, with private institutions demonstrating greater flexibility across multiple academic accommodations. These findings highlight the need for flexible academic policies within higher education to promote equity, retention, and well-being among AYA cancer patients.
First data disclosure from the first-in-human phase 1/2 trial of SMP-3124LP, the first investigational pegylated liposome CHK1 inhibitor, in patients with selected advanced solid tumors.
3081 Background: Checkpoint kinase 1 (CHK1) is a critical in the DNA damage response pathway and an important target for anticancer therapy. However, clinical development of CHK1 inhibitors has been limited by myelosuppression and a narrow therapeutic window. The use of liposomal technology potentially widens the therapeutic window by lowering rates of hematologic toxicities minimizing drug exposure to healthy tissues and maximizing delivery to tumors. SMP-3124 is a structurally distinct CHK1-selective inhibitor designed to be optimally delivered in a PEGylated liposome formulation. SMP-3124LP is being developed for malignancies with high replication stress. Methods: This ongoing Phase 1/2 study evaluated the safety, tolerability, PK, and preliminary antitumor activity of SMP-3124LP given intravenously (NCT06526819). The dose escalation included patients (pts) with selected advanced solid tumors. Results: As of 28 Nov 2025, 42 pts were enrolled at 20, 40, 60, and 90 mg/m 2 every 2 weeks. 23 pts (55%) had ≥4 prior lines of therapy. No dose-limiting toxicities (DLTs) were observed at 20 or 40 mg/m 2 . A DLT of Grade (G) 4 thrombocytopenia was noted at 60 mg/m 2 and one pt had 2 DLTs of reversible G4 thrombocytopenia and G3 febrile neutropenia at 90 mg/m 2 . Most common treatment-related adverse events (≥20%) were neutropenia (45%), infusion-related reactions (IRR, 38%), thrombocytopenia (36%), anemia (24%) and leukopenia (21%). Treatment-related G3/4 neutropenia was 33%, G3/4 thrombocytopenia and G3 anemia were 9.5% each. Cytopenias were generally transient and none led to treatment discontinuation. All IRRs were G1/2 and manageable with premedications, supportive care, and/or slower infusion rates. Dose-proportional increases in C max (4.3-fold) and AUC (6.0-fold) were observed from 20 to 90 mg/m 2 with low volume of distribution (1.99 to 2.68 L) and a geometric mean half-life of 23 to 31 hours. As of 13 Jan 2026, disease control rate (DCR) was 49%, with 5 RECIST v1.1 partial responses (PR) + 12 RECIST v1.1 stable disease (SD) out of 35 efficacy evaluable patients. Among the PRs, 2 platinum-resistant ovarian cancer (PROC, one with prior PARPi), 2 anal SCC, and 1 colorectal cancer with FBXW7 mutation. 2 other advanced PROC pts had SD with tumor shrinkage 20% or more (one with -88% CA125 response). The anal SCC and rectal cancer pts all received ≥4 prior lines of therapy. Duration of response has not been reached. Conclusions: SMP-3124LP was generally well tolerated and had a manageable safety profile. The liposomal formulation appears to reduce the incidence of cytopenias compared to historical data with non-liposomal CHK1 inhibitors. Dose-proportional increases in PK were observed. Promising signals of antitumor activity were observed with 5 RECIST v1.1 PRs and 49% DCR in pts with heavily pretreated cancers. Clinical trial information: NCT06526819 .
5-year overall survival after adjuvant treatment for stage III melanoma: An English nationwide registry-based study.
9570 Background: Adjuvant treatments for stage III cutaneous melanoma were approved based on significant improvement in recurrence free survival (RFS) with both anti-PD-1 and BRAF+MEK inhibitors. However, registration trials have not demonstrated a significant overall survival (OS) benefit to date. Given the potential patient and financial toxicity associated with adjuvant therapy, the effect on OS remains an important consideration. Methods: A retrospective study linking national registry data for all patients diagnosed with stage III melanoma in England between 2016 and 2021 were included and divided into two cohorts based on date of initial melanoma diagnostic staging: pre- and post-May 2018, when adjuvant therapy was initially approved in England. Key data collected were: patient age, sex, date of stage III melanoma diagnosis, TNM stage, systemic therapy for melanoma, cause and date of death. Data cut-off for follow-up was 1 st August 2025. Melanoma-specific survival (MSS) and OS were calculated using the Kaplan-Meier method and Cox regression analyses. Results: A total of 6,297 patients were analysed (pre-May 2018: n=2,089; post-May 2018: n=4,208). Survival outcomes improved significantly in the post-adjuvant cohort. The 5-year overall survival (OS) rose from 60.9% (95% CI: 58.8–63.0) to 64.2% (95% CI: 62.7–65.7), with a hazard ratio of 0.89 (95% CI: 0.82–0.96; p=0.004). Similarly, 5-year melanoma-specific survival (MSS) improved from 70.4% (95% CI: 68.4–72.5) to 72.8% (95% CI: 71.4–74.3), HR 0.89 (95% CI: 0.81–0.99; p=0.025). When stratifying by age, sex or melanoma TNM stage, no significant OS or MSS was observed. Conclusions: English national registry data demonstrates a statistically significant improvement in both OS and MSS for patients diagnosed with stage III melanoma after approval of adjuvant therapy for stage III melanoma. This is consistent with published real world data from France, but contrasts with findings in Sweden and the Netherlands. The reduced utilisation of subsequent therapy for metastatic disease likely reflects the established RFS benefit. The OS benefits are modest, so careful discussion of the potential risks and benefits of adjuvant therapy remains central to patient care. Cohort Pre-May 2018 Post-May 2018 Hazard ratio(95% CI) Number (N) 2,089 4,208 Median duration of follow up (years) 8.38 6.23 Median age (range) 66 (18,103) 67 (18,102) Stage (AJCC V8)3A3B3C3D3 (unspecified) 127 (6.1%)161 (7.7%)1042 (49.9%)97 (4.6%)662 (31.7%) 487 (11.6%)698 (16.6%)2085 (49.5%)168 (4%)770 (18.3%) Received adjuvant systemic therapy 148*(7%) 1772(42%) Received systemic therapy for metastatic melanoma 676(32%) 685(16%) 5-year OS (95% CI) 60.9 %(58.8 – 63.0) 64.2%(62.7 – 65.7) 0.89(0.82 – 0.96) p = 0.004 5-year MSS (95% CI) 70.4%(68.4 - 72.5) 72.8%(71.4 - 74.3) 0.89(0.81 – 0.99)p = 0.025
Understanding the impact of <i>GTF2I</i> mutations in thymic epithelial tumors: Characteristics and clinicogenomic outcomes.
e20173 Background: Thymic epithelial tumors (TETs) are rare malignancies that include thymomas, thymic carcinomas, and thymic neuroendocrine tumors. The GTF2I mutation has been reported frequently in indolent subtypes and is associated with better prognosis, but key aspects of the mutation remain poorly defined. Its incidence across thymic tumor subtypes in large, integrated datasets has not been fully characterized. Clinicogenomic associations, including co-mutational patterns and relationships with tumor mutational burden (TMB), have also not been elucidated. We used publicly accessible cohorts to evaluate the prevalence of GTF2I mutations and to clarify its potential role in molecular classification and clinical management. Methods: We queried publicly accessible TET cohorts within cBioPortal to identify tumors harboring GTF2I mutations. We created a cohort of 403 patients collected from 4 studies. The clinicogenomic data was analyzed to quantify the expression of GTF2I and describe the characteristics of these patients. Results: Of the 403 patients, 178 (44.2%) patients had the GTF2I mutation. Among those the GTF2I mutation, 46.6% of those with mutation were female compared to 35.9% of those without (p = 0.633). The ethnic distribution was similar in mutated and non-mutated groups (p = 0.920). The mean age at diagnosis was higher in the GTF2I positive cohort (61.65 ± 11.23 vs 55.03 ± 13.58 years, p < 0.01). Co-expression data revealed that GTF2I positive TET had higher rates of HRAS (16.85 vs 0.45%, p < 0.01) and TRGJP (16.29 vs 9.42%, p < 0.01) gene alteration event frequencies. TMB of GTF2I mutated cohort was lower than that without the mutation (0.5 ± 0.28 vs 0.68 ± 2.36 mut/Mb, p < 0.01). Of note, patients without the mutation had higher rates of receiving radiation therapy (18.3% vs 50.0%, p < 0.01). Patients in the unaltered group had significantly worse overall survival than those in the altered group (HR 2.56, 95% CI 1.19–5.49; log-rank p = 0.0345). Conclusions: Nearly half of TET patients carried the GTF2I mutation, with a higher incidence in indolent histologies (95% in Type A and 85% in Type AB vs 10% in Type C), suggesting its potential as a molecular adjunct to histologic diagnosis. This would be particularly helpful in settings where morphologic interpretation is challenging, or tumor heterogeneity obscures accurate classification. Additionally, given the typically indolent nature of mutation-positive TET, GTF2I mutation status may inform treatment de-intensification, as survival trajectories in mutation-negative TETs may evolve substantially with expanding immunotherapy use, particularly given its association with high TMB. Distribution of altered and unaltered samples across thymoma subtypes. Disease Type Altered (%) Unaltered (%) Thymoma- Type A 95 5 Thymoma- Type AB 85 15 Thymoma- Type B1 20 80 Thymoma- Type B2 27 73 Thymoma- Type B3 25 75 Thymoma- Type C 10 90
Employment status and occupational patterns among working-age US cancer survivors, 2020-2024.
e23074 Background: Cancer and its treatment often cause impairments constraining work ability, yet financial burdens may compel survivors to work. This complex dynamic may influence occupational choices after cancer diagnosis and treatment, but employment status and occupational patterns among working-age US cancer survivors remain understudied. Methods: This pooled cross-sectional study analyzed data from the 2020 and 2024 National Health Interview Survey to examine employment status and types of occupation among cancer survivors aged 18 to 65 years. Survivors were matched 1:3 with a non-cancer cohort based on age, sex, race/ethnicity, education, and marital status using propensity score matching. We estimated weighted employment rates for any work, full-time work (≥5 hours/week), and part-time work among cancer survivors and the matched controls. We ranked the prevalence of 23 occupational categories among those who were employed. Multivariable logistic regression identified factors associated with employment. Results: The final sample included 2,628 cancer survivors (mean age: 54.5 [SE: 0.19]; 64.1% female), representing 9.5 million U.S. adults, and 7,860 matched non-cancer controls (mean age: 54.4 [SE: 0.23]; 64.8% female). 57.9% (95% CI: 55.5–60.2) of cancer survivors were employed, including 46.4% (95% CI: 44.0–48.8) in full-time and 11.5% (95% CI: 10.0–12.9) in part-time roles. The overall employment rate of cancer survivors was lower than that of matched controls (difference: -5.6; p < 0.001), primarily driven by lower rates of full-time employment, with the widest gap observed among Hispanic survivors (diff: −9.8; p < 0.05) and those with a high school education or less (diff: −9.7; p < 0.001). Among survivors, the employment rate was significantly lower among those who were older, non-Hispanic Black, had lower education and family income, had cardiovascular conditions or diabetes, had multiple cancers, and were diagnosed after age 55 (p < 0.05). Survivors of melanoma, thyroid, and genitourinary cancers had the highest employment rates, whereas lung and gastrointestinal cancer survivors had the lowest. In multivariable logistic regression, older age, female sex, lower education, never married, and having cardiovascular conditions or diabetes were associated with unemployment among cancer survivors (p < 0.05). Cancer survivors tended to be less likely to engage in occupations with higher physical demands than non-cancer survivors, but differences were not statistically significant. Conclusions: The employment rate among cancer survivors was significantly lower than matched peers, particularly among Hispanic survivors and those with lower education. Future research is needed to explore the impact of health-related limitations and financial toxicity of cancer and its treatment on work choices to inform interventions supporting economic stability and quality of life for survivors.
From biological complexity to clinical precision: A first-in-class single-patient–level AI strategy for precision drug repurposing in relapsed, refractory, or metastatic cancers using COSMIC mutational signatures with blast-crisis CML as a model.
e15117 Background: Introduction: Relapsed, refractory & metastatic cancers (RRM) are resistant to treatment due to extreme inter-patient heterogeneity & clinical limitations of treatment paradigms [1]. COSMIC mutational signatures capture underlying mutagenic pathways & provide a biologically integrated treatment framework that transcends single-gene alterations [2]. We hypothesized that integrating COSMIC signatures with artificial-intelligence (AI) algorithms could enable clinically actionable, single-patient precision drug repurposing in RRM [3]. Blast-crisis chronic myeloid leukemia (BC-CML) a genomically unstable & fatal disease was used as a proof-of-concept example [4]. Methods: Whole-exome sequencing was performed & COSMIC mutational signatures were extracted using SigProfilerExtractor to quantify dominant mutational processes at individual-patient resolution [1,5]. Unsupervised machine learning identified biologically coherent mutational signatures in each patient [3]. AI-guided drug prioritization was performed using PanDrugs, integrating mutations, signatures, and pharmacogenomic evidence to generate patient-specific, clinically actionable drug rankings [2]. Results: Each BC-CML patient exhibited a unique COSMIC signature profile, reflecting distinct biological drivers of leukemic progression and therapeutic vulnerability. Signature-defined biology mapped patients to hallmark pathways (Table). AI-based integration prioritized distinct repurposable FDA/EMA-approved therapies for each patient. No two patients shared an identical therapeutic profile, demonstrating true N-of-1 precision beyond cohort- or cluster-level classification. Conclusions: Discussion:This is a first-in-class, single-patient precision oncology framework shifting therapeutic decision-making from static mutations to dynamic mutational processes [1,6]. Using BC-CML as a model, this strategy is broadly applicable to RRM enabling rational drug repurposing when standard therapies fail supporting real-time, patient-level clinical decision-making [4,7]. References 1: Bobo M, et al. Int J Infect Dis. Jan 2026 2: Zhang L, et al. NPJ Precis Oncol. 2025 Dec 20 3: Li W et al. Discov Oncol 2026 Jan 12 4: Bhat M. Exp Cell Res. 2026 Feb 15 5: Ochi Y et al. Nat Commun. 2021 6: Wan Z. Adv Sci. 2025 7: Noor WD et al. Expert Rev Hematol 2026 Jan 11. CML Patient IDs COSMIC Signature(s) Core Pathway Top Repurposed Drugs 1–4 S3 / S5 HR deficiency, checkpoint failure PARP inhibitors (olaparib), CDK/MDM2 inhibitors 5–7 S1 Epigenetic dysregulation IDH inhibitors (enasidenib), PARP/ATR inhibitors 8–9 S2 Replication stress ATR inhibitors (AZD6738), antimetabolites 10–12 S13 / S18 Oxidative & inflammatory stress JAK inhibitors (ruxolitinib), NAC
Analysis of genomic and clinical predictors of overall survival and PSA response: Results from the PRECISION registry.
5051 Background: Outcomes in advanced prostate cancer vary substantially according to clinical and genomic characteristics among patients with metastatic castration-resistant prostate cancer (mCRPC). We sought to identify predictors of overall survival (OS) and prostate-specific antigen (PSA) response using data from the PRECISION real-world registry of mCRPC patients treated with poly(ADP-ribose) polymerase inhibitors (PARPi). Methods: Patient-level data from five centers (Dana Farber Cancer Institute, Thomas Jefferson University, University of British Colombia, University of Washington, Yale University) were aggregated, including demographics, clinical characteristics, genomic alterations, treatments, and clinical outcomes. OS was defined as the time from the first date of PARPi treatment to death or the last date the patient was known to be alive. PSA response was defined as a confirmed ≥50% decline from the PSA level measured closest to the start of PARPi treatment. Ten candidate variables per endpoint were selected via a random forest-based feature selection. Cox models stratified by study were used for OS, and logistic regression models with study included as an additional covariate were used for PSA response. Similarly, non- BRCA mutation status was defined as the presence of any observed mutation in genes other than BRCA , including ATM , CHEK2 , MSH2 , PALB2 , BRIP1 , and BARD1 . Results: The combined dataset included n = 327 patients, with heterogeneity in baseline characteristics and treatments across studies. The prevalence of BRCA ( BRCA1 or BRCA2 ) and non BRCA mutations was 39% and 37% respectively. Median OS for patients with BRCA mutations was 21 months (95% CI:16–28), compared with 15 months (95% CI: 14–18) for those without BRCA mutations. No difference in median OS was observed between patients with and without non- BRCA mutations: 16 months (95%CI: 14-22) and 17 months (15-21), respectively. Cox models identified age, N stage, PSMA–lutetium therapy, PARPi use within a clinical trial, prior taxane treatment (docetaxel or cabazitaxel), and BRCA as important predictors of OS. The corresponding hazard ratios with 95% confidence intervals are shown in the table below. Conclusions: These results from real-world data highlight the importance of incorporating genomic information and treatment-specific variables when predicting outcomes in advanced prostate cancer and demonstrate the utility of multi-study integrative analyses. Predictor Hazard Ratio (95% CI) Age 1.02 (1.01–1.04) N stage 1.91 (1.18–3.12) PSMA–lutetium therapy 0.35 (0.20–0.62) PARPi use (within clinical trial) 0.68 (0.48–0.98) Prior taxane treatment (docetaxel or cabazitaxel) 1.44 (1.02–2.02) BRCA mutation 0.50 (0.36–0.69)