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National trends in sepsis-related mortality among decedents with malignant neoplasms in the United States, 1999–2023.

e13506 Background: Sepsis is one of the leading causes of death in cancer patients as a result of both immunosuppression, treatment-related toxicity, and comorbid conditions. With amelioration in cancer survival, sepsis has become a relatively more prominent competing cause of death. However, long-term national trends and the demographic differences in sepsis-associated death among decedents with malignant neoplasms have not been fully described. Methods: Death certificate data from the CDC WONDER database for adults aged ≥65 years from 1999 to 2023 were analyzed. Sepsis-related deaths were identified using ICD-10 codes for sepsis (A40 [streptococcal sepsis] and A41 [other sepsis]) listed as underlying or contributing causes of death among decedents with malignant neoplasms (ICD-10 codes C00–C97). Age-adjusted and age-specific mortality rates per 100,000 persons were calculated. Temporal trends were assessed using annual percent change (APC) and average annual percent change (AAPC) via Joinpoint regression. Results: From 1999 to 2023, sepsis-related mortality among individuals with malignant neoplasms in the United States increased, with the age-adjusted mortality rate (AAMR) rising from 1.27 in 1999 to 1.68 in 2023. Overall mortality increased significantly (AAPC 1.15%; 95% CI 0.61–1.69; p < 0.001). Mortality rates were higher in men than women (AAMR 1.67 vs 1.06). Among women, mortality increased overall (AAPC 1.59%; p < 0.001), with a pronounced rise from 2019–2023. Non-Hispanic Black individuals had the highest AAMR (2.12), followed by Non-Hispanic White (1.24) and Hispanic or Latino (0.89). All racial and ethnic groups exhibited post-2019 increases, with the steepest rise among Non-Hispanic Black individuals (APC 9.98%; p < 0.001). AAMRs were similar in metropolitan (1.26) and non-metropolitan areas (1.27); non-metropolitan areas showed a sustained increase (AAPC 1.05%; p = 0.004). Regionally, the Northeast had the highest AAMR (1.73), followed by the South (1.38), Midwest (1.27), and West (0.79), with post-2019 increases observed across all regions. The inflection in sepsis-related mortality after 2019 may reflect the combined effects of the COVID-19 pandemic, including health system strain, delayed cancer care, and potential changes in death certification practices. Conclusions: Targeted interventions are needed to reduce sepsis-related mortality among patients with malignant neoplasms in the United States, particularly in populations defined by sex, race and ethnicity, metropolitan status, and geographic region. Efforts should prioritize early recognition and prevention of sepsis, equitable access to timely oncologic and acute care, and focused strategies for high-risk groups.

Sex-specific risk of mood and anxiety disorders following cancer diagnosis in adolescents and young adults: A Canadian population-based study.

e24120 Background: Adolescents and young adults (AYAs) with cancer have unique medical and psychosocial needs. Despite improvements in survival outcomes, AYAs remain at elevated risk for psychological morbidity. Sex-based differences in the development of mood and anxiety disorders are not well characterized. This study examined factors associated with the development of mood and anxiety disorders among AYAs within five years of cancer diagnosis stratified by sex and tumor type. Methods: This retrospective cohort study used population-based data from the Manitoba Cancer Registry to identify individuals aged 15–39 years diagnosed with invasive cancer between 1989 and 2019. Mood and anxiety disorders were determined using validated administrative algorithms. Associations between demographic, clinical, and treatment-related factors including age at diagnosis, comorbidities, income quintile, residence, year of diagnosis, sex and tumor type (sex-specific, non-sex-specific solid, and non-solid), and receipt of chemotherapy, surgery, and radiation were evaluated using competing risks regression. Sex-specific cancers included breast, ovarian, uterine, and cervical cancers in females, and prostate and testicular cancers in males. Results: Among 3,818 AYAs with cancer, 56% were female, and 21% were aged 15-25. Most individuals had solid tumors (83%), of whom 34% had a sex-specific tumor. In competing risks regression, compared to males with a sex-specific cancer, females with sex-specific cancers [sub-Hazard Ratio (sHR) 2.28, 95% Confidence Interval (CI) 1.36–3.82], females with non–sex-specific solid tumors (sHR 2.22, 95% CI 1.33–3.70), females with non-solid tumors (sHR 2.98, 95%CI 1.55–5.71), and males with non-solid tumors (sHR 1.97, 95% CI 1.03–3.78) had a higher risk of developing mood or anxiety disorder. Additionally, younger age at diagnosis (Table 1), presence of one or more comorbidities (sHR 1.34, 95% CI 1.05-1.71), a more recent year of cancer diagnosis (sHR 1.03 per year, 95% CI 1.01-1.04), receipt of chemotherapy (sHR 1.38, 95% CI 1.03-1.84) and surgery (sHR 1.93, 95% CI 1.38-2.69) were associated with an increased risk of mood and anxiety disorders. Conclusions: Among AYAs with cancer, the risk of mood and anxiety disorders was highest among females, those with non-solid tumors, a younger age at diagnosis, presence of a comorbidity, a more recent diagnosis year, and receipt of chemotherapy or surgery. These findings underscore the need for targeted mental health screening and psychosocial support for AYA populations at a higher risk of a mood or anxiety disorder. 5-year adjusted cumulative incidence of mood and anxiety disorders post cancer diagnosis. Age at diagnosis (years) 5-year adjusted cumulative incidence (%) 15 14.0 20 10.2 25 7.9 30 7.0 35 7.2 39 7.6

A study evaluating microbiome modulation therapy in patients undergoing first-line therapy for metastatic colorectal cancer.

TPS3679 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Despite advances in systemic therapy, the 5-year overall survival for metastatic CRC remains poor. Emerging evidence suggests that the gut microbiome influences CRC development, progression, as well as chemotherapy resistance. There is strong preclinical data showing the association of Fusobacterium nucleatum and Escherichia coli with poor outcomes and chemotherapy resistance in patients with CRC. Younger patients and Black patients have been found to have a high-level colonization with F nucleatum , which could potentially contribute to healthcare disparities. If the amount of cancer-associated bacteria in the microbiome can be reduced, patients may respond better to chemotherapy and have improved outcomes. Preclinical studies indicate that targeting these bacteria with antibiotics may enhance chemotherapy efficacy. Aspirin may also be beneficial as it affects gene expression and inhibits Fusobacterium nucleatum with differential effects at varying drug concentrations. Our study evaluates the feasibility, safety, and preliminary efficacy of adding Microbiome Modulation Therapy (MBMT), including ciprofloxacin, metronidazole, +/- aspirin, to standard first-line chemotherapy in patients with metastatic CRC. Methods: This is a two-arm, noncomparative phase II trial enrolling adults (≥18 years) with stage IV CRC and measurable disease by RECIST 1.1. Eligible patients must have ECOG performance status 0–2 and planned first-line 5FU-based standard of care chemotherapy. Patients are excluded if they have recent antibiotic use to treat an infection within 30 days of treatment start (prophylactic preoperative antibiotics are allowed), have had a total colectomy, or are taking probiotic treatments. Patients are randomized to standard chemotherapy alone (investigators choice) or chemotherapy plus MBMT (ciprofloxacin, metronidazole, +/- aspirin for 28 days). The primary endpoint is objective response rate (ORR) per RECIST 1.1. Secondary endpoints include overall survival (OS), progression-free survival (PFS), safety, and tolerability of MBMT. Exploratory endpoints include changes in microbiome composition as measured by shotgun sequencing of fecal samples at baseline and after one month of treatment with chemotherapy +/- MBMT. Correlative studies will use shotgun sequencing to assess microbiome signatures, microbiota diversity, and changes with treatment. Correlative analyses will explore microbiome modulation as a novel therapeutic strategy to overcome chemoresistance in metastatic CRC. Enrollment is ongoing at Virginia Commonwealth University Massey Comprehensive Cancer Center in Richmond, Virginia. Clinical trial information: NCT06728072 .

Association of SGLT2 inhibitors and GLP-1 receptor agonists or DPP-4 inhibitors with incident cancer in patients with type 2 diabetes.

10590 Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) exert potential anti-tumor effects. Emerging data suggest SGLT2i are associated with reduced cancer incidence in type 2 diabetes (T2D), while incretin-based therapies show mixed results varying by cancer type. Among patients with T2D, we tested that hypothesis that use of SGLT2i, as compared to GLP-1 receptor agonists (GLP-1RA), and dipeptidyl peptidase-4 inhibitors (DPP-4i), would be associated with lower risk of overall and individual cancer types. Methods: Matched cohort study using MarketScan US claims database (2016–2022). T2D patients with ≥1 metformin prescription and >90 days enrollment before 2 nd line therapy initiation were included. SGLT2i users were matched with up to 5 users of other therapies by age, sex, enrollment, and 2 nd line therapy initiation dates. ICD codes were used to identify cancer. Cox models adjusted for demographics, comorbidities, and medications. Results: Among 365,494 matched patients (mean±SD age 54.2±10.0 years, 48.5% female), 5,422 incident cancers occurred over median 1.43 (maximum 6.75) years follow-up. Cohort included 133,210 SGLT2i users (empagliflozin 55%, dapagliflozin 32%, canagliflozin 12%) and 232,284 comparators (GLP-1RA 60.4%, DPP-4i 39.6%). SGLT2i users showed modestly lower composite cancer risk versus other therapy users [Hazard ratio (HR) 0.94, 95% CI 0.89-0.99]. Compared with DPP-4i use, SGLT2i use demonstrated 10% lower cancer risk (HR 0.90, 95% CI 0.85-0.97), but showed no significant difference versus GLP-1RA use (HR 0.97, 95% CI 0.91-1.04). Analyses by cancer type revealed no significant differences in HR for breast (0.92, 0.84-1.04), prostate (0.96, 0.84-1.08), colorectal (0.96, 0.82-1.12), lung (0.95, 0.78-1.16), pancreatic (1.04, 0.84-1.28), hepatocellular (1.01, 0.76-1.33), renal cell (0.92, 0.76-1.11), endometrial (1.01, 0.79-1.29), or thyroid cancers (0.84, 0.66-1.06). Cancer risk was comparable across individual SGLT2i(p>0.05). Conclusions: SGLT2i demonstrated a 10% reduction in overall cancer risk versus DPP-4i and comparable efficacy to GLP-1RA, reinforcing SGLT2i's potential oncologic benefits. No associations were observed with individual cancer types, though interpretation is nuanced due to poor precision and short follow-up. Comparable risk among individual SGLT2i suggest a class-wide effect. Future prospective studies with extended follow up are needed to validate these associations and clarify whether SGLT2i offer meaningful cancer risk reduction beyond their established cardiometabolic benefits. Hazard ratios (95% CI) for incident cancer, Marketscan databases, 2016-2022. N (events / total) HR (95% CI) SGLT2i vs. DPP-4i SGLT2i 1,559 / 93,494 0.90 (0.85 - 0.97) DPP-4i 1,749 / 93,494 Ref SGLT2i vs. GLP-1RA SGLT2i 1,699 / 123,955 0.97 (0.91 - 1.04) GLP-1RA 1,757 / 123,955 Ref

Correlation of baseline testosterone (T) level with survival outcomes in patients (Pts) with metastatic hormone-sensitive prostate cancer (mHSPC): Analysis of patient (pt)–level data from SWOG 1216 study.

5096 Background: Retrospective data suggest that low baseline serum T may be associated with inferior survival outcomes in mHSPC [PMID: 38444678]. Whether this relationship persists in rigorously controlled, randomized clinical trial populations remains unclear. We examined the prognostic impact of baseline T using patient-level data from the phase 3 SWOG 1216 trial which randomized pts with mHSPC in 1:1 to ADT + bicalutamide (standard arm) or ADT + orteronel (experimental arm). Methods: Patients treated on SWOG 1216 trial with available baseline T levels were eligible and included in this secondary analysis. Baseline T was summarized by median (IQR) and dichotomized at the median as ≤ median vs > median. Overall survival was the primary endpoint; progression-free survival (PFS) and prostate-specific antigen (PSA) response were secondary endpoints. PSA response rates were divided into complete response (CR; PSA <0.2 ng/mL), partial response (PR; PSA between 0.2 and 4.0 ng/mL), and no response (NR; PSA >4.0 ng/mL) at a 7-month landmark following randomization. OS and PFS were estimated by Kaplan-Meier within each arm, with median survival (95% CI) and number of events reported. Comparisons were performed using the log-rank test. PSA response was summarized as n (%), and groups were compared using Pearson’s chi-squared test. All tests were two-sided with alpha = 0.05. Results: Of 1279 pts, 218 pts had baseline T levels. Median T level was 312.5 ng/ml (IQR 89.25 - 462 ng/ml). In both experimental and standard arms, there was no significant difference in OS, PFS, or PSA response between patients with baseline T levels above vs below the median (Table). Similarly, in both arm, there was no difference in outcomes based on baseline T levels grouped by quartiles, as well as baseline T levels as a continuous variable (data will be presented at the conference). Conclusions: In this patient-level analysis of a phase 3 trial, there was no statistically significant association between baseline T and outcomes in mHSPC. Based on these data, baseline T may not be used for prognostication or treatment selection in patients receiving systemic therapy in mHSPC. Limitations include a small sample size. These hypothesis-generating data require external validation before clinical application. Treatment Arm T Level OS Median (95% CI), months N (events) P-value PFS Median (95% CI), months N (events) P-value PSA complete response n (%) PSA partial response n (%) No PSA Response (%) P-value Experimental ≤ Median 63 (47, NR) 71 (37) 0.11 30 (20, 64) 71 (49) 0.11 37 (50%) 18 (60%) 16 (62%) 0.5 > Median NR (68, NR) 59 (22) 57 (26, NR) 59 (30) 37 (50%) 12 (40%) 10 (38%) Standard ≤ Median 72 (45, NR) 38 (20) 0.7 19 (12, 34) 38 (29) 0.9 14 (42%) 9 (45%) 15 (43%) >0.9 > Median 57 (43, NR) 50 (22) 19 (13, 35) 50 (39) 19 (58%) 11 (55%) 20 (57%)

Comments on the LUNAR Trial in Oligorecurrent Hormone-Sensitive Prostate Cancer

Zongertinib in previously treated advanced HER2-mutant non-small cell lung cancer: A single-center study.

e20727 Background: HER2 mutations are present in 2-4% of advanced non-small cell lung cancer (NSCLC). The HER2 YVMA (A775_G776insYVMA) mutation is the most common mutation found in HER2 -mutant NSCLC and is estimated to occur in about 40-60% of cases. Zongertinib is a novel HER2-selective tyrosine kinase inhibitor which received accelerated approval by the U.S. Federal Drug Administration for the treatment of previously treated HER2-mutant NSCLC. We describe our experience treating patients with zongertinib at a large academic center in a diverse, urban U.S. population. Methods: We reviewed our electronic health records and included all patients with next generation sequencing confirmed HER2 -mutant advanced NSCLC treated with zongertinib from January 1, 2022 through January 23, 2026. Disease characteristics, treatment sequencing, outcomes, and adverse events data were collected and reported. Results: 15 patients were treated with zongertinib with a median length of follow-up of 12.6 months. The objective response rate (ORR) was 60.0%. 6- and 12-month progression-free survival rates were 66.7% and 52.5% respectively. In 6 patients previously treated with trastuzumab deruxtecan (T-Dxd), the ORR for zongertinib was 50%. In 9 patients not previously treated with T-Dxd, the ORR was 66.7%. 2 patients had sequential T-Dxd after progression on zongertinib; both had partial responses (PRs) while on T-Dxd. 1 of these patients had a durable response of 9.0 months followed by disease progression. The intracranial ORR for zongertinib in patients with baseline brain metastases was 25%. The ORR was 37.5% for 8 patients with a YVMA mutation and 85.7% for 7 patients with non-YVMA mutations. The most common mutation aside from YVMA was V777L, which was found in 3 patients (20%). Diverse mutations were identified, including in a patient with V659E (non-tyrosine kinase domain), who had a PR, and in another patient with L755P (non-exon 20), who had a PR with a durable response of 20.5 months. Treatment-related adverse events (AEs) were reported in 93.3% of patients; grade 3 or higher AEs were reported in 1 patient (increased ALT and AST). The most commonly reported AEs were diarrhea (73.3%) and rash (60%), which were predominantly grade 1. Conclusions: Our clinical experience suggests that zongertinib is safe and effective in a diverse, urban U.S. population, including patients previously treated with a HER2-targeted agent. Our findings show that in patients treated with either T-Dxd or zongertinib, subsequent treatment with another HER2-targeted agent still yielded objective responses, suggesting some distinct mechanisms of resistance against different HER2-targeted therapies. Our findings also potentially suggest that patients with HER2 non-YVMA mutations may respond to zongertinib with greater efficacy compared to those with a YVMA mutation, and further molecular analysis is underway.

Real-world effectiveness and safety of adjuvant capecitabine in triple-negative breast cancer (TNBC) patients with residual disease following neoadjuvant chemotherapy.

543 Background: The presence of residual disease in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy is associated with high recurrence risk and poor prognosis. The CREAT-X study demonstrated improved recurrence risk and survival outcomes with adjuvant capecitabine in this population [1]. We previously reported long-term outcomes in nonmetastatic TNBC, but the population is unselected, and the impact of adjuvant capecitabine is not assessed in the Indian scenario [2]. Methods: This single-center retrospective study included TNBC patients with residual disease after neoadjuvant chemotherapy treated between January 2020 and December 2024 with adjuvant capecitabine. Baseline clinicopathological characteristics were analyzed descriptively. Survival outcomes were assessed using the Kaplan–Meier method, and recurrence-free survival (RFS) and overall survival (OS) were estimated. Factors associated with survival outcomes were evaluated using univariate and multivariate Cox proportional hazards regression models. Results: Among 1548 patients diagnosed with Stage I-III TNBC, 1044 patients treated with neoadjuvant therapy underwent surgery; 671 patients had residual disease, out of which 315 patients who received adjuvant capecitabine were included in this retrospective analysis. The majority were premenopausal (66.3%), were older than 40 years (59.7%), and had stage III residual disease (71.4%). At a median follow-up of 25 months, the 2-year overall survival (OS) was 79.6%, with a median OS of 49.7 months. The 2-year recurrence-free survival (PFS) was 49.3%, with a median RFS of 23.9 months. On univariate analysis, higher nodal status (P < 0.001) and advanced stage (P < 0.05) were significantly associated with inferior RFS, while higher nodal status was also associated with inferior OS (P < 0.05). Multivariate analysis confirmed nodal status as an independent predictor of poor survival (P < 0.01). Conclusions: Adjuvant capecitabine demonstrated poor outcomes in our TNBC patients with residual disease compared to the randomized study; nodal status independently predicted poorer outcomes, emphasizing risk stratification and prospective validation. References: Toi M, Lee SJ, Lee ES, Ohtani S, Im YH, Im SA, Park BW, Kim SB, Yanagita Y, Takao S, Ohno S. Abstract S1-07: a phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). Cancer Research. 2016 Feb 15; 76(4_Supplement): S1-07. Bajpai J, Kashyap L, Vallathol DH, Das A, Singh M, Pathak R, Rath S, Sekar A, Mohanta S, Reddy A, Joshi S. Outcomes of non-metastatic triple negative breast cancers: Real-world data from a large Indian cohort. The Breast. 2022 Jun 1;63:77-84. Clinical trial information: CTRI/2026/01/101798 .

Survival and functional outcomes in octogenarians with lung cancer.

e20099 Background: The incidence of lung cancer is increasing among octogenarians, yet this population is less likely to receive guideline-concordant cancer-directed therapy. In addition to a higher comborbidity load and reduced physiologic reserve to tolerate treatment, many octogenarians may prioritize quality of life and avoidance of treatment burden over potential survival benefit. Consequently, a better understanding of survival and functional outcomes associated with cancer-directed therapy among octogenarians is needed to inform shared, goal-concordant decision-making. Methods: We conducted a retrospective cohort study using the TriNetX Research Network. Patients diagnosed with lung cancer at age 80 and older were identified and stratified by receipt of cancer-directed therapy (surgery, chemotherapy, immunotherapy, radiation, and/or tyrosine kinase inhibitor therapy) versus no treatment. Patients diagnosed prior to age 80 or without at least one follow-up visit were excluded. Baseline demographics and comorbidities were assessed. To reduce confounding, cohorts were balanced using 1:1 greedy nearest-neighbor propensity score matching based on demographics and comorbidities, with adequate balance defined as a standardized mean difference < 0.1. Post-matching outcomes included new oxygen requirements, utilization of physical or occupational therapy or home health services, and all-cause mortality. Results: After 1:1 propensity score matching, 27,012 patients aged ≥ 80 years with lung cancer were identified. 13,506 elected to receive some form of treatment and 13,506 remained untreated. Within 1 year of diagnosis, treated patients had higher odds of developing a new oxygen requirement compared with untreated patients (OR 1.33, 95% CI 1.19–1.50), but lower odds of physical/occupational therapy or home health utilization (OR 0.73, 95% CI 0.60–0.90). Treated patients also demonstrated lower short-term all-cause mortality (OR 0.79, 95% CI 0.75–0.84). Over longer follow-up (1 day to 5 years), treatment was associated with increased odds of new oxygen requirement (OR 1.38, 95% CI 1.25–1.52), no difference in functional support utilization (OR 0.99, 95% CI 0.84–1.18), and higher all-cause mortality (OR 1.08, 95% CI 1.03–1.13). Conclusions: Treatment in octogenarians with lung cancer improves short-term survival but increases pulmonary morbidity. Importantly, treatment was not associated with improved long-term survival, highlighting the need for individualized treatment decisions that carefully weigh potential short-term benefit against treatment-related morbidity in octogenarians.

Immune-related adverse events and patient outcomes in non–small cell lung cancer: A silver lining?

e20060 Background: Immune checkpoint inhibitor (ICI) therapy has prolonged survival in non-small cell lung cancer (NSCLC), but can also trigger immune-related adverse events (irAEs) requiring therapy discontinuation and re-challenge. Data on morbidity and response outcomes after irAEs, as well as tolerability of re-challenge after irAE, remains limited in these patients. Methods: We conducted a retrospective, single-institution analysis of patients with primary lung malignancy who received immunotherapy at the University of Virginia Emily Couric Cancer Center between 2011-2023. Data on treatment patterns, demographics, survival outcomes, irAEs, and rechallenge after irAE were collected. IrAEs were graded using CTCAE v5. criteria via chart review. Median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Hazard ratios (HR) were from multivariable Cox regression models, and associated p-values were calculated from Wald tests. Results: Of 598 NSCLC patients who received ICI, 55.7% were male, 81.8% were White, and median age was 65 years. 61.7% had Stage IV disease at diagnosis, and 57.0% of patients had adenocarcinoma on histology. 282 (47.2%) patients experienced an irAE. The most common irAEs experienced were rash (24.8%), pneumonitis (22.7%), and hypothyroidism (11.0%). Of patients who experienced an irAE, 194 (68.8%) underwent ICI re-challenge. Of patients who underwent re-challenge, 59 (30.3%) experienced a subsequent irAE. OS for the whole cohort was 29.1 months (95% CI: 24.8-33.9 months) and PFS was 6.9 months (95% CI: 6.4-8.2 months). Having squamous cell carcinoma histology was associated with decreased OS (HR = 1.47, p = 0.002) compared to adenocarcinoma, as was stage IV disease at diagnosis (HR = 1.83, p = 0.001) vs. stage I. Patients who experienced an irAE had improved OS (HR = 0.55, p < 0.001) and PFS (HR = 0.46, p < 0.001) compared to patients who did not experience one. Conclusions: Occurrence of irAE was associated with improved OS and PFS in NSCLC patients. Additionally, ICI re-challenge is feasible in most patients after irAE. Further studies are needed to evaluate factors associated with successful ICI re-challenge.

Rivaroxaban versus low molecular weight heparin in cancer-associated thrombosis: Assessment of clinical equipoise and bleeding risk from randomized evidence.

e24200 Background: Direct oral anticoagulants are increasingly adopted for cancer-associated thrombosis (CAT) due to ease of administration; however, robust comparative safety and efficacy data against low molecular weight heparin (LMWH) remain limited. We conducted a meta-analysis of randomized trials to evaluate whether rivaroxaban provides superior clinical outcomes in patients with active malignancy. Methods: A systematic search of PubMed, EMBASE, and Cochrane Library identified randomized controlled trials comparing rivaroxaban with LMWH in adults with active cancer and acute venous thromboembolism. Outcomes included recurrent VTE, deep vein thrombosis (DVT), major bleeding, and minor bleeding. Pooled risk ratios (RR) were calculated using random-effects models. Heterogeneity was assessed using I² statistics. Results: Four randomized trials comprising 1,195 patients (rivaroxaban n = 591; LMWH n = 604) were included. Rivaroxaban showed no statistically significant reduction in recurrent VTE compared with LMWH (RR 0.59, 95% CI 0.33–1.05; p = 0.07; I² = 0%) and no difference in DVT recurrence (RR 0.70, 95% CI 0.44–1.12; p = 0.13). Importantly, rivaroxaban demonstrated a numerically higher major bleeding risk (RR 1.47, 95% CI 0.86–2.53) and a significant increase in minor bleeding events (RR 1.90, 95% CI 1.01–3.55; p = 0.05), indicating a clinically relevant bleeding signal. This corresponds to approximately one additional bleeding event for every 53 patients treated with rivaroxaban without a proportional reduction in thrombotic recurrence. Conclusions: In patients with active cancer and venous thromboembolism, rivaroxaban does not provide superior thrombotic protection over LMWH and is associated with increased bleeding events. These findings demonstrate persistent clinical equipoise and suggest that widespread substitution of LMWH with rivaroxaban should be approached cautiously. Personalized anticoagulant selection based on bleeding risk may be critical to optimizing outcomes in this high-risk oncology population.

Integrating objective sarcopenia assessment into geriatric screening as a predictor of treatment tolerance.

1665 Background: Geriatric assessment (GA)–based screening tools, including the G8 screening tool, the Korean Cancer Study Group Geriatric Score (KG-7), and the Cancer and Aging Research Group (CARG) toxicity score, are widely used to guide treatment decisions in older patients with cancer. However, these tools incompletely capture biological reserve and show limited accuracy in predicting treatment tolerance, particularly in patients with indeterminate risk. We evaluated whether incorporating objective sarcopenia assessment could improve risk stratification. Methods: We retrospectively analyzed 97 elderly patients with cancer (age ≥70 years) who underwent GA screening prior to treatment decision-making at a single tertiary center between May 2024 and December 2025. In addition to standard GA tools (G8, KG-7, and CARG toxicity score), skeletal muscle index (SMI) and functional frailty were assessed. SMI was measured using the DYPHI body water analysis (BWA) system, which estimates appendicular lean mass through multi-frequency bioelectrical impedance analysis. Functional frailty was evaluated using the Short Physical Performance Battery (SPPB). Treatment intolerance was defined as grade 3–5 toxicity, unplanned hospitalization, emergency room visit, or treatment discontinuation. Multivariable logistic regression and subgroup analyses were performed. Results: The median age was 76 years (range, 61–87), and 77 patients (79.4%) were male. Most patients had advanced-stage disease (72.2%), and 55.7% received palliative treatment. Initial dose reduction (<100%) occurred in 63.9%. GA tools, sarcopenia, and frailty showed modest concordance. Among GA tools, G8 demonstrated the strongest association with treatment intolerance (odds ratio [OR] per point increase 0.86, 95% confidence interval [CI] 0.74–0.99; p=0.03; area under the curve [AUC] 0.64). Sarcopenia was independently associated with treatment intolerance (OR 2.45, 95% CI 1.02–5.87; p=0.045) and improved discrimination across G8, KG-7, and CARG tools (ΔAUC up to +0.12). The benefit of sarcopenia was greatest in borderline or intermediate GA risk groups (ΔAUC approximately +0.10–0.12), with minimal improvement in low- or high-risk groups (ΔAUC ≤0.02). A minimal model incorporating G8, sarcopenia, and Eastern Cooperative Oncology Group (ECOG) performance status achieved the best performance (cross-validated AUC 0.68). Conclusions: Incorporation of objective sarcopenia assessment using the DYPHI BWA system significantly improves prediction of treatment tolerance beyond established GA tools, particularly in intermediate-risk subgroups. A pragmatic model combining G8, sarcopenia, and ECOG performance status may refine risk stratification and personalize treatment decisions in geriatric oncology.

The efficacy and safety of sosimerasib monotherapy in pretreated colorectal cancer with KRAS G12C mutation: Results from a phase 1b study.

3596 Background: KRAS G12C mutation is a key driver in approximately 3-4% of colorectal cancer (CRC) cases with poor prognosis. Sosimerasib is a novel, potent, and highly selective KRAS G12C inhibitor. This Phase 1b study evaluates the efficacy and safety of sosimerasib in patients with KRAS G12C-mutated locally advanced or metastatic CRC. Methods: Eligible patients who had received prior standard chemotherapy were enrolled in this study. Patients were administered sosimerasib at 500 mg orally once daily. The primary efficacy endpoint was the objective response rate (ORR) assessed by investigators according to RECIST 1.1. Results: As of May 3, 2025, a total of 56 patients were enrolled with a median age of 59 years (53.6% male). All patients had stage IV disease at baseline with an ECOG score of 0 (19.6%) or 1 (80.4%). Prior treatment lines ranged from 1 to 3, and most patients (38; 67.9%) had received oxaliplatin, irinotecan, and fluoropyrimidine as systemic therapy during the advanced disease period. With a median follow-up period of 9.9 months (range: 2.1-13.4), the confirmed ORR was 39.3% (95% CI: 26.5-53.3), the median time to response was 1.4 months (range: 1.3-4.2), and the disease control rate was 98.2% (95% CI: 90.5-100). The median duration of response was 8.6 months (95% CI: 4.2-NA). The median progression-free survival was 8.3 months (95% CI: 5.6-11.0). The median overall survival (OS) was not reached, with a 12-month OS rate of 71.5%. Among the patients who had previously received oxaliplatin, irinotecan, and fluoropyrimidine in the advanced setting, the confirmed ORR was 31.6% (95% CI: 17.5-48.7). Treatment-related adverse events (TRAEs) were reported in 53 (94.6%) patients, with grade 3-4 TRAEs occurring in 14 (25.0%) patients. No TRAE was fatal. The most common TRAEs were increased alanine aminotransferase (48.2%), increased aspartate aminotransferase (46.4%), anaemia (32.1%), and decreased white blood cell count (26.8%). TRAEs led to drug interruption in 9 (16.1%) patients, dose reduction in 3 (5.4%) patients, and permanent discontinuation in 1 (1.8%) patient. Conclusions: Sosimerasib monotherapy demonstrated clinically meaningful anti-tumor activity with an acceptable safety profile in patients with KRAS G12C-mutated locally advanced/metastatic CRC, supporting its potential for further development. Clinical trial information: ChiCTR2200059986.

Clinical characteristics, treatment patterns, and outcomes of patients with small bowel cancer: A real-world cohort from a tertiary cancer center.

e15726 Background: Small bowel cancers (SBC) are rare malignancies accounting for < 5% of gastrointestinal (GI) cancers. Data on real-world epidemiology, molecular profiles, and treatment outcomes remain limited. We aimed to characterize the clinicopathologic features, treatment patterns, and survival outcomes of patients (pts) with SBC treated at a single tertiary cancer center. Methods: We conducted a retrospective cohort study of adult pts diagnosed with SBC at the American University of Beirut Medical Center between 2016 and 2024. Clinical, pathological, and molecular data were extracted from electronic medical records, including tumor location, histology, stage, systemic therapies, and outcomes. Results: A total of 1,118 pts diagnosed with GI cancers were reviewed, of whom 36 pts (3.2%) were diagnosed with SBC. Median age at diagnosis was 59 years (range 25-85), and 58.3% were males. Histologies included adenocarcinoma (44.4%), neuroendocrine tumors (NET) (27.8%), and GIST (27.8%). The most common primary site was duodenum (44%). At diagnosis, 23 pts (64%) had metastatic disease, 91% of whom had liver metastasis. 26 pts underwent surgical resection. Patterns of systemic therapy for pts who received it are shown in table 1. Molecular profiling was mostly performed for adenocarcinoma histology (4/16 (25%)). Among 8 biopsies tested by IHC, 100% were MSS. Among GIST cases, 2 patients underwent genomic testing, both harboring KIT exon 9 alterations. NET tumors were predominantly low–intermediate grade (grade 1: 30%; grade 2: 70%), with Ki-67 ranging from < 3% to 15%. Overall survival at 1, 2, 5 and 7 years was 100%, 95%, 88% and 70% respectively. Conclusions: In this real-world cohort, most patients presented with advanced disease and near-universal hepatic tropism with liver involvement in most metastatic cases. Multimodality management with histology-directed systemic was widely implemented, integrating surgical resection with subtype-specific therapies. Although survival outcomes showed a high proportion of patients alive at follow-up, SBC continue to require improved early detection and broader molecular characterization. Further studies are warranted to better define disease-specific prognostic and genomic determinants to support personalized treatment strategies and improve long-term outcomes in SBC. Summary of systemic therapies by histology. Histology First-line Second-line Third-line Adenocarcinoma (n=13) Combination 5-FU +/- oxaliplatin or irinotecan (61.5%)5-FU based chemotherapy regimen + targeted therapies (30.8%)Capecitabine (7.7%) Gemcitabine +cisplatin (7.7%) - NET (n=10) Lanreotide (20%)Octreotide (10%)Lu 177 (10%) Everolimus (10%)Capecitabine (10%) - GIST (n=10) Imatinib (100%) Sunitinib (30%) Regorafenib (20%)

Prognostic significance of body fat in early-stage breast cancer.

e12737 Background: Body fat is increasingly recognized as a key determinant of cancer biology and clinical outcomes. Although obesity is generally associated with poorer outcomes, the obesity paradox suggests a potential survival advantage in obese patients. While this phenomenon has been reported in several malignancies, its relevance in early-stage breast cancer remains unclear. Therefore, this study aimed to evaluate the prognostic impact of body fat in early-stage breast cancer. Methods: This retrospective cohort study included 134 female patients with early-stage breast cancer who presented between January 2018 and January 2020. Fat mass (FM) was assessed at the time of diagnosis using a Tanita Body Composition Analyzer. A fat mass cut-off value of 35%, determined as optimal by receiver operating characteristic (ROC) analysis, was examined for its association with survival outcomes. Results: The median age at diagnosis was 47 years (range 23–77), and 62.7% of patients were premenopausal. Median FM value at diagnosis were 35.5%. A FM cut-off of 35% was determined, with 70% sensitivity and 60% specificity [AUC:0.344, 95% CI:0.242–0.446, p=0.009]. Patients with baseline FM >35% had a mean event-free survival (EFS) of 99 months and mean overall survival (OS) of 104 months, while those with FM ≤35% had a mean EFS of 75 months and mean OS of 82 months. In multivariate analysis, estrogen receptor (ER) positivity (p=0.021), higher T stage (p=0.024), N3 disease (p=0.002), and baseline FM >35% (p<0.001) were independently associated with EFS. Similarly, ER positivity (p=0.015), higher T stage (p=0.006), N3 disease (p=0.040), and baseline FM >35% (p<0.001) were independent predictors of OS (Table). Conclusions: In our study, advanced tumor stage and N3 disease were associated with worse survival whereas ER positivity and baseline fat mass >35% were linked to improved EFS and OS. These findings suggest that baseline fat mass may serve as an independent prognostic factor in this patient population consistent with the obesity paradox. While this phenomenon has been reported in several cancer types, its relevance in early-stage breast cancer remains unclear and warrants further investigation. Multivariate Analyses of Event-Free Survival and Overall Survival. EFS OS HR 95% CI P value HR 95% CI P value ER status (Negative* vs Positive) 0.38 0.17-0.86 0.021 0.25 0.08-0.76 0.015 Clinical T stage (T1-2* vs T3-4) 2.54 1.12-5.73 0.024 5.16 1.59-16.65 0.006 Clinical N stage N0* Reference 0.017 Reference 0.07 N1 1.86 0.57-6.03 0.30 2.16 0.54-8.65 0.27 N2 2.31 0.74-7.22 0.14 0.95 0.23-3.93 0.94 N3 9.17 2.12-38.01 0.002 6.10 1.08-34.48 0.04 Fat Mass initially (%) (≤35* vs >35) 0.21 0.09-0.48 <0.001 0.41 0.008-0.20 <0.001 HR: Hazard Ratio; CI: Confidence Interval; ER: Estrogen Receptor; (*): Reference category.

A single-center retrospective analysis of antibody-drug conjugate utilization and associated toxicities in patients with solid tumors.

e15025 Background: Antibody-drug conjugates (ADCs) are increasingly used to treat both hematologic and solid malignancies. Although designed to minimize off-target toxicity, ADCs have demonstrated a more complex adverse event profile than initially anticipated. Despite their expanding use, real-world data describing ADC utilization patterns and toxicities remain limited. Methods: We retrospectively reviewed 678 patients who were treated with one or more ADC at the Brown University Health Cancer Institute from 2015 to 2025. Among these patients, 339 received an ADC for a solid tumor. As some patients received more than one ADC, a total of 375 unique ADC exposures were recorded. Data abstracted from electronic medical records included patient demographics, malignancy type, ADC type, and presence and type of ADC-related toxicities. Toxicity rates were calculated per unique ADC exposure with 95% confidence intervals using the Clopper-Pearson method. Additional analyses were descriptive. Results: The cohort was predominantly female (231/339, 68.1%), reflecting high ADC utilization in treatment of breast cancer (156/339, 46.0%). Other treated malignancies included urothelial (122/339, 36.0%), gastroesophageal (21/339, 6.2%), gynecologic (17/339, 5%), lung (13/339, 3.8%), cholangiocarcinoma, colorectal, and head and neck (each 3/339, 0.9%), and testicular (1/339, 0.3%) cancers. ADC-related toxicities occurred in 20.5% (77/375) of exposures. The most common toxicities were gastrointestinal (25/77, 32.5%), neurologic (20/77, 26.0%), cutaneous (16/77, 20.8%), and pulmonary and hematologic (each 14/77, 18.2%). Less common toxicities included ocular and cardiac (each 2/77, 2.6%) and renal and endocrine (each 1/77, 1.3%). Toxicity rates were similar among the most frequently used ADCs (Enfortumab vedotin, Trastuzumab deruxtecan, and Ado-trastuzumab emtansine), ranging from 17.8% to 23.7%, whereas less frequently administered agents had wide confidence intervals due to small sample sizes. Corresponding data are shown in the table below. Conclusions: In this single-center analysis, ADC-related toxicities occurred in roughly one-fifth of exposures, with comparable rates among commonly used agents and greater variability among less frequently administered ADCs. These findings provide real-world insight into ADC safety and highlight the need for further studies to better define toxicity patterns and guide management. ADC ADC Exposures, N (%) Exposures with Toxicity, N (%) 95% CI, % Enfortumab vedotin 118 (31.5) 28 (23.7) 16.4 - 32.4 Trastuzumab deruxtecan 118 (31.5) 21 (17.8) 11.4 - 25.9 Ado-trastuzumab emtansine 98 (26.1) 21 (21.4) 13.8 - 30.9 Sacituzumab govitecan 28 (7.5) 3 (10.7) 2.3 - 28.2 Mirvetuximab soravtansine 11 (2.9) 3 (27.3) 6.0 - 61.0 Tisotumab vedotin 2 (0.5) 1 (50.0) 1.3 - 98.7 Overall 375 (100) 77 (20.5) 16.6 - 25.0

Transposon-engineered hypoxia-inducible T cells for treatment of solid tumors.

2565 Background: Engineered cell therapies expressing a chimeric antigen receptor (CAR) in human T cells have demonstrated significant promise for the treatment of hematological malignancies. However, translating CAR T cell therapies to solid tumors remains challenging due to two limitations: (1) specificity, as few antigens are truly unique to solid tumors, leading to off-target toxicities; and (2) suppression, as solid tumors establish immunosuppressive microenvironments that limit T cell survival and cytotoxicity. To address these challenges and improve the safety and potency of solid tumor cell therapies, we engineered cells with synthetic circuits designed to amplify hypoxia-induced signaling through feedback and synthetic transcriptional control, enabling augmented and tunable responses within both modestly and profoundly hypoxic environments. Methods: We evaluated circuit architectures in HEK293FT cells in which the HBS promoter drove either native HIF transcription factors or synthetic transcription factors and promoters controlling a fluorescent reporter. Circuits were stably integrated using PiggyBac transposon vectors, and cells were cultured under normoxic (21% O₂), modestly hypoxic (5% O₂), and profoundly hypoxic (1% O₂) conditions. Fluorescent reporter expression was quantified by flow cytometry over three days, and candidate circuits exhibiting high-output, low-background expression under hypoxia were identified. These candidate circuits were subsequently introduced into primary human T cells using transposon vectors. CAR expression in engineered T cells was measured by flow cytometry after culture for three days in modest or profound hypoxia, and cytotoxic activity was assessed in co-culture assays with BT-474 breast cancer and SKOV3 ovarian cancer cells. Results: We identified novel circuit architectures that produced rapid induction with minimal background under hypoxia and defined design rules governing transgene amplification. Circuit topologies incorporating synthetic transcription factor–mediated feedback exhibited markedly amplified expression relative to native HIF-based circuits. CAR-expressing T cells demonstrated cytotoxic activity compared with unmodified T cells in co-culture assays. Conclusions: We present a therapeutic platform that enables hypoxia-dependent sensing and high-output control of therapeutic gene expression within solid tumor microenvironments. This approach has the potential to improve the safety and efficacy of engineered cell therapies for solid tumors and to provide mechanistic insights that inform the development of hypoxia-responsive cell therapies.

Temporal trends in cardiovascular and cerebrovascular mortality among U.S. decedents with malignant neoplasms of the bronchus and lung, 1999–2020.

e20110 Background: Lung cancer is associated with substantial cancer-specific mortality; however, cardiovascular diseases remain important competing causes of death due to shared risk factors such as tobacco exposure, advanced age, and cardiometabolic comorbidities. Data describing long-term national trends in specific cardiovascular causes of death among individuals with lung cancer are limited. We evaluated temporal trends in mortality due to ischemic heart disease (IHD), hypertensive diseases, heart failure (HF), and cerebrovascular disease (CeVD) among U.S. decedents with malignant neoplasms of the bronchus and lung. Methods: Using a population-based analysis, CDC WONDER , multiple cause of death database from 1999 to 2020, decedents with malignant neoplasms of the bronchus and lung (ICD-10: C34) and ischemic heart disease (I20–I25), hypertensive diseases (I10–I15), heart failure (I50), or cerebrovascular disease (I60–I69) as the underlying cause of death were identified. Age-adjusted mortality rates (AAMRs) per 100,000 population were calculated using the 2000 U.S. standard population. Temporal trends were analyzed using the National Cancer Institute Joinpoint Regression Program to estimate annual percent change (APC) and average annual percent change (AAPC). Stratified analyses were performed by sex, age group, race, and geographic region. Results: Ischemic heart disease mortality declined significantly in both females (AAPC −4.1%, p < 0.001) and males (AAPC −4.8%, p < 0.001). Among males, a late joinpoint demonstrated a non-significant increase after 2017 (APC 2.17%, p = 0.12). Heart failure mortality also declined modestly in females (APC −2.1%, p = 0.009) and males (APC −2.74%, p = 0.001). In contrast, hypertensive disease mortality increased significantly in recent years, particularly among males (APC 23.64% from 2018–2020, p < 0.01) and females (APC 7.46% from 2009–2020, p = 0.018). Significant increases were observed in older age groups (65–74 years: APC 7.31%, p = 0.01; 75–84 years: APC 7.02%, p = 0.013) and among Black/African American individuals (APC 31.5% from 2018–2020, p < 0.001). Cerebrovascular disease mortality declined overall in females (AAPC −1.9%, p < 0.001) and males (AAPC −3.3%, p < 0.001), followed by recent increases among males after 2011 (APC 7.5%, p = 0.023) and among Black/African American individuals after 2015 (APC 6.4%, p = 0.046). Across all cardiovascular outcomes, mortality increased with advancing age. Conclusions: Despite declining ischemic heart disease, heart failure, and cerebrovascular mortality, hypertensive disease–related deaths are increasing among individuals with lung cancer, particularly in older adults and Black/African American populations, highlighting the need for early blood pressure control and integrated cardio-oncology care.

Predictive role of immune cell subsets and intestinal flora in immune-related adverse event of small cell lung cancer.

8112 Background: While immune checkpoint inhibitors (ICIs) have reshaped the therapeutic landscape for extensive-stage small-cell lung cancer (ES-SCLC), they are frequently associated with immune-related adverse events (irAEs) that may lead to treatment disruption. Early prediction of irAEs remains challenging due to their atypical clinical manifestations. This study aimed to identify risk factors and predictive biomarkers for irAEs in ES-SCLC patients undergoing ICIs therapy. Methods: 88 patients with ES-SCLC who received ICIs treatment between May 2021 and September 2023 were enrolled. Fecal samples were collected at baseline and before each treatment cycle until therapy discontinuation. The metagenomic and untargeted metabolomic analyses were performed on the fecal samples. Peripheral blood samples were collected from patients for flow cytometry analysis. Tumor response was assessed in accordance with RECIST 1.1 criteria, and irAEs were graded based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: Among 88 patients, 41 developed irAEs (median onset: 118 days), with the most common manifestations being pneumonia (41.5%) and hepatitis (22.0%). Patients who developed irAEs exhibited distinct peripheral immune profiles. Compared to their own baseline levels, these patients exhibited decreased peripheral B-cell counts alongside elevated percentages of activated CD4 + and CD8 + T cells, including early-activated CD8 + T cells (CD3 + CD8 + CD69 + T cells), late-activated helper T cells (CD3 + CD4 + CD38 + T cells), and Th2 cells. Furthermore, at baseline, the irAE group demonstrated a significantly higher percentage of PD-1 in CD8 + T cells compared to the non-irAE group. Metabolomic analyses revealed distinct baseline metabolic profiles between the two groups, Micrococcus was significantly enriched at baseline in the irAE group, whereas Phocaeicola coprocola and Oscillibacter were more abundant in patients without irAEs, and calcitriol was identified as a potential predictive biomarker for irAEs. Following irAE onset, significant enrichment of Selenomonadaceae , Ruminococcus , Actinobacteria , and Erysipelatoclostridium was observed, along with significant shifts in metabolites and related metabolic pathways. Conclusions: In ES-SCLC patients treated with ICIs, the development of irAEs is associated with distinct alterations in peripheral immune cell subsets, as well as gut microbial and metabolic profiles at baseline. Monitoring these features, particularly PD-1 expression on CD8+ T cells and calcitriol levels, may help predict the risk of irAEs. Dynamic changes in the gut microbiome and metabolome after ICIs initiation further aid in the early recognition of irAEs.

Incremental impact of community-delivered HPV self-sampling on screening uptake within an active outreach system: A quasi-experimental implementation study in rural Thailand

Background Thailand has still not achieved the cervical cancer screening coverage target set by the World Health Organization (WHO). Although HPV self-sampling has been introduced to reduce access barriers, delivery remains largely facility-based, requiring women to attend primary care units during working hours. Community-delivered approaches have been proposed as an alternative; however, evidence comparing strategies within the same service context remains limited. This study aimed to assess the incremental benefit of a community-delivered approach, incorporating structured workshops and same-day sample return, within an already active outreach system, compared with a facility-based approach with similar outreach support, on screening uptake; secondary outcomes included operational feasibility and acceptability. Methods We conducted a quasi-experimental comparative study in a rural subdistrict of Thailand. Eligible women aged 30–60 years were recruited from two villages and allocated at the village level to either a community-delivered approach (CD group) or a facility-based approach with active outreach (FB group). Screening uptake was defined as the return of a completed self-sampling kit and is presented using proportions and 95% confidence intervals. Feasibility and acceptability were also assessed descriptively using process indicators and participant-reported experiences. Results A total of 108 participants were enrolled, with 106 included in the primary analysis. Screening uptake was 52% (28/54; 95% CI: 42% to 61%) in the CD group and 35% (18/52; 95% CI: 26% to 45%) in the FB group. The observed absolute difference was 17% (95% CI: −1% to 34%). All returned samples were adequate for HPV testing. Participant-reported confidence, usability, and overall experience with self-sampling were favorable and similar across groups. Conclusions HPV self-sampling was operationally feasible and acceptable under both delivery approaches in this rural Thai setting. Screening uptake was numerically higher in the community-delivered group; however, the confidence interval included no difference, indicating uncertainty in the direction and magnitude of effect. These findings are suggestive but inconclusive evidence. Further adequately powered studies with rigorous implementation evaluation are needed, particularly to optimize service delivery, including increasing flexibility in scheduling, strengthening implementation fidelity, and evaluating workforce and cost implications, to better determine effectiveness and scalability. Trials Registration: Thai Clinical Trials Registry (TCTR): TCTR20241231010.