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Prognostic significance of muscle quantity and quality for overall survival in non-metastatic castration-resistant prostate cancer.
e17047 Background: This study evaluated whether computed tomography–derived skeletal muscle quantity and quality are associated with therapeutic response, safety, and overall survival (OS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with androgen receptor signaling inhibitors (ARSIs). Methods: In this multicenter retrospective study, 344 patients with nmCRPC were analyzed. Muscle quantity and quality were assessed using the psoas–lumbar vertebral index (PLVI) and intramuscular adipose tissue content (IMAC), respectively. Lower PLVI and higher IMAC indicated reduced muscle quantity and quality, respectively. The primary endpoint was OS. Secondary endpoints included PSA declines ≥50% and ≥90%, PSA progression-free survival (PSA-PFS), metastasis-free survival (MFS), and ARSI-related adverse events (AEs). Results: The median age was 76 years, and median follow-up was 48 months. A total of 137 patients (40%) died during follow-up. In univariable analyses, lower PLVI and higher IMAC were associated with shorter OS. In multivariable analysis, higher IMAC remained independently associated with shorter OS (HR 1.792; 95% CI 1.137–2.825; P = 0.012), whereas PLVI did not (HR 1.265; 95% CI 0.838–1.909; P = 0.263). Neither muscle quantity nor quality was associated with PSA response, PSA-PFS, MFS, or ARSI-related AEs. Conclusions: CT-derived muscle quality, but not muscle quantity, independently predicts OS in nmCRPC. However, muscle status does not appear to influence ARSI treatment response or safety. Multivariable analysis for overall survival. Factor P value Hazard ratio 95% CI Age Continuous 0.092 1.027 0.996–1.060 Performance status ≥ 1 0.121 1.408 0.913–2.169 Hypertension Present 0.177 0.766 0.521–1.128 Diabetes mellitus Present 0.296 0.766 0.464–1.264 Cardiovascular disease Present 0.319 0.780 0.478–1.272 Biopsy Gleason score ≥ 8 0.093 1.502 0.935–2.413 Diagnosis of nmCRPC before 2014 Positive 0.890 1.036 0.629–1.706 ARSI therapy during nmCRPC Received 0.020 0.609 0.401–0.926 PSA doubling time < 3.0 months < 0.001 2.206 1.449–3.359 Psoas‒lumbar vertebral index < 0.49 0.263 1.265 0.838–1.909 Intramuscular adipose tissue content ≥ -0.27 0.012 1.792 1.137–2.825 ARSI, androgen receptor signaling inhibitor; CI, confidence interval; nmCRPC, non-metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen.
Use of LIF and LIFR expression to characterize survival and tumor microenvironment composition in lung adenocarcinoma.
8553 Background: In lung adenocarcinoma (LUAD), EGFR-directed therapy has transformed clinical practice, yet heterogeneity in treatment response persists. Novel biomarkers are needed to refine therapeutic selection and identify new treatment targets. Leukemia inhibitory factor (LIF) and its receptor (LIFR) have emerged as potential mediators of the tumor microenvironment (TME), but their clinical significance in LUAD remains poorly defined. This study sought to investigate LIF and LIFR expression in LUAD, especially EGFR -mutant (EGFRm), and their TME composition and impact on survival outcomes. Methods: 10,041 LUAD tumors underwent next-generation sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome) at Caris Life Sciences. Tumors were stratified by LIR and LIFR RNA expression quartiles (Q1, low; Q4, high). QuantiSEQ was used to profile TME. Statistical analyses were performed using chi-square and Mann–Whitney U tests. Overall survival (OS) was estimated from insurance claims data using Cox proportional hazards models to calculate hazard ratios and log-rank tests to determine p-values. Results: In LUAD, LIF Q4 tumors demonstrated lower abundance of CD8⁺ T cells (fold change (FC) 0.75, p < 0.001), but higher abundance of NK cells, M1 macrophages, neutrophils, Tregs and B cells vs LIF Q1 tumors (FC 1.1-1.4, p < 0.001). LIFR Q4 tumors exhibited higher abundance of dendritic cells, NK cells and M2 macrophages vs Q1 tumors (FC: 1.2-1.5, p < 0.001). For LIF, Q4 tumors had higher median MAPK activation (1.73 vs −0.93, p < 0.001) and T-cell–inflamed scores (94 vs −2, p < 0.001). LIFR Q4 tumors demonstrated higher MAPK activation (1.51 vs −0.83, p < 0.001), and higher T-cell–inflamed scores (105 vs −29, p < 0.001). IFN-γ signaling was modestly lower in LIF Q4 and LIFR Q4 tumors. Longer OS was observed in LIF Q1 vs Q4 (HR 0.79, 95% CI: 0.75-0.84, 25.1 vs 18.1 m, p < 0.001) but shorter OS in LIFR Q1 vs Q4 (HR 1.59 , 95% CI: 1.5-1.7, 14.0 vs 27.9 m, p < 0.001). EGFR mutations were significantly more frequent in LIF Q1 vs Q4 (21.2% vs 12.8%, p < 0.001) and LIFR Q4 vs Q1 (27.2% vs 7.6%, p < 0.001). In EGFR m tumors treated with osimertinib, OS differences based on LIF expression were accentuated:(LIF Q1 vs Q4, HR 0.681, 95% CI: 0.58-0.80, 35.7 vs 24.7 m, p < 0.00001). Conclusions: Findings demonstrate distinct transcriptional immune activation profiles between LIF- and LIFR-driven states, with superior survival in low LIF and high LIFR expressors. Despite elevated T-cell–inflamed scores, differences in immune cell composition suggest qualitative differences in immune activation between LIF- and LIFR-driven states. These findings support their relevance as prognostic and biologically informative biomarkers, and identify the LIF–LIFR axis as a key stratifier of immune state and survival heterogeneity in LUAD, with additional survival differences observed in EGFRm LUAD treated with osimertinib.
Tumor immune microenvironment of metastatic HR+ HER2- breast cancer treated with CDK4/6 inhibitors.
e13059 Background: Adding a CDK4/6 inhibitor (CDKi) to endocrine therapy has meaningfully improves outcomes for patients with metastatic HR+ HER2- breast cancer (mHRBC). In addition to their cytostatic effects on cancer cells, translational work in early-stage HRBC suggested that CDKi have pro-inflammatory effects which could facilitate anti-cancer immune activity. Combination checkpoint inhibitor and CDKi strategies have been studied though toxicities limit further development. CDKi impact on the tumor immune microenvironment (TIME) in mHRBC is not well-defined to date. Methods: We retrospectively identified patient cases with mHRBC treated with a CDKi and available archival samples obtained within 2.5 years of CDKi initiation and 1 year of CDKi discontinuation. FFPE slides from each sample were processed for multiplexed immunohistochemical staining to phenotype immune cell subsets including T cells and functional subsets, dendritic cells, macrophages, and monocytes. Up to ten 1mm 2 regions of interest (ROI) per sample were selected for imaging, optimized for tumor tissue. Individual cells were defined and phenotyped according to a pre-specified hierarchical strategy. Cellular abundance was quantified as immune cell count per mm 2 . Where appropriate due to limitations in sample size, means comparisons were made between groups using the t-test, and unadjusted p values are presented. This study was approved by the OHSU Institutional Review Board. Results: 12 pre-CDKi and 8 post-CDKi samples were collected from 16 unique patients. CDKi resulted in numeric decreases in B cell, CD4+ T cell, CD8+T cell, and monocyte abundance. Decreased macrophage abundance was statistically significant (pre-CDKi mean +/- std dev: 32.37 +/- 30.43 cells/mm 2 ; post-CDKi 12.99 +/- 19.09 cells/mm 2 , p < 0.05) and included CD163+ and CSF1R+ macrophages. Rapid disease progression (rPD) was defined as within 6 months of initiating CDKi, and we observed differences in pre-CDKi immune cell composition between rPD and non-rPD samples. 70% of non-rPD ROI had fewer than 250 immune cells/0.8mm 2 , compared with 22.5% of rPD ROI. rPD samples were characterized by greater abundance of T regulatory cells (rPD 114.81 +/- 70.15 cells/mm 2 ; non-rPD 47.83 +/- 58.61 cells/mm 2 ); and naïve CD8+ T cells (rPD 141.45 +/- 73.51 cells/mm 2 ; non-rPD 56.23 +/- 36.32 cells/mm 2 ). Among our 4 cases with paired pre- and post-CDKi samples, CDKi resulted in an increase in macrophage, Treg and ex-Treg abundance in the rPD case, but decreases in the 3 non-rPD cases. Conclusions: In this dataset of mHRBC samples, CDKi resulted in decreased macrophage abundance rather than increased pro-inflammatory cells. Furthermore, we observed that an immunologically ‘cold’ tumor immune microenvironment was not associated with worse outcome in mHRBC. The TIME of patients with rapid progression during CDKi treatment had higher abundances of immunosuppressive immune cells.
Essential but unaffordable: Real-world costs of WHO essential cancer medicines in a low-income setting.
1508 Background: The World Health Organization (WHO) Essential Medicines List (EML) defines priority anticancer medicines. In many low-and-middle-income countries (LMICs), EML inclusion may not translate into financial accessibility. Using Nepal as a case study, we mapped availability pathways and real-world prices to quantify affordability of WHO EML regimens. Methods: We conducted a cross-sectional audit of WHO EML anticancer medicines in Nepal. Regimens were selected for high-incidence and high-curability cancers and to reflect commonly used standard-of-care regimens. Patient prices were abstracted from Nepal distributor and manufacturer price lists (2024–2026), using the lowest listed patient price when multiple listings existed. Regimen costs were estimated using standard dosing and typical cycle numbers. Metastatic regimens were excluded because treatment duration is open-ended. Fixed-duration curative-intent regimens were analyzed. The primary outcome was affordability, expressed as regimen cost divided by annual GDP per capita (Y), used as a proxy for yearly income. Results: WHO EML drugs were broadly identifiable, but free access to high-cost agents via NGO programs was confined to three city hospitals, creating a geographic lottery. Using Y = US$1,447/year, estimated total costs for standard regimens were substantial: dd AC-T for breast cancer US$552 (0.38Y); FOLFOX for colon cancer US$1,226 (0.85Y); CAPOX US$1,090 (0.75Y); FLOT for gastric cancer US$1,063 (0.73Y); and R-CHOP for lymphoma US$1,144 (0.79Y). Add-on biologics were far higher: trastuzumab for HER2-positive therapy (17 cycles) was US$3,998 (2.76Y). Pembrolizumab (9 cycles) was US$27,246 (18.83Y). One year of oral targeted therapy was osimertinib US$4,448 (3.07Y) and olaparib US$10,716 (7.41Y). Conclusions: In this LMIC case study, most WHO EML curative regimens approached/exceeded one year of average income, while add-on components approached two decades. EML prioritization alone was insufficient to ensure financial access at the point of care. The findings support targeted national procurement with financial-risk protection for a small set of high-impact medicines, complemented by high income countries (HIC)–LMIC access partnerships, like said NGO-programs, to extend reach beyond a geographically advantaged catchment. Nepal oncology regimen costs. Regimen Cost/cycle (USD) Total treatment cost (USD) Cycles/duration Breast dd AC-T 68 551 8 dd AC-TH 235 3,998 17 TNBC-pembro 3,027 27,246. 9 Colon FOLFOX 102 1,226 12 CAPOX 136 1,089 8 NSCLC Paclitaxel + carboplatin 119 715 6 Pemetrexed + carboplatin 78 470 6 SCLC Carboplatin + etoposide 40 245 6 EGFR TKI in NSCLC Osimertinib 4,393 1 BRCA+ breast/ovarian Olaparib (300 mg BID assumption) 10,716 1 Gall bladder Gemcitabine + carboplatin 108 653 6 Gemcitabine + capecitabine 145 874 6 Stomach FLOT 177 1,062 6 NHL CHOP 13 81 6 R-CHOP 190 1,144 6 HL ABVD 27 108 4
The use of multimodal machine learning models for predicting overall survival in patients with non-small cell lung cancer: A systematic review.
e20000 Background: Multimodal machine-learning (ML) models that fuse imaging, pathology, omics, and clinical data may improve overall-survival (OS) prediction in non–small-cell lung cancer (NSCLC) beyond staging-based tools. We systematically reviewed the design, performance, and methodological quality of these models. Methods: Following PRISMA 2020, we searched Ovid (MEDLINE/Embase/CENTRAL/CDSR), Scopus, IEEE Xplore, and arXiv (January 2017–July 2025). Eligible studies developed or validated ML models integrating ≥2 modalities to predict OS in adults with NSCLC and reported either time-to-event or fixed-horizon binary outcomes. Two reviewers independently screened, extracted, and assessed risk of bias using PROBAST with PROBAST-AI items. Due to heterogeneity, results were synthesized narratively. Results: We included 18 studies (2021–2025) with per-study sample sizes ranging from 115 to 2,898. Outcome framing: time-to-event OS only (n=11), fixed-horizon binary OS only (n=4), and both (n=3). Modalities most often used were clinical structured data (15/18), CT (12/18), PET (6/18), molecular omics (7/18), pathology whole-slide images (4/18), and EHR text (1/18). Fusion strategies clustered as early/concatenation (10/18), interaction-based (attention/bilinear/graph; 5/18), and late/score-level (3/18). For time-to-event OS, internal C-indices ranged 0.658–0.893, with the highest internal value 0.893 (CT+clinical). One study reported external C-index (0.678, pathology+genes). An additional study reported external time-dependent AUC 0.845 at 1-year for a PET/CT-genomics survival model (n=32). For binary OS, internal AUROCs were 0.802–0.888 (2–5-year horizons), and internal accuracies ranged 0.68–0.93 (1–5 years). External binary performance included accuracy 0.72 at 1-year in an immunotherapy cohort. Across studies, multimodal models typically outperformed the best single-modality comparator by ~+0.06 C-index or AUROC, though absolute gains varied. Risk of bias was frequently high in the analysis domain (internal-only validation, optimistic tuning, sparse calibration reporting); code/weights were publicly available in 5/18 studies. Conclusions: Multimodal ML models for NSCLC show consistent, modest improvements in OS discrimination versus single-modality approaches, with CT+clinical the most translationally pairing. However, independent validation, calibration, and transparency remain limited, constraining clinical adoption. Future work should prioritize multi-center datasets, standardized reporting, and open workflows.
Single cell spatial profiling for identification of organ-specific immune features in the peritumoral microenvironment of triple-negative breast cancer with liver metastases.
1126 Background: Breast cancer liver metastasis (BCLM) is associated with poor prognosis. Prior studies have described liver metastases as immune-cold, yet the mechanisms underlying this phenotype remain incompletely understood. We hypothesized that the peritumoral microenvironment, in addition to the tumor itself, contributes to the distinct immunobiology of BCLM. Methods: We performed imaging mass cytometry (IMC) with a 42-antibody panel on TNBC tissues from primary breasts (PB) (n = 22) and liver metastases (LM) (n = 26). For each case, one region of interest (ROI) from tumor bed and one from peritumoral tissue were profiled. Cell segmentation was performed using DeepCell. Single-cell phenotyping and clustering were conducted using Scanpy with lineage markers. Functional marker expression was analyzed and differences between PB and LM were assessed using non-parametric tests with Benjamini–Hochberg false discovery rate (FDR) correction. Spatial analysis was performed using Squidpy with Wilcoxon testing and FDR correction across all tested interaction pairs. Results: IMC analysis resolved 407,160 cells into distinct immune, stromal, and tumor cell clusters across compartments. Within tumor beds, PB and LM exhibited largely similar functional marker expression and spatial organization, indicating minimal tumor-intrinsic divergence. In contrast, peritumoral tissues diverged substantially between PB and LM. Peritumoral tissues in PB demonstrated M2 macrophage dominance while LM exhibited M1 macrophage dominance. The comparative analysis of peritumoral tissues revealed that cancer cells in LM demonstrated significantly increased spatial proximity to CD8 T cells compared to PB with concurrent upregulation of PD-L1 on macrophages and NK cells, alongside elevated PD-1 expression on multiple immune cell types, indicating that CD8 T cells are potentially exhausted despite their physical presence. Additionally, CCR7, CD6, and CXCL13 were significantly elevated across all cell types in LM, while PB demonstrated higher expression of CD44, CXCR3 and CXCL12, indicating broad immunophenotypic differences in peritumoral tissues. Spatial analysis further revealed that CD4 T cells maintained closer proximity to cancer cells, M1 macrophage, and stromal populations in PB, indicating distinct spatial organization between sites. Conclusions: Single-cell spatial profiling reveals that organ-specific tumor and immune biology in TNBC BCLM is encoded primarily within the peritumoral tissue rather than the tumor bed itself. Our findings reveal a paradoxical phenotype in BCLM where CD8 T cells successfully infiltrate and localize near cancer cells but show features consistent with functional impairment. These findings support further investigation of immunotherapy in TNBC BCLM and biomarker validation.
Butaselen combined with radiotherapy for newly diagnosed H3K27M-mutant spinal diffuse midline glioma: A single-arm phase Ib trial.
2014 Background: Patients with H3K27M-mutant spinal diffuse midline glioma (sDMG) have a median overall survival (OS) of approximately 13 months and the medical interventions remain limited. Radiation induced senescence (RIS) is a major cause of radiotherapy resistance and tumor recurrence in H3K27M-mutant sDMG. In pre-clinical study, we observe that thioredoxin reductase 1 (TrxR1) protects senescence sDMG cells from oxidative damage caused by radiation, and novel TrxR1 inhibitor Butaselen dramatically induces apoptosis of sDMG cells. Therefore, Butaselen combined radiotherapy is a new strategy to prolong the OS and progression-free survival (PFS) for newly diagnosed H3K27M-mutatnt sDMG patients. Methods: Patients age 18-70 years with newly diagnosed H3K27M-mutant sDMG were eligible for this phase Ib trial (ChiCTR2600116732). All subjects received fixed radiation dose at 45Gy/1.8f/25d. Dose-escalation of Butaselen was performed in phase Ib trial and 9 subjects were enrolled in three dose levels (3+3 design: DL1: 450mg, oral, bid; DL2: 600mg, oral, bid; DL3: 750mg, oral, bid). Butaselen was orally administered in combination with radiotherapy for first 5 weeks, and then administered alone until tumor progression occurs or death. Follow-up visits were conducted at Q8W during 0-6 months and Q12W afterwards. The primary outcome was the safety of the Butaselen, as determined on the basis of adverse events (AEs) and serious adverse events (SAEs). The secondary outcomes were the 12-month OS/PFS rate, OS, PFS, objective response rate (ORR, RANO 2.0 criteria), and objective neurological function scale. Results: Between Apr 18, 2024 and May 21, 2025, 9 eligible subjects were enrolled. 9 subjects (age 26-57 years) received Butaselen therapy with no report of severe adverse event (SAE) or dose-limiting toxicity. As a result, 6-month and 12-month PFS rate (PFS%) was 100% and 88.9% (8/9), respectively, while both 6-month and 12-month OS rate (OS%) reached 100%. The longest PFS has exceed 22 months. 1 subject was died due to disease progress (OS=14.7 month; PFS=6.9 month), 1 subject experienced second operate resecting after disease progress (PFS=12.9 month), and the remaining 7/9 subjects are currently still in the progression-free survival phase. The overall ORR assessed by RANO 2.0 was 33% (3/9) and DCR was 100% (9/9). All subjects (9/9, 100%) experienced the relieve of neurological functions, as measured by Japanese Orthopedic Association (JOA) Scores and McCormick Scores. Grade 3 drug-related treatment-emergent adverse events (TEAEs) occurred 2 times; and no grade 4 TEAEs occurred. Conclusions: Butaselen combined with standard radiotherapy was well tolerated, and exhibited meaningful prolongation of survival period, durable objective responses and neurological function improvements in primary H3K27M-mutant sDMG patients. Clinical trial information: ChiCTR2600116732.
Cost-effectiveness analysis of eight treatments for metastatic hormone-sensitive prostate cancer (mHSPC) stratified by homologous recombination repair (HRR) status.
e17060 Background: After approval of androgen deprivation therapy (ADT) with niraparib and abiraterone/prednisone (NAAP) for homologous recombination repair (HRR)-deficient mHSPC, we conducted a U.S. public-payer cost-effectiveness analysis (CEA) comparing NAAP with abiraterone/prednisone (AAP). We also assessed CEA for seven established first-line mHSPC options regardless of HRR status: ADT mono, and ADT combined with docetaxel (DA), abiraterone (AAP), apalutamide (AAT), enzalutamide (ET), darolutamide plus docetaxel (DAD), and enzalutamide plus docetaxel (EAD). Methods: A partitioned-survival model with monthly cycles over a lifetime horizon (progression-free, post-progression, death) incorporated overall survival (OS) and radiographic progression free (rPFS) data derived from survival curves. Drug acquisition costs were from 2025 Federal Supply Schedule. Administration, subsequent-therapy, and adverse event costs and utilities were obtained from literature. Incremental cost-effectiveness ratio (ICER) was estimated at a willingness-to-pay (WTP) threshold of $150,000-$200,000/Quality of life Years (QALY). Deterministic and probabilistic sensitivity analyses assessed parameter uncertainty. Results: A CEA model for NAAP Vs. AAP showed that mean lifetime costs were $62,180 for AAP and $768,069 for NAAP. Mean QALYs were higher for NAAP than AAP (3.31vs 3.01). ICER for NAAP was $2.35M/QALY, far exceeding WTP. Across seven treatment strategies (N = 8,333 pts) lifetime costs ranged from $43K (ADT) to $728K (DAD) and Quality of Life Years (QALYs) from 3.38 to 4.42. ET, EAD, and AAT regimens were more costly and less effective than alternatives. Among non-dominated options, DA had an ICER of $30,823/QALY vs ADT, and AAP yielded $314,796/QALY. Although DAD achieved the highest lifetime QALYs (4.42), its incremental cost was large (ICER $1.41M/QALY). Conclusions: From a U.S. public-payer perspective, the addition of NAAP offered incremental benefit for pts with HRR-positive mHSPC; however, the ICER for NAAP was $2.35M/QALY. In mHSPC pts without considering HRR status, DA is consistently cost-effective, and AAP may be considered cost-effective at higher WTP thresholds. Cost-effectiveness results. HRR-deficient mHSPC Cost (2025-USD) Effectiveness (QALY) ICER AAP +ADT $ 62,180 3.01 NAAP +ADT $ 768,069 3.31 $ 2,352,600 non-HRR deficient status ADT mono $ 43,120 3.38 DA $ 59,656 3.92 $ 30,823 AAP +ADT $ 71,878 3.95 $ 314,796 ET $ 359,095 2.57 $ Dominated a EAD $ 493,402 4.12 $ Dominated b AAT $ 558, 518 4.27 $ Dominated b Darolutamide + ADT + Docetaxel (DAD) - results in text. a This treatment strategy is more costly and less effective than another treatment strategy (ie, absolute dominance). b This treatment strategy is more costly and less effective than a linear combination of other treatment strategies (ie, extended dominance).
Earlier CRS identification with continuous wearable monitoring in outpatient CAR T-cell therapy.
1633 Background: CAR-T cell therapy has transformed outcomes of hematologic malignancies and is poised to expand into solid malignancies. However, broader use of CAR-T remains constrained by the need for timely cytokine release syndrome (CRS) detection. Current episodic monitoring may miss early physiologic changes. Wearable digital health technologies (DHTs), offering continuous monitoring and real-time alerts, could enable earlier CRS detection, further support outpatient delivery, and expand access to CAR-T and potentially other immunotherapies associated with CRS. Methods: This single-center observational study (NCT05018208) enrolled patients receiving FDA-approved CAR-T products in the outpatient setting at Mayo Clinic, Rochester MN. Management of post-CAR-T complications (e.g. CRS) followed the institution’s standard of care. Patients were monitored from day -5 to day +30 post infusion with intermittent remote patient monitoring (SoC) and an arm-worn wearable device for continuous monitoring (DHT). Patients were included in this analysis if DHT data were available for ≥ 5h of data/day or ≥ 2h of data/night on ≥2 days or nights for baseline and ≥1 day or night within 72h prior to CRS, or at least 2h within 4h of CRS onset, or if DHT was available for ≥7 days/nights post infusion with no CRS event. CRS detection time by DHT was defined as the onset of pyrexia or threshold-based deviation from an individual’s baseline pulse distributions. Results: 32 patients were included in this report (median age 64 years, gender 12 F/20 M, diagnoses 18 MM/14 NHL). 25 patients experienced a CRS event, with maximum CRS grades ranging from 1-3 (16 G1, 8 G2, 1 G3). 24/25 patients with CRS required tocilizumab/steroid. Median CRS onset time was 3.4 days (range 0.4-18.4). 12/32 patients had sufficient DHT data (7 CRS, 5 no CRS) for analysis. 5 patients with CRS had a DHT detection time in advance of the SoC by a median of 13h (range 2.8 - 69.2). The DHT prediction of CRS by baseline HR change was earlier than the first episodic fever by a median of 14.5h (range 13-77.5). The remaining 2/7 patients who did not have CRS detected by the DHT had missing DHT data for more than 45h before a treated CRS event. DHT detected CRS in 2/5 patients without CRS according to SoC. One patient had fever caught with intermittent monitoring. The other was treated for neutropenia fever with suspicion of CRS and/or infection. Conclusions: These results offer evidence that continuous DHT can identify CRS events earlier than intermittent monitoring (SoC). Despite limitations related to compliance with wearable device use and data missingness, and variability in clinical management of CRS, we highlight the usability of DHT and its potential for future studies with optimized strategies to address these limitations. Clinical trial information: NCT05018208 .
Safety and survival outcomes of immune checkpoint inhibitors in metastatic lung cancer patients with pre-existing autoimmune disease: A propensity-matched real-world analysis.
e20615 Background: Patients with cancer and pre-existing autoimmune diseases (AID) are frequently excluded from immune checkpoint inhibitor (ICI) trials due to concerns about severe immune-related adverse events (irAEs) and AID flares. Real-world data on safety and outcomes of immunotherapy in this population remain limited. Methods: This retrospective cohort study used the TriNetX US Collaborative Network to identify adults with lung cancer (ICD-10 C34) and metastatic disease codes (C77–C79) treated with PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab, or cemiplimab) between 2018 and 2025. Patients with prior transplant, HIV, chronic viral hepatitis, or CTLA-4 inhibitor exposure were excluded. Those with pre-existing AID diagnosed prior to ICI initiation were compared with those without AID using 1:1 propensity score matching to balance demographics and major comorbidities. The primary outcome was overall survival; secondary outcomes included hospitalization, emergency department visits, systemic steroid use and organ-specific irAE proxies. Results: After propensity score matching, 3,159 patients were included in each cohort. Overall mortality did not differ between groups (54.5% vs 52.9%; HR, 1.03; 95% CI, 0.96–1.10; p = 0.43). However, patients with pre-existing AID experienced significantly higher rates of hospitalization (63.4% vs 59.2%; RR, 1.072; p = 0.001). Organ-specific irAEs were significantly elevated in the pre-existing AID cohort, including pulmonary irAEs (28.5% vs 24.0%; RR, 1.186; p < 0.001), gastrointestinal irAEs (19.8% vs 12.1%; RR, 1.638; p < 0.001), endocrine irAEs (14.8% vs 5.1%; RR, 2.895; p < 0.001), and myositis (1.4% vs 0.7%; RR, 2.143; p = 0.003). Systemic steroid use was common and similar between groups. Emergency department visits and dermatologic irAE proxies did not differ significantly. Conclusions: In this real-world study, metastatic lung cancer patients with pre-existing AID receiving PD-1/PD-L1 inhibitors demonstrated comparable overall survival to those without AID, supporting the use of ICIs in this population. However, significantly elevated rates of organ-specific irAEs—particularly gastrointestinal, endocrine, and pulmonary toxicities—and increased hospitalizations underscore the need for enhanced monitoring and multidisciplinary management. These findings support risk-adapted use of PD-1/PD-L1 inhibitors rather than routine exclusion of patients with AID.
Chrono-chemotherapy combined with IMRT in locoregionally advanced nasopharyngeal carcinoma: A prospective randomized study.
6113 Background: Induction chemotherapy followed by radiotherapy with concurrent cisplatin is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The TPF induction regimen combined with intensity-modulated radiation therapy (IMRT) improves tumor control but causes substantial toxicity. Circadian rhythms regulate tumor biology and drug metabolism. Docetaxel, cisplatin, and 5-fluorouracil show circadian-dependent pharmacologic properties. Chrono-chemotherapy aligns drug administration with circadian rhythms and may reduce toxicity. This study compared long-term outcomes and late adverse events between chrono-chemotherapy and conventional chemotherapy combined with IMRT in LA-NPC. Methods: This single-center, prospective, randomized clinical trial was registered at ClinicalTrials.gov (NCT03196869). Between April 2017 and May 2018, 128 patients with newly diagnosed stage III–IVa nasopharyngeal carcinoma were randomly assigned to chrono-chemotherapy or conventional chemotherapy. All patients received three cycles of TPF induction chemotherapy, followed by IMRT with two cycles of concurrent cisplatin chemotherapy. Survival outcomes were analyzed using the Kaplan–Meier method and compared by log-rank test. Late toxicities were graded using CTCAE v5.0. Quality of life was assessed with the EORTC QLQ-C30 questionnaire. Results: A total of 124 patients were included in the survival analysis. No significant differences were observed between groups in 5-year overall survival (P=0.709), progression-free survival (P=0.492), distant metastasis-free survival (P=0.467), or locoregional recurrence-free survival (P=0.697). The chrono-chemotherapy group showed lower rates of xerostomia (P=0.034) and dysphagia (P=0.019). No grade ≥4 late toxicities were observed. Global health status scores were higher in the chrono-chemotherapy group (P=0.043). Conclusions: Chrono-chemotherapy combined with IMRT achieved long-term survival outcomes comparable to conventional chemotherapy in LA-NPC. This approach reduced selected late toxicities and improved overall health status. Chrono-chemotherapy may represent a toxicity-sparing treatment option. Clinical trial information: NCT03196869 . Late toxicities and quality of life. Outcome Conventional Chemotherapy Chrono-chemotherapy P value Xerostomia, n (%) 24/36 (66.7) 16/38 (42.1) 0.034 Dysphagia, n (%) 24/36 (66.7) 15/38 (39.5) 0.019 Global health status score* 58.33 (50.00–72.92) 75.00 (50.00–83.33) 0.043 *Scores derived from the EORTC QLQ-C30 questionnaire; values are presented as median (interquartile range).
Comparative mortality burden of primary brain malignancies versus brain metastases in the United States.
e14011 Background: Primary brain malignancies and brain metastases represent major contributors to neurological morbidity and mortality among cancer patients in the United States. Analyzing two decades of CDC WONDER data provides insights into mortality disparities and demographic variations. Methods: Using the CDC WONDER database for adults aged ≥25, we analyzed age-adjusted and crude mortality rates (AAMRs and CMRs) per 100,000 for primary brain malignancies (ICD-10) and brain metastasis (ICD-10) by year, sex, race/ethnicity, and geography. Joinpoint regression estimated average annual percentage change (AAPC) and annual percentage change (APC) with 95% confidence interval (CIs). Results: The overall mortality related to brain metastasis has declined more steeply compared to primary brain malignancies (AAPC: –0.76 vs –0.13). Primary brain malignancies showed a significant decline between 1999 and 2006 (APC: −1.18; 95% CI: −1.74 to −0.61), followed by a modest long-term increase. In contrast, brain metastases had a steep initial decline from 1999 to 2007 (APC: −4.46; 95% CI: −4.87 to −4.04), followed by sharp increases from 2013-2016 (APC: 4.03; 95% CI: 0.05 to 8.17) and from 2016-2023 (APC: 1.42; 95% CI: 0.95 to 1.89). The annual change in mortality among female patients was not significant for either cause, whereas among men, the decline in mortality related to brain metastases (AAPC: −1.18; p<0.001) was steeper compared with primary brain malignancies (AAPC: −0.32; p=0.02), with the most significant decline observed between 1999 and 2007 (APC: −5.08; 95% CI: −5.62 to −4.53). When stratified by race, the NH Black or African American population showed an overall significant decline in mortality related to brain metastases (AAPC: −1.42; p<0.001), while overall change was non-significant among all other racial groups. For primary brain malignancies, overall mortality increased notably in the NH Asian or Pacific Islander population (AAPC: 1.06; p<0.001). Conclusions: Mortality related to brain metastases has declined more steeply than primary brain malignancies over the past two decades; however, recent increases and demographic disparities highlight the need for targeted interventions and equitable access to neurological care. Average annual percentage changes (AAPC) per 100,000 for trends related to primary brain malignancies and brain metastases from 1999 to 2023. Variable AAPC (95%CI) for Primary Brain Malignancy AAPC (95%CI)for Brain Metastasis Overall -0.13(-0.31 to 0.04) -0.76(-1.29 to -0.24) Male -0.32(-0.62 to -0.03) -1.18(-1.58 to -0.77) Female -0.14(-0.33 to 0.03) -0.37(-0.97 to 0.23) NH Blacks 0.12 (-0.46 to 0.72) -1.42(-1.89 to -0.95) NH Asians 1.06 (0.62 to 1.50) 0.59(-0.32 to 1.52) NH Americans -0.16 (-1.17 to 0.85) 0.45(-0.27 to 1.18) NH Whites 0.12 (-0.02 to 0.28) -0.47(-1.05 to 0.10) Hispanic or Latinos -0.06 (-0.78 to 0.64) -0.32(-1.02 to 0.37)
Trends in melanoma mortality among U.S. adults aged ≥55 before and after the introduction of immunotherapy: A CDC WONDER Joinpoint-style analysis.
e21579 Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced melanoma and produced durable survival benefits in clinical trials. However, the population-level impact of immunotherapy on melanoma mortality remains incompletely characterized. We examined national melanoma mortality trends before and after the introduction of ICIs to assess whether therapeutic advances translated into accelerated reductions in mortality at the population level. Methods: We conducted a retrospective population-based analysis using the CDC WONDER Underlying Cause of Death database from 1999–2020. Deaths due to malignant melanoma (ICD-10 C43) among adults aged ≥55 years were identified. Annual age-adjusted mortality rates standardized to the 2000 U.S. population were analyzed using Joinpoint-style segmented log-linear regression to identify changes in temporal trends and estimate annual percent changes (APC) before and after the identified breakpoint. Results: From 1999 to 2020, melanoma mortality among adults aged ≥55 years demonstrated a significant inflection point in 2012. Prior to 2012, age-adjusted mortality increased by an average of 1.1% per year. After 2012, mortality declined significantly, with an accelerated decrease of 2.2% per year (p<0.001 for change in slope). The post-2012 decline was sustained through 2020, reaching the lowest mortality rates observed during the study period. The timing of the inflection closely corresponded with the early dissemination of immune checkpoint inhibitors in routine clinical practice. Conclusions: In this nationwide analysis of adults aged ≥55 years, melanoma mortality demonstrated a modest decline prior to the availability of immune checkpoint inhibitors, followed by a significantly accelerated and sustained reduction thereafter. This temporal pattern is consistent with substantial population-level benefits associated with the introduction of modern immunotherapy. Continued surveillance and efforts to expand equitable access to early detection and advanced systemic therapies may be critical to further reducing melanoma mortality and minimizing disparities across demographic groups. Joinpoint-style analysis of melanoma mortality trends among U.S. adults aged ≥55 years, 1999–2020. Time period Years Annual Percent Change (APC) P value Interpretation Pre-immunotherapy 1999-2011 +1.1 per year < 0.001 Mortality increased prior to immunotherapy Immunotherapy era 2012-2020 -2.2% per year < 0.001 Accelerated decline in mortality after immunotherapy Breakpoint year: 2012. Outcome: Age-adjusted melanoma mortality per 100,000 (2000 U.S. standard population). Method: Joinpoint-style segmented log-linear regression.
Relationships between clinical stage, pathological stage, and disease-free (DFS) survival in renal cell carcinoma as used to inform future neoadjuvant study design: ECOG-ACRIN EA8143 PROSPER analysis.
4540 Background: Estimating risk of renal cell cancer (RCC) relapse based only on pre-surgical data is key to future neoadjuvant trial design. The EA PROSPER phase 3 study accrued pts with clinical stage ≥T2 or T any N+ RCC of any histology for nephrectomy. Pts were randomized to presurgical nivolumab (nivo) followed by primary tumor resection and 9 cycles of adjuvant nivo, or surgery alone followed by observation. We used PROSPER data to assess how baseline data informs risk. We reviewed cT to pT stage transitions, associated cT stages with outcome, and asked if size in addition to cT stage increases predictive accuracy. Methods: Pts with clear cell (cc) RCC were included. cT to pT concordance was assessed by TNM 8 th edition. DFS analysis (time from surgery to recurrence, second primary, or any cause death) was performed; pts with no event were censored at date of last assessment. DFS analysis compared cT groups (cT1/cT2 vs cT3/cT4) in the overall eligible study population and within each study arm. A subset DFS analysis by tumor size among cT2a (> 7-8cm vs >8-10cm) and cT3a (< 7cm vs 7-8cm vs > 8cm) was explored. Cox proportional hazards models were used, and log-rank test was reported to represent global p-value of each model. Wald test p-value was reported for individual group comparison (in assessing more than two groups). Two-sided p-values are reported, all p-values were considered significant at 0.05. Results: Of 819 pts randomized, 732 ccRCC pts (382 surgery only, 350 nivo + surgery) had data available. DFS was significantly different between cT1/cT2 vs. cT3/cT4 group, favoring cT1/cT2 among all pts (HR [cT1/cT2 as reference]=1.56, two-sided log-rank p < 0.001) and in each of the treatment arms separately (nivo + surgery arm HR=1.48, two-sided log-rank=0.04 ; surgery only arm HR=1.63, two-sided log-rank p=0.007). About half of cT1/T2 pts were upstaged to pT3/4, whereas <10% of cT3a were downstaged to pT1b. Higher grade cT1/T2 were more likely to upstage (p-value < 0.001).119 pts with cT2a and 233 pts with cT3a had tumor size data available. There was no significant DFS difference between tumor size groups in the cT2a subset. In cT3a patients, DFS analysis by tumor size showed a trend of increasing risk for 7-8cm and > 8cm groups when compared to < 7cm group, with a statistically significant difference comparing > 8cm vs < 7cm (HR=3.33, two-sided Wald p < 0.001) signifying worse outcome for pts if tumor size > 8cm. Conclusions: In ccRCC pts, baseline cT assessment is associated with DFS outcome. High grade cT1/2 pts risk pathological upstaging to pT3. cT3+ identifies high risk pts, with <10% being downstaged. Pts with cT3a > 8cm have a worse prognosis than patients with < 7cm tumors. These findings should be accounted for in eligibility criteria and risk assessment models for neoadjuvant trials, and explored in other international datasets.
Occult neoplasia in risk-reducing bilateral salpingo-oophorectomy: Pathological findings and clinical implications.
e22558 Background: RRSO is a well-established risk-reducing strategy for ovarian and fallopian tube cancer in genetically high-risk women, particularly BRCA1/2 carriers. With increasing recognition of the fallopian tube as the site of origin of high-grade serous carcinoma, detailed pathological evaluation has become critical to identify occult malignancies and precursor lesions such as serous tubal intraepithelial carcinoma (STIC). We aimed to evaluate the prevalence of occult neoplasia and clinical outcomes in high-risk women undergoing RRSO at a tertiary cancer center. Methods: We conducted a retrospective cohort study of consecutive high-risk women who underwent RRSO between 2020 and 2024 at A.C. Camargo Cancer Center. Clinical characteristics, germline genetic results, surgical details, pathological findings, peritoneal cytology, and oncologic outcomes were reviewed. High-risk status was defined by the presence of pathogenic germline variants and/or strong family history of cancer. Pathological evaluation followed institutional protocols for detailed examination of ovaries and fallopian tubes. Results: A total of 232 risk-reducing surgeries were performed; 225 patients (96.9%) underwent bilateral salpingo-oophorectomy and 7 (3.0%) salpingectomy alone. Median age at surgery was 48.9 years. Most patients had a prior diagnosis of breast cancer (n = 166, 71.5%), while 20% underwent surgery based solely on presymptomatic genetic counseling and family history. Germline testing revealed pathogenic variants predominantly in BRCA1 (n = 98, 42.2%) and BRCA2 (n = 76, 32.7%), followed by mismatch repair genes (n = 17, 7.3%), PALB2 (n = 13, 5.6%), RAD51C (n = 7, 3.0%), RAD51D (n = 5, 2.1%), and other genes (n = 16, 6.8%). Peritoneal lavage was performed in 139 patients (59.9%), with malignant cells identified in 3 cases (2.2%). Pathological examination demonstrated benign ovarian and tubal findings in 228 patients (98.3%). Occult neoplastic lesions were identified in 4 patients (1.7%): one invasive high-grade serous ovarian carcinoma (FIGO stage IIIC) associated with STIC, two isolated STIC lesions, and one ovarian metastasis from breast cancer. After a median follow-up of 69 months, overall survival was high, with only two deaths reported. No subsequent primary gynecologic cancers were diagnosed. Cancer recurrence occurred in four patients with prior breast cancer and in one patient with melanoma. Conclusions: In this large single-center cohort of high-risk women undergoing RRSO, occult intraepithelial or invasive malignancies were uncommon. Nevertheless, the detection of STIC and advanced ovarian cancer reinforces the importance of meticulous pathological assessment following risk-reducing surgery. These findings support the oncologic safety of RRSO while highlighting its diagnostic value in identifying clinically occult disease.
Allostatic load, neutrophil-to-lymphocyte ratio, and body composition in patients with metastatic prostate cancer.
e17135 Background: Allostatic load (AL), a composite biomarker index of multisystem physiologic dysregulation, and neutrophil-to-lymphocyte ratio (NLR), a systemic inflammatory marker, have been independently related to poor prognosis when ascertained at diagnosis in various cancers (e.g., breast, colorectal). However, their associations with adverse body composition phenotypes (sarcopenia, sarcopenic obesity or myosteatosis) in metastatic prostate cancer (MPC) remain largely unexplored. This study examines associations between AL, NLR and adverse body composition phenotypes in men with newly diagnosed MPC. Methods: A cross-sectional study using clinical data collected from the electronic medical records was conducted in adult men with newly diagnosed MPC. Eligibility criteria included a CT scan at the L3 vertebral level and laboratory data at date of cancer diagnosis. AL was calculated using nine clinical biomarkers (range 0–9). NLR was calculated by dividing an absolute neutrophil by an absolute lymphocyte count. Sarcopenia, sarcopenic obesity, and myosteatosis were defined using validated CT-based thresholds for skeletal muscle (SM) quantity and SM radiodensity (i.e., a marker of SM quality). Multivariable logistic regression was used to evaluate associations among AL, NLR, body composition phenotypes, and age. Results: Among 144 eligible men (35.5% White, 39.3% Black/African American, and 23.5% Latinx, mean age 69.6 ± 10.9 years), 64% had sarcopenia, 12.6% had sarcopenic obesity, and 57.9% had myosteatosis at diagnosis. AL was positively correlated with NLR (rho = 0.317, p < 0.001). In adjusted models, AL was associated with higher odds of sarcopenia (OR = 1.61, p = 0.004), sarcopenic obesity (OR = 1.99, p = 0.001), and myosteatosis (OR = 1.42, p = 0.031). Conversely, elevated NLR was negatively associated with sarcopenia (OR = 0.91, p = 0.006), sarcopenic obesity (OR = 0.648, p = 0.006), and myosteatosis (OR = 0.897, p = 0.008). Conclusions: In men with MPC, elevated AL was positively associated with all three adverse body composition phenotypes at diagnosis while NLR was negatively associated. These findings underscore the potential link between chronic exposure to stress, inflammation, and the development of adverse body composition phenotypes of muscle loss and muscle quality in men with newly diagnosed MPC.
HistoChrome: Virtual multiplex immunohistochemistry from routine H&E in colorectal cancer.
3523 Background: In colorectal cancer (CRC), immunohistochemistry (IHC) is central to assessment of spatial protein expression but is typically limited to few stains per case due to cost, tissue availability, and limited multiplexing. As a result, many relevant markers are not evaluated systematically. It remains unclear which pathobiologically relevant protein expression patterns are reliably encoded in morphological cues visible on routine haematoxylin and eosin (H&E) whole-slide images (WSIs). Markers of epithelial differentiation (CDX2, MUC2), immune infiltration (CD8), and mucin biology (MUC5) are clinically informative in colorectal cancer, yet their correspondence with H&E morphology is poorly defined. We investigate whether whole-slide virtual multiplex IHC (mIHC) can be generated from routine H&E for this marker panel. Methods: We trained a generative adversarial neural network with domain-specific constraints to enable whole-slide virtual mIHC generation from H&E. The model operates in stain concentration space using explicit stain separation and recombination and enforces spatial coherence during tiled whole-slide inference via an overlap consistency loss. Training used 52,579 paired H&E-mIHC patches (960×960 at 0.5 microns per pixel) extracted from adjacent, registered sections stained for CDX2, CD8, MUC2, MUC5, and hematoxylin, across 128 WSIs from 23 patients. Performance was evaluated on an independent cohort of 27 paired H&E-mIHC WSIs. Results: HistoChrome generates visually realistic and spatially coherent virtual mIHC WSIs from routine H&E. Biological fidelity was assessed by computing patch-wise Spearman correlations between mean stain intensities in real and virtual mIHC, restricted to tumor regions to avoid inflation from morphologically trivial normal tissue. Strong agreement with biological ground truth was observed for epithelial differentiation markers, with correlations of 0.79 for CDX2 and 0.63 for MUC2. CD8-positive immune infiltration was also captured with moderate accuracy (ρ = 0.49). In contrast, MUC5 expression showed only modest correspondence with biological ground truth (ρ = 0.25). Conclusions: HistoChrome enables whole-slide virtual multiplex immunohistochemistry from routine H&E, offering scalable access to biologically grounded protein markers without additional tissue or staining. Accurate inference of CDX2, MUC2, and CD8 supports slide-level pathological stratification of differentiation and immune contexts, with direct relevance for prognostic assessment and patient selection in therapeutic studies. The modest performance for MUC5 underscores that not all proteins may be morphologically encoded in H&E, highlighting the importance of marker-specific validation. Together, these findings position virtual mIHC as a practical adjunct to routine pathology and a discovery tool for CRC.
Clinicogenomic profile and progression patterns in lung squamous cell carcinoma treated with immune checkpoint inhibitors.
e20593 Background: Lung squamous cell carcinoma (LUSC) is associated with inferior outcomes to immune-checkpoint inhibitors (ICIs), compared to lung adenocarcinoma. However, the underlying mechanisms of ICI resistance in LUSC remain poorly understood. Methods: The GEMINI database was queried to identify advanced or metastatic LUSC patients who were treated with ICI or in combination with chemotherapy (ICI-chemo). Clinical pathologic, genomic, and outcome data were extracted. PD-L1, TMB, standard of care genomic, and Xenium data on patient tumor samples were analyzed. Results: A total of 569 patients with LUSC treated with ICIs were identified, including 421 in the first-line setting. Overall, 66.5% were male, and 91% were smokers. At baseline, 290 (51%) patients had intrathoracic disease, while 279 (49%) had distant metastasis, including 90 with liver involvement and 71 with brain metastases. The overall response rate was 34%, with a median PFS of 6.5 months (95%CI, 5.9 – 7.3) and a median OS of 19.3 months (95%CI, 16.5 – 22.3). Median PFS was 3.5 months (95%CI, 2.5 – 4.9) for cases with liver metastases, and 5.1 months (95%CI 4.0 – 12.2) for those with brain metastases. Among the 420 cases with progression disease, 256 were limited to baseline organs, 55 involved new organ sites excluding the liver or brain, and 109 had progression in the liver or brain. Patients with liver or brain progression had the worst PFS and OS (p < 0.0001) compared to other progression patterns. The addition of CTLA4 inhibitor or chemotherapy did not enhance outcomes of ICI monotherapy in LUSC patients with low PD-L1 or with liver and brain metastases. At baseline, the median TPS level of PD-L1 expression was negative in non-responders versus 20% in responders (complete or partial response) (p < 0.001). There is no significant difference of TMB between responders and non-responders (7.5 vs 8, p = 0.337). LUSC tumors were enriched for TP53 (84%), CDKN2A (18%), PIK3CA (14%), and NFE2L2 (12%). KMT2C mutations were associated with favorable response (p = 0.01). In contrast, MYC amplification was associated with de-novo progression disease (p = 0.05). From preliminary Xenium analysis of human tissue samples, we observed that the patient who achieved a complete response to pembrolizumab monotherapy exhibited a higher density of immune cell populations and stronger immune signals compared with the 3 patients who demonstrated de-novo resistance to ICI. Conclusions: In LUSC patients, liver metastases are associate with a shorter time to acquired resistance, and progression in the liver or brain correlates with poorer outcomes. Adding a CTLA-4 inhibitor or chemotherapy did not improve outcomes over ICI monotherapy. A more immune enriched tumor microenvironment at baseline may be associated with clinical response to ICIs. Further analysis of the Xenium data is ongoing to explore the resistance mechanism of ICI therapy in LUSC.
Commercial price variation in precision oncology testing across US hospitals.
11062 Background: Precision oncology testing using clinically validated biomarker tests is standard of care for solid tumors and is endorsed by clinical guidelines and professional societies. However, these tests represent a substantial and growing component of cancer care costs. Commercial payer-negotiated prices for these tests and their variation across hospitals and payers have not been examined. Methods: We conducted a cross-sectional analysis of hospital-reported commercial payer-negotiated prices, aggregated by Turquoise Health as of January 2026, for biomarker tests commonly used in breast, colon, and non-small cell lung cancer and identified using the National Comprehensive Cancer Network Biomarkers Compendium and Centers for Medicare and Medicaid Services Clinical Laboratory Fee Schedule. We included tests with unique Current Procedural Terminology codes and extracted prices negotiated between short-term acute care hospitals and the four largest US payers (Aetna, Blue Cross Blue Shield, Cigna, UnitedHealthcare). Prices were adjusted using ZIP code-level Geographic Adjustment Factors. We assessed within- and between-hospital variation in prices for each test using the median 90th-to-10th percentile price ratio and compared prices across payers using Kruskal-Wallis tests. Results: We identified 422,515 payer-negotiated prices for 28 biomarker tests from 2,142 US hospitals. Oncotype DX Breast Recurrence Score and CEA expression testing were the most frequently reported panel- and non-panel-based tests, with median (interquartile range [IQR]) prices of $4,129 ($3,869–$10,680) and $28 ($20–$59), respectively, across hospitals. The percentage of hospitals reporting negotiated prices, price amounts, and price variation are summarized in the Table. Cigna had the highest prices for 20 (71.4%) tests, whereas UnitedHealthcare had the lowest price for all tests. Conclusions: Commercial payer-negotiated prices for precision oncology testing varied substantially across payers and hospitals, with greater variation between than within hospitals for the same tests. Given the central role of these biomarker tests in guideline-recommended cancer care, price variation has important implications for payer spending, clinical decision-making, patient out-of-pocket costs, and equitable care access. Price variation for precision oncology testing. Biomarker Tests Percentage of hospitals in Turquoise Health database reporting negotiated price, Median (IQR) Negotiated price, USD, Median (IQR) Within-hospital ratios, Median (IQR) 1 Between-hospital ratios, Median (IQR) 1 Panel-based (N=13) 18.3% (17.2%-18.8%) $3,704 ($3,096-$4,129) 1.5 (1.4-1.5) 5.5 (5.5-5.6) Non-panel-based (N=15) 30.3% (22.2%-37.8%) $301 ($157-$485) 1.6 (1.5-1.7) 5.2 (5.1-5.4) 1 Median (IQR) of ratios of the 90 th :10 th percentile payer-negotiated prices within each hospital and across all hospitals for the same test.
Cytokine dynamics in a phase II trial of metronomic carboplatin/paclitaxel combined with cemiplimab in recurrent/metastatic head and neck squamous cell carcinoma.
6044 Background: Standard-dose chemotherapy combined with immunotherapy improves response rates in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but its use is often constrained by significant toxicity. Metronomic chemotherapy (MCT) offers a potentially better-tolerated alternative while preserving immune-modulatory properties. We evaluated cytokine profiles and their longitudinal dynamics to investigate the relationship between immune-mediated mechanisms and clinical outcomes in patients treated with MCT plus cemiplimab. Methods: Single- arm phase II trial (NCT04862650). R/M HNSCC pts received first-line cemiplimab 350 mg IV Q3W (≤35 cycles) plus weekly carboplatin (AUC1) and paclitaxel (25 mg/m²) for 24 weeks. Primary endpoint was overall response rate (ORR) per RECIST v1.1 at week 12. Forty immune-modulatory cytokines were assessed at baseline, week 3, and week 6 using the Luminex xMAP platform. Results: From Nov 2021 to Dec 2024, 40 evaluable patients were enrolled (median age was 66 years, 82.5% were male; 35% were HPV-positive). Median follow-up was 10 months (range 1–28). ORR was 42.5% (15% CR) and Median OS was 14.8 months (95% CI, 10.3–23.9). Responders had significantly higher IFN-β at all timepoints (P=.008–.04). Elevated IL-4, IL-5, and IL-10 at baseline were associated with improved ORR. Overall, LIGHT, FasL and TGF-α decreased while PD-L1 increased over time (all q<0.001). Compared to baseline, on week 6, responders showed decreased VEGF-A, TSLP, FasL, and IL-4 (P < .03), while non-responders exhibited increased IFN-γ, PD-L1, and IL-6Rα (P < .04). Changes in IFN-γ (HR 3.23, P=.006) and IL-4Rα (HR 3.06, P=.008) from baseline to week 3 were associated with worse overall survival. Conclusions: MCT combined with cemiplimab demonstrated clinically meaningful antitumor activity. Alterations in plasma concentrations of select cytokines were associated with therapeutic response and overall survival. These results are hypothesis-generating and support the need for prospective validation. Clinical trial information: NCT04862650 .