Background: Dendritic and histiocytic cell sarcoma (DHCS) and clear cell sarcoma (CCS) are ultra-rare soft-tissue sarcomas characterized by diagnostic ambiguity, limited treatment guidelines, and poor outcomes. Their rarity has restricted the development of evidence-based management strategies, leaving clinical decisions reliant on small case series and institutional experience. DHCS typically presents without a unifying molecular driver and is often misclassified without comprehensive immunophenotyping. CCS is defined by EWSR1-ATF1/CREB1 fusions but exhibits low responsiveness to conventional chemotherapy. There remains a clear need to clarify natural history, therapeutic responses, and molecular characteristics in both. Methods: We conducted a retrospective cohort study of adult patients with histologically confirmed DHCS or CCS seen at The Ohio State University Comprehensive Cancer Center between 2010 and 2022. Demographics, treatment modalities, clinical outcomes, and molecular profiles were extracted and analyzed descriptively. Time to progression (TTP) and progression rates by treatment modality were recorded. A structured literature review was conducted to provide context for the findings. Results: Outcomes are descriptive and cohort-specific, reflecting institutional experience rather than generalizable estimates. A total of 10 patients with DHCS and 5 with CCS were evaluable. Most DHCS patients presented with metastatic disease. Among DHCS patients who received systemic therapies, 5 of 8 (62.5%) experienced progression during or shortly after treatment. Among CCS patients who received systemic therapies, 3 of 4 (75%) progressed during or shortly after treatment. Overall mortality occurred in 4 of 10 DHCS patients (40%) and 3 of 5 CCS patients (60%). TP53 mutations were identified in 4 of 7 next-generation sequencing (NGS)-tested DHCS cases, and PD-L1 positivity was detected in 5 of 7 tested DHCS cases and 1 of 5 tested CCS cases. Conclusions: Despite multimodal treatment, this referral-based cohort of patients with ultra-rare DHCS and CCS showed high rates of progression and mortality. Our findings underscore the urgent need for multi-institutional collaboration and biomarker-driven clinical trials to guide management of these ultra-rare sarcoma subtypes.

TPS11590 Background: Soft tissue sarcomas (STS) are biologically heterogeneous with limited effective systemic options in advanced disease. While 18F-FDG PET/CT provides metabolic assessment, it does not identify actionable receptor targets. Somatostatin receptor 2 (SSTR2) is expressed in subsets of mesenchymal tumors, and SSTR-targeted imaging with 68Ga-DOTATATE PET/CT is routinely used to select patients with neuroendocrine tumors for peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. Whether receptor-targeted PET screening can feasibly characterize SSTR expression across STS subtypes and support future PRRT trial design is unknown. This study evaluates the feasibility and yield of 68Ga-DOTATATE PET/CT as a screening strategy in STS. Methods: This is a prospective, open-label, single-center pilot study enrolling 30 adults with any-stage STS who are candidates for systemic therapy and who have undergone standard-of-care PET/CT within 30 days. Participants undergo a single 68Ga-DOTATATE digital PET/CT within 14 days of consent, acquired approximately 60 minutes post-injection with non-contrast CT for attenuation correction and anatomic localization. Quantitative metrics including SUVmax and total tumor volume are centrally derived. Optional biobanking permits pre-imaging blood collection for exploratory circulating biomarkers. Key exclusions include recent long-acting somatostatin analog use, pregnancy or lactation, acute infection, hypersensitivity to somatostatin analogs, or inability to complete imaging. The primary endpoint is screening feasibility, defined by successful scan acquisition and interpretable image quality. Secondary endpoints include lesion-level detectability, safety, and characterization of uptake patterns using modified Krenning-style criteria and quantitative PET parameters across histologic subtypes. Imaging findings may be reviewed at multidisciplinary sarcoma tumor board as part of routine clinical care, including discussion of potential PRRT eligibility, but tumor board recommendations are not study endpoints. Exploratory analyses will assess concordance between imaging findings and available tumor immunohistochemistry or circulating biomarkers. Analyses are descriptive. The planned accrual is 30 patients over approximately 24 months at a high-volume sarcoma center. Enrollment and imaging are ongoing. This study will establish the feasibility of receptor-targeted PET screening in STS and characterize the frequency and distribution of SSTR-positive disease, providing data necessary to inform the feasibility and design of subsequent 177Lu-DOTATATE interventional trials. Clinical trial information: NCT06500065 .

Introduction Aggressive surgical resection is the cornerstone of treatment for retroperitoneal sarcomas (RPS), but recurrent disease occurs in up to 50% of patients. Palbociclib, an oral CDK4/6 inhibitor, in adjuvant setting may delay the need for additional surgery. However, it is unclear which patients derive an oncologic benefit from Palbociclib and what duration is required to prevent recurrence. We sought to evaluate recurrence patterns in patients with high risk RPS who completed adjuvant Palbociclib. Methods Patients with no evidence of disease after resection of RPS and treated with adjuvant Palbociclib were identified from a prospectively-maintained institutional database. We performed bulk RNA sequencing of primary tumor samples. Results Of the thirty-four patients who received adjuvant Palbociclib, 8 met the inclusion criteria and 5 developed recurrence after stopping treatment. Most (n=7) patients completed at least 12 months of Palbociclib. The three patients without recurrence currently have disease-free interval of 16, 25, and 33 months. On RNA sequencing, the epithelial-mesenchymal transition pathway is significantly enriched in the recurrence cohort compared to the no-recurrence cohort. Conclusion Half of the patients in this cohort developed short interval recurrence after completing adjuvant Palbociclib. Studies with larger patient cohorts and genomic analysis of tumors may lend additional insight.

e23573 Background: With the expanding use of immune checkpoint inhibitors (ICI) in selected soft tissue sarcoma (STS) subtypes, clinical factors associated with outcomes at ICI initiation remain poorly defined. Proton pump inhibitor (PPI) exposure has been associated with inferior ICI outcomes in other malignancies, while line of therapy may reflect both disease biology and prior treatment resistance. We evaluated the association of PPI use and line of systemic therapy at ICI initiation with overall survival (OS) and progression-free survival (PFS) in patients with advanced STS treated in routine clinical practice. Methods: Patients with advanced STS treated with ICI at The Ohio State University from 2015–2023 were identified from a retrospective sarcoma immunotherapy database. Advanced disease was defined as stage IV disease or receipt of ≥3rd-line systemic therapy. Variables of interest included PPI use at ICI initiation (yes/no) and line of systemic therapy at ICI initiation (1st, 2nd, ≥3rd). OS and PFS were estimated using Kaplan–Meier methods and compared by log-rank tests. Cox proportional hazards models adjusted for age and ECOG performance status were used to evaluate associations between line of therapy and survival outcomes, reported as hazard ratios (HR) with 95% confidence intervals. Results: A total of 192 patients were included; 49 (26%) were receiving PPI therapy at ICI initiation. No significant differences in OS (P = 0.42) or PFS (P = 0.83) were observed based on PPI use. Most patients received ICI in the ≥3rd line (n = 99; 1st line n = 40, 2nd line n = 52). Compared with first-line ICI, OS was significantly worse for ≥3rd-line ICI (HR 2.0, P = 0.001), but not for second-line ICI (HR 1.03, P = 0.92). PFS was also significantly worse for ≥3rd-line ICI (HR 3.36, P = 0.0002), with no difference between first- and second-line treatment (P = 0.80). Conclusions: In patients with advanced STS treated with ICI, later line of therapy at treatment initiation was associated with significantly worse OS and PFS, while concurrent PPI use was not associated with adverse outcomes. Line of therapy may serve as a pragmatic prognostic marker in STS immunotherapy studies and should be considered in stratification and interpretation of future trials. Prospective studies are needed to identify biologic correlates of resistance beyond clinical surrogates.

11549 Background: Sarcomas are rare, biologically heterogeneous malignancies with limited targeted treatment options. Antibody–drug conjugates (ADCs) have demonstrated clinical efficacy across multiple solid tumors by exploiting tumor-associated surface antigens; however, their development in sarcoma has been limited by incomplete characterization of ADC target expression across subtypes. We evaluated expression of clinically relevant ADC targets across sarcoma histologies using bulk RNA sequencing and compared these patterns to cancer types with established ADC activity to generate a sarcoma-wide map of ADC target expression. Methods: We analyzed expression of 18 genes encoding cell-surface ADC targets that are FDA-approved or in active clinical development across more than 1,000 sarcoma samples spanning multiple histologic subtypes. Transcriptomic data were derived from The Cancer Genome Atlas (TCGA), an institutional sarcoma registry, and the Oncology Research Information Exchange Network (ORIEN). Per-sample z-scores were generated using pan-cancer distributions to enable standardized comparison. Z-score distributions were summarized using ordinal bins to define target enrichment across sarcoma subtypes. Parallel pan-cancer analyses were performed for contextual comparison. Results: Sarcomas demonstrated heterogeneous but subtype-specific expression of multiple ADC targets across datasets. Several subtypes exhibited elevated expression of select ADC targets, with z-scores comparable to or exceeding those observed in tumor types where ADCs have established clinical activity. ADC targets of particular interest included LRRC15 and CD276 (B7-H3). LRRC15, currently in investigation as an ADC in breast cancer, demonstrated enrichment in sarcoma, with 28% of undifferentiated pleomorphic sarcoma and 38% of dedifferentiated liposarcoma samples exhibiting z-scores > 2, compared to 12% in breast cancer. CD276 similarly showed subtype-specific overexpression across these sarcoma subtypes. No single target was uniformly overexpressed across all sarcomas, underscoring biologic heterogeneity. Pan-cancer comparison revealed that certain sarcoma subtypes ranked among the highest expressors for specific ADC targets. Conclusions: Across a cohort exceeding 1,000 sarcoma patients with diverse histological subtypes, we identify subtype-specific overexpression of multiple clinically relevant ADC targets. This subtype expression map provides a biologic rationale for expanding ADC development into molecularly selected sarcoma subpopulations and supports biomarker-enriched approaches to ADC trial design. Ongoing studies will validate these findings at the protein level using a sarcoma surfaceome approach, including immunohistochemistry and mass spectrometry based profiling.

11554 Background: Many patients with sarcoma deal with adverse impacts on their (QoL) related to their underlying disease as well as treatment-related effects. Unplanned hospital admissions and emergency department (ED) visits occur from uncontrolled symptoms that delay treatment and lead to poor hospital system metrics. The PROMIS Global Health v1.2 (PROMIS-10) survey is a validated tool to assess patients’ physical and mental well-being at the time of the survey, with a higher number indicating a better state of health. There are limited studies evaluating longitudinal QoL assessments during sarcoma treatment. Our objective was to analyze PROMIS-10 scores for patients with advanced sarcoma and their temporal relationship with negative outcomes of interest. Methods: We performed a retrospective registry-based longitudinal analysis of routinely collected PROMIS-10 surveys at The Ohio State University. Patients were consented to the sarcoma registry (NCT02677961) from 6/1/2018 to 12/31/2024. We collected baseline, serial and overall change in physical and mental PROMIS-10 raw and normalized t-scores for each patient during their treatment as well as clinical characteristics, mortality, disease progression (RECIST), and ED visits/unplanned hospital admissions. Survival analyses with time-varying covariates were performed using the marginal Cox model approach for statistical analysis. Results: A total of 241 patients were included in the study. Patients with higher PROMIS-10 physical scores had a 13% decrease in risk of death (HR 0.87; P < 0.001), 3% decrease in risk of progression (HR 0.97; P = 0.027), and 6% decrease in risk of ED visit/unplanned hospital admission (HR 0.94; P < 0.001). Patients with a higher PROMIS-10 mental health score had a 7% decrease in risk of death (HR 0.93; P < 0.001), but no association with disease progression or risk of hospital utilization. The larger positive change in physical PROMIS-10 score from baseline to final assessment was associated with an 11% decreased risk of mortality (HR 0.89; P < 0.001) and 9% decreased risk of ED visit/hospital admission (HR 0.91; P = 0.032), but no association with progression. The larger positive change in mental PROMIS-10 score was associated with a 7% decrease in risk of progression (HR 0.93; P = 0.010) but there was no association with mortality or hospital utilization. Conclusions: We demonstrated that obtaining longitudinal patient-reported outcomes to evaluate patients’ physical and mental health during sarcoma treatment can predict mortality, disease progression and ED visits/unplanned hospital admissions. Higher physical PROMIS-10 scores are strongly associated with decreased mortality and hospital utilization risk, whereas a larger positive change in mental PROMIS-10 scores is associated with decreased risk of progression. To our knowledge, this is the largest cohort (241 patients) of advanced sarcoma analyzing QoL impacts.

e23523 Background: Soft tissue sarcomas (STS) comprise a heterogeneous group of malignancies with limited biomarkers for real-time disease monitoring. Circulating tumor DNA (ctDNA) represents a minimally invasive approach to assess tumor burden and treatment response; however, its clinical utility in STS remains incompletely defined. We evaluated ctDNA dynamics across diverse STS subtypes in a real-world clinical cohort. Methods: We retrospectively analyzed plasma-derived ctDNA from 57 patients with STS enrolled in a prospective EHR-based Comprehensive Bone and Soft Tissue Tumor Registry (NCT02677961) at The Ohio State University Comprehensive Cancer Center. ctDNA was assessed using Tempus (n = 34) and Signatera (n = 23) platforms. ctDNA levels were compared with radiographic tumor volume, histologic grade, and disease stage. Tumor burden was quantified using volumetric imaging, and clinical response was assessed by RECIST criteria or physician evaluation. Serial ctDNA measurements were available for a subset of patients. Results: ctDNA was detectable in over 75% of patients. ctDNA levels strongly correlated with tumor volume in both the Signatera (Spearman r = 0.84, p = 2.04 × 10⁻⁹) and Tempus (Spearman r = 0.63, p = 0.0375) cohorts. ctDNA detection was significantly associated with higher histologic grade (p = 0.0217), with Grade 3 tumors demonstrating the highest detection rates. ctDNA presence was not associated with surgical stage (p = 0.666). Among 20 patients with serial sampling, ctDNA dynamics closely mirrored changes in tumor burden during surgery, chemotherapy, and radiation. The sensitivity of ctDNA detection in patients with radiographically evident disease was 79.2%, and in 82% of cases, increases in ctDNA levels preceded radiographic evidence of disease progression across histological subtypes. Conclusions: In this real-world STS cohort, ctDNA levels were associated with tumor burden, histologic grade, and longitudinal treatment response across multiple sarcoma subtypes and assay platforms, with ctDNA increases frequently preceding radiographic disease progression. These findings support ctDNA as a promising biomarker for real-time disease monitoring in STS and provide a rationale for incorporation into prospective sarcoma clinical trials. Larger, multi-institutional studies are warranted to validate these observations.

In the original publication [...].

Ketogenic dietary interventions (KDIs) are increasingly explored as adjuncts in oncology due to their metabolic and immunomodulatory effects. One mechanism by which KDIs are expected to modulate the immune system is by altering the gut microbiome, which has been shown to affect treatment outcomes, particularly in the context of immunotherapies. This review synthesized findings from 43 clinical trials to evaluate the current landscape of KDIs in cancer care, with a focus on the gut microbiota and immunotherapy. Although 47% of identified trials are completed, none have yet published results combining KDIs with immunotherapy. Since 2020, however, there has been a significant increase in ongoing studies investigating this combination and incorporating microbiome endpoints. While KDIs may help shape an immunotherapy-permissive environment, further clinical evaluation is necessary to determine the full extent of KDIs on the microbiome. Future research should prioritize longitudinal microbiome profiling and standardized adherence reporting to clarify the therapeutic potential of KDIs as a metabolic adjuvant to immune checkpoint inhibitors.

e23518 Background: Gastrointestinal Stromal Tumors (GIST) are rare mesenchymal neoplasms of the gastrointestinal tract. Most GISTs harbor activating mutations in KIT or PDGFRA. In contrast, GISTs that are negative for KIT/PDGFRA mutations on next generation sequencing (NGS) are defined as wild-type (WT) GIST. While KIT/PDGFRA-mutant GISTs often respond to TKIs, the biology, treatment responsiveness, and outcomes of WT GIST are not well defined. We present a single institution retrospective review of WT GIST. Methods: 370 patients were screened for pathologically confirmed GIST with an absence of both KIT and PDGFRA mutations on NGS. Demographic information, primary site, molecular genomic profiles, therapeutic regimens, and survival data were included. Results: 365 patients were confirmed on pathology to have GIST. 184 patients had NGS completed; 18 patients met WT criteria (9.8% of 184). The most frequent primary locations were stomach (n = 12, 66.7%) and small intestine (n = 3, 16.7%). SDH-deficient GIST were most common (n = 9, 50%), followed by “quadruple WT” (n = 4, 22.2%), and RAS pathway mutations (n = 3, 16.7%); 2 patients did not have SDH testing (16.7%). At time of diagnosis, most of the cohort had stage IV disease (n = 10, 55.5%), followed by stage III (n = 4, 22.2%), then stage II (n = 2, 11.1%) and stage I disease (n = 2, 11.1%). 17 patients underwent surgical resection; 1 surgery was aborted due to disease burden. Imatinib was the most used systemic therapy (n = 14, 77.8%) and first-line in 13 cases; median imatinib duration was 415 days. It was most often discontinued for disease progression (n = 5, 35.7.5%) or treatment related toxicity (n = 2, 14.3%). Subsequent TKIs (sunitinib, regorafenib, ripretinib) and immune checkpoint inhibitors were used in a subset of later-line settings. Across all WT GIST patients, 5-year overall survival (OS) was 88.9% (95% CI 75.5–100%) with median OS of 129 months; 5-year progression-free survival was 55.6% (95% CI 36.8–84.0%) with median time to first progression of 73 months. Conclusions: KIT/PDGFRA WT GIST represents a rare but clinically important subset at our institution, with pronounced molecular heterogeneity driven predominantly by SDH-deficient and RAS pathway–altered tumors and a distinct minority of quadruple WT cases. In this series, long-term survival was unexpectedly favorable despite a high proportion of patients with advanced-stage disease, highlighting the critical role of comprehensive genomic profiling to correctly classify WT GIST. Robust, multi-institutional cohorts are urgently needed to refine prognostic estimates and to develop and test tailored treatment strategies for SDH-deficient and quadruple WT GIST.

Proton pump inhibitors (PPIs) are one of the most widely used medications in the world. They have been associated with an altered microbiome, which is demonstrated to be important for immune checkpoint inhibitor (ICI) response. We sought to determine whether PPI use was associated with shorter overall survival (OS) in patients treated with ICIs, and whether these changes were associated with altered microbiomes and immune cell composition. Our retrospective study of patients with advanced cancer (n = 1078) evaluated the impact of PPI use on OS. We also analyzed stool samples from melanoma patients treated with ICIs (n = 42) and stool and blood samples from patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma treated with ICIs (n = 8). With the data from our prospective study, we assessed microbiome composition from stool samples using metagenomic whole-genome shotgun; immune cell populations from blood samples were determined using CyTOF. Associations between PPI use, clinical outcomes, the microbiome, and immune cell populations were evaluated using survival analyses, diversity metrics, and multivariable models. PPI use was associated with shorter OS in patients with advanced cancers treated with ICIs, with the strongest effects seen in melanoma. PPI use was associated with worse clinical outcomes and microbiome alterations in patients with advanced cancers treated with ICIs, suggesting that its use may influence the efficacy of immunotherapy; prospective studies implicate its effect on the microbiome. These findings underscore the importance of considering the microbiome and concomitant medications when to enhance treatment response and efficacy.

Selected log2 fold change results for microbes found to be significantly enriched in hypoxic tumors in both mice and human subjects.

Modeling results for gene expression differences between responders and non-responders

Boxplots showing the immune cell fractions for immune cells with significantly different expression in high and low hypoxia mouse samples at p-value <0.05. No differences remained significant after correction for multiple hypothesis testing.

Boxplot comparing Fusobacterium counts in low and high hypoxia 16s samples.

Boxplots comparing immune fractions in low and high hypoxia groups in the ORIEN radiation cohort, displaying cells with significantly different abundance with an adjusted p-value <0.05.

Predictive values (AUROC) of the 16 gene signatures in the ORIEN cohort (IO_NOVA_Mel) and 22 other melanoma cohorts

Hypoxia scores by stage (A) or sex (B) for the ORIEN radiation-treated cohort.