Siontis, Brittany L.

Abstract Purpose: Soft-tissue sarcomas are rare malignancies with poor prognosis and limited systemic treatment options. We conducted a phase II study to assess the efficacy and safety of trabectedin and olaparib in patients with advanced disease. Patients and Methods: Patients with soft-tissue sarcoma who received ≥1 prior therapy were recruited into two cohorts. Cohort 1 included leiomyosarcoma and liposarcoma; cohort 2 included other histologies. All patients received trabectedin (1.1 mg/m2 24-hour infusion every 21 days) and olaparib (150 mg twice daily continuously). The study was conducted using a Simon minimax two-stage design with a primary endpoint of objective response (OR) rate per RECIST 1.1. Results: Twenty-nine (cohort 1, 16; cohort 2, 13) patients enrolled; one patient in cohort 2 was not evaluable. There were no confirmed ORs in cohort 1; the best response was stable disease in 12 (75%) patients and progressive disease in four (25%). Two partial responses were observed in cohort 2 (n = 12). The most common adverse events were fatigue (75%), neutropenia (75%), anemia (68%), and thrombocytopenia (68%). The median progression-free survival and overall survival for all patients were 3.5 (95% confidence interval, 3.3–8.2) and 13.2 months (95% confidence interval, 10.3–20.9), respectively. Next-generation sequencing of 17 tumors revealed multiple abnormalities, most commonly in TP53, RB1, and ATRX. Conclusions: Trabectedin plus olaparib conferred high rates of toxicity and failed to demonstrate ORs in leiomyosarcoma and liposarcoma. Preliminary evidence of clinical benefit in two patients in cohort 2 suggests potential value of either or both drugs in other sarcomas.

ABSTRACT Background and Objectives Hepatic epithelioid hemangioendothelioma (HEHE) is an uncommon vascular neoplasm characterized by variable clinical behavior. Our aim was to describe the therapeutic approach for HEHE at diagnosis and define clinicopathological characteristics associated with tumor progression and long‐term survival. Methods This is a retrospective study that includes patients with HEHE who received treatment at Mayo Clinic Rochester between 1984 and 2023. Results Eighty patients were included in the study (median age: 44 years; 62.5% female), 24 underwent liver transplantation, 26 underwent liver resection, and 30 were managed medically. The 3‐year overall survival rates were 86.7%, 80.9%, and 51.1%, respectively. Notably, 26 patients had extrahepatic metastases at the time of diagnosis, four (16.7%) in the transplantation group, four (15.4%) in the resection group, and 18 (69.2%) in the nonsurgical group. On multivariable modeling, bone metastasis was independently associated with long‐term mortality (HR 6.3, p < 0.001) while lung metastasis and surgical intervention were not associated with long‐term mortality (HR 0.8, p = 0.8; HR 1.1, p = 0.9, respectively). Conclusion Bone metastasis emerged as a strong predictor of poor survival. Hence, aggressive surgical intervention may not be advantageous in patients with skeletal metastases but can still be offered for those with other extrahepatic metastases.

Background: Myxoid liposarcoma predominantly affects young and middle-aged individuals, and little is known regarding treatment tolerability and outcomes in older patients. This study aims to better understand this older patient population. Methods: This single institution retrospective study included patients aged 70 years and older with localized (non-metastatic) myxoid liposarcoma. Results: Sixteen patients were included. The median age was 75 years, and 9 (56%) were female. Fourteen (88%) were extremity tumors and two (12%) were trunk. The median tumor size was 10.4 cm (range, 3.6 to 28 cm). Five (31%) tumors had a round cell component. All patients had surgery. Fourteen (88%) had perioperative radiation, and three (19%) had perioperative chemotherapy. One patient had postoperative infection, and one patient had neutropenic fever from preoperative chemotherapy. The median follow up from surgery was 6.3 years. Eight (50%) patients died from MLPS. The median relapse-free survival and overall survival were 34 months and 75 months, respectively. Conclusions: Most older patients with localized MLPS received perioperative radiation therapy with surgery, and few serious toxicities were reported. Even with treatment, half of the patients relapsed.

Background: Synovial sarcoma is rare and may present as a small, slow-growing mass. These tumors are often mistaken as benign and are therefore prone to unplanned and/or non-oncologic excision. We sought to identify the rate of unplanned excision of synovial sarcoma and risk factors for recurrence and survival among this cohort. Methods: The medical records of 246 patients evaluated at a single institution for synovial sarcoma between 1997 and 2022 were retrospectively reviewed. Of these, 87 (35%) underwent unplanned, non-oncologic excision. The mean age of the cohort was 49 years. Primary tumors were located in the extremity (n = 63), abdomen (n = 6), thorax (n = 7), head/neck (n = 8), and paraspinal region (n = 3). The median maximum pre-treatment dimension of the primary tumor was 4.8 cm (IQR 7–2.4). Seventy-seven (86%) patients underwent re-excision of the tumor bed, 39 (45%) received chemotherapy, and 63 (72%) received radiation therapy. Results: Among patients who underwent unplanned excision, local recurrence-free survival (LRFS) was 98% at 1 year and 82% at 5 years. Metastasis-free survival (MFS) was 91% at 1 year and 72% at 5 years. Disease-specific survival (DSS) was 98% at 1 year and 72% at 5 years. When adjusting for tumor size, tumors which underwent unplanned excision did not have worse recurrence or survival compared to those which had planned excision (p > 0.10). Size > 5 cm, monophasic subtype, and axial location were associated with increased risk of disease recurrence. Forty-six patients had residual tumor following re-excision, which was associated with worse MFS (HR 8.17, 95% CI [1.89, 35.2], p < 0.01) and DSS (HR 7.66, 95% CI [1.76, 33.4], p < 0.01). Patients who received radiotherapy had improved MFS (HR 6.4, 95% CI [1.42, 29.0], p = 0.02) and DSS (HR 5.86, 95% CI [1.27, 26.9], p = 0.02). Conclusions: One-third of patients presenting with synovial sarcoma were diagnosed after unplanned, non-oncologic excision. Patients with large, axial tumors had worse survival. Approximately half of patients who underwent unplanned excision had no residual tumor after pre-operative radiation. The use of radiation was associated with decreased rates of recurrence and improved disease-specific survival. Our results suggest that margin-negative re-resection and radiotherapy should be considered when feasible following unplanned excision of synovial sarcoma.

Background: Liposarcoma, one of the most prevalent sarcoma histologies, is recognized for its tendency for extra-pulmonary metastases. While oligometastatic cardiac disease is rarely reported, it poses a unique challenge as oligometastatic sarcomas are often managed with surgical resection. Case Report: We present a case of a 62-year-old man diagnosed with an oligometastatic myxoid liposarcoma (MLPS) to the heart 19 years after the primary tumor resection from the lower limb. The metastatic mass, situated in the pericardium adjacent and infiltrating the left ventricle, was not managed surgically but with a combination of chemotherapy and radiotherapy. The patient’s disease remains stable to date, for more than 10 years. Literature Review: We conducted a review of the literature to determine the preferred management approach for solitary cardiac metastases of sarcomas. We also conducted an in-depth analysis focusing on reported cases of MLPS metastasizing to the heart, aiming to extract pertinent data regarding the patient characteristics and the corresponding management strategies. Conclusions: Although clinical diagnoses of solitary or oligometastatic cardiac metastases from sarcomas are infrequent, this case underscores the significance of aggressive management employing chemotherapy and radiotherapy for chemosensitive and radiosensitive sarcomas, especially when surgical removal is high-risk. Furthermore, it challenges the notion that surgery is the exclusive therapeutic option leading to long-term clinical benefit in patients with recurrent sarcomas.

11526 Background: There are no FDA-approved treatments for advanced cCS. Chemotherapy provides limited benefit. IDH1/2 mutations (m) occur in 50% of cCS. Both IDHm and wild-type cCS harbor epigenetic dysregulation. In preclinical models, HDAC + DNMT inhibition (i) suppressed growth by inducing apoptosis, reversing the hypermethylated state, and upregulating expression of interferon (IFN) response genes including PDL1(1). This prompted a phase 2 study of HDACi + DNMTi in cCS, which failed to meet the 1° endpoint of ORR. The majority of pts had a best response of stable disease, with a trend towards improved mPFS in IDHm (2). Here we report correlative analysis of NCI 10330. Methods: NCI 10330 is a single-arm, multicenter, phase 2 study of belinostat with SGI-110 or ASTX727 in advanced cCS. All pts were required to have pre- and on-treatment (tx) biopsies (Cycle 2, Day 3-5). Tissue was evaluated with whole exome sequencing (WES) and RNA sequencing (RNAseq). From RNAseq, Tumor Inflammation Signature Scores (TISS) and Tumor Microenvironment functional Gene Set Enrichment Analysis scores (TME GSEA) were calculated as the mean of the log2 normalized counts of 18 signature genes (Danaher et al. J Imm Can 2018) and pre-defined gene sets (3), respectively. Wilcoxon rank sum test was used to analyze TME GSEA between pre- and on-tx samples. Differential expression was significant if |FC| > 1.33, adjusted P <0.01. Results: 19 pts were treated; all received paired biopsies. WES was adequate in 7/19 (37%) pts, with IDHm identified in 3/7 (43%) pts. All pts were MSI-stable, TMB: 1.01-3.57 mut/Mb. RNAseq was adequate in 7/19 (37%) pts at pre-tx and 5/19 (26%) pts at on-tx. TISS ranges trended higher for pre-tx (8.77-10.14) vs on-tx (7.36-9.51) samples. TME GSEA identified significantly enriched tumor immune infiltration (p < 0.05) in pre- vs on-tx samples. Differential analysis identified several gene sets related to inflammation overexpressed in pre-tx samples only, including IFN response. On-tx samples were enriched in myogenesis and coagulation gene sets. Conclusions: This is the first study to describe transcriptomic changes following epigenetic tx in cCS. Contradictory to our preclinical data, HDACi + DNTMi resulted in low expression of inflammation. Prior studies reported that the immune infiltrate of CS at progression is immunosuppressive; higher immune infiltrate is correlated with worse outcomes (4). Loss of inflammation may have implications for disease stability experienced by most pts on NCI 10330. Further analyses are planned to correlate TME (pro- vs anti-inflammatory infiltrates) and outcomes. Analyses are limited by small sample size, highlighting the challenges in collecting adequate CS specimens. 1. Sheikh, Schwartz et al. Mol Cancer Ther 2021. 2. Lacuna et al. ASCO 2023: #11531. 3. Bagaev et al. Can Cell 2021. 4. Richert et al. J Bone Onc 2020. Clinical trial information: NCT04340843 .

11521 Background: Osteosarcomas (OS) comprise the majority of new primary bone tumors in the US and affect a bimodal distribution of young adults (2nd-3rd decades) and older adults >65 yrs. Most large collaborative studies demonstrating the efficacy of HDMTX-containing chemotherapy regimens in OS limited enrollment to patients <40 yrs. Our study aims to fill the gap of reported clinical outcomes in adult OS patients ≥ 40 yrs by describing the feasibility and tolerability of HDMTX in these patients at Mayo Clinic. Methods: We conducted a retrospective chart review of patients ≥18 yrs with OS seen at our institution between 1/1/1980-9/30/2019 and who received ≥1 dose of HDMTX (12 g/m2, max 20 g). Extraosseous OS were excluded. Survival analyses were run for both the entire study population and the subset of patients age ≥40. Patient demographics, disease characteristics, and clinical outcomes were collected. The primary outcome evaluated was 5-year overall survival (5-yr OS). Results: We identified 94 patients whose demographic data are summarized (Table). Twenty-three of 94 (24%) were ≥40 yrs. Both the median number of HDMTX doses received and number of patients who received ≥50% recommended doses were significantly less among patients ≥40 yrs. However, HDMTX-related AKI and median number of hospital days did not differ significantly between the age groups. Among all patients, 5-yr OS was significantly improved (p=0.0025) at 45% (95% CI 35%-58%) for those who received ≥50% doses HDMTX compared to 5-yr OS of 25% (95% CI 12%-53%) for those who did not. Among patients ≥40 yrs, 5-yr OS was significantly improved (p=0.017) at 86% (95% CI 63%-100%) for those who received ≥50% doses HDMTX compared to 5-yr OS of 31% (95% CI 14%-68%) for those who did not. Conclusions: In our cohort, 5-yr OS was superior in those patients who received at least 50% of the planned doses of HDMTX. Older adults were significantly less likely to receive the majority of planned doses, which may be due to clinician bias regarding anticipated toxicity. However, we show that common HDMTX-associated toxicities did not vary significantly by age. If feasible, we recommend referring older patients with osteosarcoma to centers equipped to handle the staffing and supportive care needs of HDMTX administration. [Table: see text]

Abstract Background Radiation‐associated soft tissue sarcomas (RA‐STS) are rare complications of patients receiving radiation therapy (RT) and are generally associated with a poor prognosis. Most of the literature surrounding RA‐STS of the chest is centered on angiosarcoma. Therefore, we aim to document the management and outcome of patients with non‐angiosarcoma RA‐STS of the chest. Methods We reviewed 17 patients (all female, median age 65 years) diagnosed with RA‐STS. The most common primary malignancy was breast carcinoma ( n = 15), with a median RT dose of 57.9 Gy. All patients underwent surgical resection; five patients (29%) received radiotherapy; and five patients (29%) received peri‐operative chemotherapy. Results The 5‐year local recurrence and metastatic‐free survival were 61% and 60%, while the 5‐year disease‐specific survival was 53%. Local recurrence was associated with death due to disease (HR 9.06, p = 0.01). Complications occurred in nine of patients, most commonly due to a wound complication ( n = 7). At the most recent follow‐up, the median Musculoskeletal Tumor Society Score was 63%. Conclusion RA‐STS involving the chest wall are aggressive tumors with a high risk of local relapse and death due to disease. Local recurrence was associated with death due to disease; as such, we recommend aggressive surgical management with evaluation for adjuvant therapies.

e23554 Background: Follicular dendritic cell sarcoma (FDCS) is a low-grade neoplasm arising from follicular dendritic cells. Its diagnosis is challenging due to its extreme rarity, and the optimal management remains unknown. Methods: We conducted a retrospective study of FDCS patients (pts) seen at Mayo Clinic, MN since 2018. Time to event analyses were done from the time of diagnosis. Results: Ten pts with FDCS were identified (Table). The median age was 60 years (range, 38-76) and 5 were males. Abdominal pain was the most common presenting symptom (30%) followed by constitutional symptoms, shortness of breath, and vision change. In 3 pts, the diagnosis was incidental. The 2 most common primary locations were abdomen/pelvis (50%) and mediastinum (30%). Six pts (60%) presented with advanced disease and 3 (30%) had Castleman’s disease. Most (60%) had advanced disease. Six pts had Epstein-Barr virus in situ hybridization and all tested negative. Seven pts had next generation sequencing and 5 (83%) had genetic alterations detected with CDKN2A/B alterations being most frequent (3 pts, all with advanced disease). The median follow up was 4.3 years (range, 0.2-13.3). In the 4 patients with localized disease, 3 underwent complete surgical excision resulting in complete remissions (CRs). The one who received radiation had a partial remission (PR). The median time to progression after 1st line treatment was 4 months (all with advanced disease). All 3 pts who died had advanced disease and 2 had CDKN2A/B alterations. Conclusions: In FDCS, localized diseases managed by surgical excision with or without radiation can achieve long term remissions. Advanced diseases generally do not respond to multimodality therapy including immunotherapy but can have disease stabilization with variable survival. CDKN2A/B mutations were common and potentially associated with a worse outcome. Better understanding of the impact of the FDCS mutational landscape on prognosis may provide novel approaches to therapy. [Table: see text]

Abstract Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ–CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE. Patients and Methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ– CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires. Results: 44 patients enrolled and 42 started trametinib. TAZ– CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094–19.0], median PFS was 10.4 months (95%CI, 7.1–NA), and 2-year OS rate was 33.3%(95%CI, 19.1–58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib. Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552