Desmoplastic Small Round Cell Tumor Patients Research Articles

Off-label use of fam-trastuzumab deruxtecan-nxki with early activity in a cohort of patients with desmoplastic small round cell tumor.

11584 Background: Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive sarcoma occurring predominantly in pediatric, adolescent and young adult biologic males, and is molecularly characterized by the pathognomonic EWSR1-WT1 fusion. Despite aggressive multi-modality therapy outcomes for those with DSRCT remain poor, and more effective therapies are urgently required. Prior pre-clinical data and transcriptomic analyses of DSRCT patients has suggested the relevance of the ERBB2 pathway in this disease, prompting the off-label use of fam-trastuzumab deruxtecan-nxki (T-DXd) in the treatment of patients of DSRCT patient with relapsed and refractory disease. Methods: Patients with relapsed/refractory DSRCT received T-DXd 5.4 mg/kg intravenously in 21-day cycles. Whole body PET and CT of the chest, abdomen and pelvis were used for monitoring. Response was correlated with HER2 immunohistochemistry (IHC) status and transcriptomic analysis by RNA sequencing (RNAseq) when available. Results: Seven patients received the agent, and at the time of submission 3 patients had at least one follow up imaging test after receiving between 6 and 9 cycles of T-DXd. Treatment was overall well tolerated with the only grade 3 toxicity of transaminitis (in patients with known liver metastases), which self-resolved. All other toxicities including constipation, nausea, and fatigue were grade 2 or less. All 3 patients have experienced clinical benefit including one patient with a RECIST 1.1 partial response and two patients with stable disease. Additionally, favorable responses were noted by PET imaging. Four additional patients with relapsed/refractory DSRCT have initiated off-label treatment with T-DXd and are pending imaging responses. 7/7 and 4/7 patients have available IHC and ERBB2 RNA expression data available respectively. All ERBB2 RNA expression data is elevated when compared with the median across all evaluated pediatric tumors in our institutional series. Conclusions: The use of anti-HER2 therapy in a limited and unselected group of heavily pre-treated DSRCT patients is demonstrating an early signal of activity with minimal toxicity and suggests that formal assessment as monotherapy or in other relevant combinations in clinical trials is warranted. Further correlation with IHC and RNAseq expression data may help optimize correlatives and/or generate biomarkers for future clinical trials.

Evaluating antitumor activity and response determinants to trastuzumab deruxtecan in pediatric solid tumors.

10049 Background: Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate (ADC) linked to a topoisomerase inhibitor FDA-approved for several indications, including the treatment of HER2+ breast and gastric cancer. Although HER2 amplification is uncommon in pediatric cancers, recent demonstration of T-DXd efficacy in HER2-low breast cancer patients prompted us to examine the potential clinical relevance of T-DXd in pediatrics by evaluating HER2 expression and activity of T-DXd in preclinical pediatric solid tumor models. Methods: Cell viability was assessed in a panel of histologically diverse pediatric solid tumor cell lines and 2 HER2-amplified adult cancer cell lines treated with T-DXd, payload (DXd), and a control IgG-ADC. HER2 protein expression in patient-derived xenograft (PDX) tumors was evaluated by immunohistochemistry (IHC) using 5 clinically validated anti-HER2 antibodies. RNAseq was performed on clinical (n=290) and PDX (n=184) tumors to determine relative expression of ERBB2. In vivo activity of T-DXd was evaluated in osteosarcoma (OS, n=10), Wilms tumor (WT, n=1) and malignant rhabdoid tumor (MRT, n=1) PDX models and a desmoplastic small round cell tumor (DSRCT) cell line xenograft model. Differences in tumor volume and time to disease progression was assessed and compared across treatments and models. Responses were correlated with HER2 expression by IHC. Results: In vitro, HER2-amplified control cell lines demonstrated a >30-fold reduction of IC50 when comparing T-DXd to ADC control. In contrast, the ADC control IC50 was nearly identical to T-DXd across all pediatric cancer cell lines, consistent with the absence of HER2 amplification in these models. We observed focal and membranous staining of HER2 by IHC in PDXs but was quite variable across antibodies tested: WT 0-17% HER2+ cases (n=6), MRT 0-40% (n=5), DSRCT 0-33% (n=24), OS 0-7% (n=30). ERBB2 gene expression was highest in DSRCT followed by WT, OS and MRT. In vivo efficacy studies demonstrated complete and partial responses in OS, WT, and DSRCT and improved disease control rates (OS: 67%, p=0.006, Mann-Whitney; WT: 100%; DSRCT: 100%). However, T-DXd and ADC control demonstrated similar activity in all tumor types with no consistent correlation between in vivo response and HER2 expression. Consistent with these preclinical studies, 4 patients with progressive DSRCT were treated with T-DXd via compassionate/off-label access with signs of clinical and radiographic responses. Conclusions: T-DXd shows significant preclinical antitumor activity across multiple pediatric solid tumors but little correlation with HER2 expression suggesting a mechanism of action similar to the clinical activity observed in HER2-low breast cancer. Xenograft efficacy studies and preliminary clinical experience with T-DXd in DSRCT patients warrant formal clinical trial investigation in this largely incurable disease.

Abstract 6: Defining and therapeutically targeting a fusion-derived public neoantigen in desmoplastic small round cell tumor using T cell receptor gene therapy

Abstract Sarcomas are a heterogenous group of mesenchymal cell malignancies that are difficult to treat and often respond poorly to current immunotherapies. Approximately 30% of sarcomas are associated with oncogenic driver fusion proteins. Desmoplastic small round cell tumor (DSRCT) is a prototypical fusion-driven sarcoma defined by a pathognomonic EWSR1-WT1 fusion event. The resultant EWSR1-WT1 fusion protein contains a shared junctional amino acid sequence that is clonally conserved and significantly divergent from normal human proteins. Consequently, the EWSR1-WT1 fusion might yield a highly immunogenic shared, or public, neoantigen (NeoAg) that may serve as a target for novel immunotherapeutic approaches.Using a functional HLA-immunoprecipitation/mass spectrometry (HLA-IP/MS) screen, we identified a 9-amino acid peptide sequence derived from the junction of the most common EWSR1-WT1 fusion protein that is presented in the context of the prevalent HLA-A*03 and -A*11 alleles. We confirmed that HLA-A*03+ DSRCT cells physiologically present the same peptide sequence. Using fluorophore-conjugated HLA-multimers loaded with the HLA-IP/MS-derived fusion NeoAg, we identified a rare population of circulating NeoAg-specific CD8+ T cells in HLA+ DSRCT patients. Through antigen-directed clonal expansion, we discovered n=3 HLA-A*03-restricted and n=1 HLA-A*11-restricted fusion NeoAg-specific T cell clones and retrieved the paired TCRαβ gene sequences of their T cell receptors (TCRs) using 10x single-cell sequencing. Polyclonal CD8+ T cells transduced with candidate TCRαβ gene sequences robustly upregulated TNFα after coculture with HLA+/Fusion+ target cells but not HLA−/Fusion+ or HLA+/Fusion− control cells. Further, T cells expressing candidate TCRs, but not viral-protein-specific TCRs, lysed HLA+ DSRCT cells in vitro and controlled established DSRCT tumors in vivo. Finally, we discovered that one TCR was capable of cross HLA allele fusion NeoAg recognition and could lyse both HLA-A*03+ and -A*11+ DSRCT cells. These findings imply that a single TCR therapeutic could cover >36% of North American DSRCT patients.Collectively, our data establish for the first time that DSRCT cells present a junction-spanning fusion-derived neoantigen in the context of two prevalent HLA alleles that may be therapeutically targeted using TCR gene therapy. These data lay the foundation for first-in-human clinical translation of a T-cell based therapy targeting EWSR1-WT1. More broadly, these findings establish proof-of-principle that recurrent fusion proteins are an actionable source of immunogenic public NeoAgs, providing a framework for developing targeted immunotherapies for other fusion-driven malignancies. Citation Format: Lauren Banks, Hannah Arkin, Smita Chandran, Emily Slotkin, Madelyn Espinosa-Cotton, Neerav Shukla, Luc Morris, Marc Ladanyi, Andrew Kung, Martin Klatt, Christopher Klebanoff. Defining and therapeutically targeting a fusion-derived public neoantigen in desmoplastic small round cell tumor using T cell receptor gene therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6.

Establishment of predictive nomogram and web-based survival risk calculator for desmoplastic small round cell tumor: A propensity score-adjusted, population-based study.

Desmoplastic small round cell tumor (DSRCT) is a rare undifferentiated malignant soft tissue tumor with a poor prognosis and a lack of consensus on treatment. This study's objective was to build a nomogram based on clinicopathologic factors and an online survival risk calculator to predict patient prognosis and support therapeutic decision-making. A retrospective cohort analysis of the Surveillance, Epidemiology and End Results (SEER) database was performed for patients diagnosed with DSRCT between 2000 and 2019. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to identify the individual variables related to overall survival (OS) and cancer-specific survival (CSS), as well as to construct online survival risk calculators and nomogram survival models. The nomogram was employed to categorize patients into different risk groups, and the Kaplan-Meier method was utilized to determine the survival rate of each risk category. Propensity score matching (PSM) was used to assess survival with different therapeutic approaches. A total of 374 patients were included, and the median OS and CSS were 25 (interquartile range 21.9-28.1) months and 27 (interquartile range 23.6-30.3) months, respectively. The nomogram models demonstrated high predictive accuracy. PSM found that patients with triple-therapy had better CSS and OS than those who received surgery plus chemotherapy (median survival times 49 vs 34 months and 49 vs 35 months, respectively). The nomogram successfully predicted the DSRCT patients survival rate. This approach could assist doctors in evaluating prognoses, identifying high-risk populations, and implementing personalized therapy.

Establishment of predictive nomogram and web-based survival risk calculator for desmoplastic small round cell tumor: A propensity score-adjusted, population-based study.

Desmoplastic small round cell tumor (DSRCT) is a rare undifferentiated malignant soft tissue tumor with a poor prognosis and a lack of consensus on treatment. This study's objective was to build a nomogram based on clinicopathologic factors and an online survival risk calculator to predict patient prognosis and support therapeutic decision-making. A retrospective cohort analysis of the Surveillance, Epidemiology and End Results (SEER) database was performed for patients diagnosed with DSRCT between 2000 and 2019. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to identify the individual variables related to overall survival (OS) and cancer-specific survival (CSS), as well as to construct online survival risk calculators and nomogram survival models. The nomogram was employed to categorize patients into different risk groups, and the Kaplan-Meier method was utilized to determine the survival rate of each risk category. Propensity score matching (PSM) was used to assess survival with different therapeutic approaches. A total of 374 patients were included, and the median OS and CSS were 25 (interquartile range 21.9-28.1) months and 27 (interquartile range 23.6-30.3) months, respectively. The nomogram models demonstrated high predictive accuracy. PSM found that patients with triple-therapy had better CSS and OS than those who received surgery plus chemotherapy (median survival times: 49 vs 34 months and 49 vs 35 months, respectively). The nomogram successfully predicted the DSRCT patients survival rate. This approach could assist doctors in evaluating prognoses, identifying high-risk populations, and implementing personalized therapy.

A phase I/II study of prexasertib in combination with irinotecan in patients with relapsed/refractory desmoplastic small round cell tumor and rhabdomyosarcoma.

11503 Background: Prexasertib (PRX) is an inhibitor of CHK1, prevents DNA repair leading to mitotic catastrophe, and can enhance the activity of DNA-damaging chemotherapy. Translocation driven sarcomas exhibit high levels of replication stress and have demonstrated susceptibility to CHK1 inhibition in preclinical models. Desmoplastic small round cell tumor (DSRCT) and rhabdomyosarcoma (RMS) are aggressive sarcomas of children, adolescents and young adults for which novel therapies are urgently required. Methods: We conducted a phase I/II trial of PRX with irinotecan (irino) in patients ≥ 12 months of age with relapsed or refractory DSRCT or RMS. Eligible patients could have any number of prior therapies, including irino. Dose level 1 was PRX 80 mg/m2 on day 1 + irino 20 mg/m2 for 10 days. Dose levels 2 and 2A were PRX 105 or 150 mg/m2 (>21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 10 (level 2) or 5 (level 2A) days. All cycles were 21 days. The primary objectives were to determine the RP2D of PRX with irino, and to determine the best overall response rate (ORR) in 6 months at the RP2D (RECIST v1.1) in DSRCT, with 3 or more responses out of 16 considered promising. Results: 21 patients were enrolled (DSRCT: 19; 2 RMS:2). The RP2D was dose level 2A. Treatment was well tolerated with the most common adverse events being neutropenia (48%), nausea (48%), and fatigue (52%). Cytopenias were managed with the aid of growth factor support in all patients once the RP2D was established. The DSRCT expansion enrolled 13 of 16 planned patients due to discontinuation of PRX supply prior to study completion. Four patients remain on therapy at the time of this submission. Responses in DSRCT patients at all dose levels are shown in Table. Sixteen of 21 enrolled patients, and 5 of 6 patients achieving PR had previously received irino. The median (range) number of cycles was 7 (2-26). Both RMS patients treated at the RP2D experienced SD as best response. The estimated ORR at the RP2D was 23%, and lower boundary of the one-sided 90% confidence interval was 9%, exceeding the unpromising rate of 5%. The two-sided 90% confidence interval was 7 to 49%. In addition, 3 patients had a PR at doses lower than the RP2D, bringing the ORR for all dose levels (n = 19) to 32% (90%CI: 15 to 53%). Conclusions: The RP2D of PRX in combination with irino is PRX 105 or 150 mg/m2 (>21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 5 days in 21 day cycles with myelosuppression successfully managed with growth factor support. The study met its primary objective to consider PRX + irino promising in DSRCT and should be further investigated. Clinical trial information: NCT04095221. [Table: see text]

Multi-site desmoplastic small round cell tumors are genetically related and immune-cold

Desmoplastic small round cell tumor (DSRCT) is a highly aggressive soft tissue sarcoma that is characterized by the EWSR1-WT1 fusion protein. Patients present with hundreds of tumor implants in their abdominal cavity at various sites. To determine the genetic relatedness among these sites, exome and RNA sequencing were performed on 22 DSRCT specimens from 14 patients, four of whom had specimens from various tissue sites. Multi-site tumors from individual DSRCT patients had a shared origin and were highly related. Other than the EWSR1-WT1 fusion, very few secondary cancer gene mutations were shared among the sites. Among these, ARID1A, was recurrently mutated, which corroborates findings by others in DSRCT patients. Knocking out ARID1A in JN-DSRCT cells using CRISPR/CAS9 resulted in significantly lower cell proliferation and increased drug sensitivity. The transcriptome data were integrated using network analysis and drug target database information to identify potential therapeutic opportunities in EWSR1-WT1-associated pathways, such as PI3K and mTOR pathways. Treatment of JN-DSRCT cells with the PI3K inhibitor alpelisib and mTOR inhibitor temsirolimus reduced cell proliferation. In addition, the low mutation burden was associated with an immune-cold state in DSRCT. Together, these data reveal multiple genomic and immune features of DSRCT and suggest therapeutic opportunities in patients.

Desmoplastic Small Round Cell Tumors With EWS-WT1 Transcript Expression: Should We Consider Children and Adult Patients Differently?

Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma occurring in the young, teenager, and adult populations. The aim of this study is to compare initial tumor presentation, therapeutic management and scalability between pediatric and adult DSRCT patients and investigate the possibility of specific therapeutic approaches. A multicenter retrospective study of 81 Franco-Belgian medical files with DSRCT harboring Ewing sarcoma-Wilm tumor transcript was made. Median age was 17 years (3 to 58) with 42 children (13.5 y [3;17]) and 39 adults (28 y [18;58]). No significant differences were found between the 2 groups regarding initial symptoms and metastasis at diagnosis. The therapeutic approaches were similar for both groups: use of neoadjuvant chemotherapy (78.6% vs. 79.5%, P=1), primary surgery (71.4% vs. 69.2%, P=0.73), adjuvant chemotherapy (54.8% vs. 61.5%, P=0.99), radiotherapy (23.8% and 10.3%, P=0.11) and intraperitoneal chemotherapy (14.3% vs. 2.6%; P=0.11). Median time to recurrence was 12 versus 18 months (P=0.13). Overall survival at 2 years and recurrence free were 46.4% versus 60.1% (P=0.83) and 14.3% versus 16%, respectively (P=0.16). Clinical presentation, initial therapeutics and outcome of DSRCT are equivalent suggesting that similar management should be considered for children and adults with DSRCT.

Genomic and transcriptomic characterization of desmoplastic small round cell tumors.

Desmoplastic small round cell tumor (DSRCT) is a highly aggressive soft tissue tumor primarily affecting children and young adults. Most cases display a pathognomonic EWSR1-WT1 gene fusion, presumably constituting the primary driver event. Little is, however, known about secondary genetic changes that may affect tumor progression. We here studied 25 samples from 19 DSRCT patients using single nucleotide polymorphism arrays and found that all samples had copy number alterations. The most common imbalances were gain of chromosomes/chromosome arms 1/1q and 5/5p and loss of 6/6q and 16/16q, all occurring in at least eight of the patients. Five cases showed homozygous deletions, affecting a variety of known tumor suppressor genes, for example, CDKN2A and NF1. As almost all patients died of their disease, the impact of individual imbalances on survival could not be evaluated. Global gene expression analysis using mRNA sequencing on fresh-frozen samples from seven patients revealed a distinct transcriptomic profile, with enrichment of genes involved in neural differentiation. Two genes - GJB2 and GAL - that showed higher expression in DSRCT compared to control tumors could be further investigated for their potential as diagnostic markers at the protein level.

Mini-Review on Targeted Treatment of Desmoplastic Small Round Cell Tumor.

Desmoplastic small round cell tumor (DSRCT) is a devastating disease which most commonly affects adolescents, with a male predominance. Despite the best multimodality treatment efforts, most patients will ultimately not survive more than 3–5 years after diagnosis. Some research trials in soft-tissue sarcoma and Ewing sarcoma include DSRCT patients but few studies have been tailored to the specific clinical needs and underlying cytogenetic abnormalities characterizing this disease such as the typical EWSR1-WT1 gene fusion. Downstream activation of EWSR1-WT1 gene fusion includes signaling pathways of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and insulin growth factor (IGF)-1. Other biological pathways that are activated and expressed in DSRCT cells include endothelial growth factor receptor (EGFR), androgen receptor pathway, c-KIT, MET, and transforming growth factor (TGF) beta. Investigation of somatic mutations, copy number alterations (CNA), and chromosomes in DSRCT samples suggests that deregulation of mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) and DNA damage repair (DDR) may be important in DSRCT. This mini review looks at known druggable targets in DSRCT and existing clinical evidence for targeted treatments, particularly multityrosine kinase inhibitors such as pazopanib, imatinib, and sorafenib alone or in combination with other agents such as mTOR (mammalian target of rapamycin) inhibitors. The aim is to increase shared knowledge about current available treatments and identify gaps in research to further efforts toward clinical development of targeted agents.

Expression profiles of exosomal miRNAs isolated from plasma of patients with desmoplastic small round cell tumor.

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive mesenchymal tumor, lacking biomarkers for diagnosis, treatment stratification and prognosis. We investigated the exosomal miRNA profile in plasma samples collected from DSRCT patients, evaluating their potential as circulating biomarkers for this tumor. We isolated exosomes from plasma of three DSRCT adolescents and four age-matched healthy controls; expression of circulating miRNAs was quantified by qPCR. We identified 55 miRNAs significantly modulated compared with healthy controls. Among these miRNAs, 14 were highly dysregulated in at least one patient and 5 were expressed in all patients. To our knowledge, this is the first report describing exosomal miRNAs as promising biomarkers to characterize disease status in DSRCT patients.

Anesthesia and Pain Management for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Desmoplastic Small Round Cell Tumors in Children, Adolescents, and Young Adults

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may improve survival. A retrospective review of anesthetic management and postoperative pain control strategies after CRS/HIPEC for DSRCT from 2013 to 2017 was performed. The review analyzed 10 CRS/HIPEC procedures performed for nine DSRCT patients with a median age of 19years (range 10-24years). Six of these patients were Caucasian, and seven were men. The median operative duration was 551min (range 510-725min), and the median anesthesia duration was 621min (range 480-820min). Postoperative mechanical ventilation was necessary in 5 patients for a median duration of 1day (range 0-2days). The median intraoperative intravenous fluid administration was 13ml/kg/h (range 6.3-24.4ml/kg/h), and the colloid administration was 12ml/kg (range 0.0-53.0ml/kg). The median blood loss was 15ml/kg (range 6.3-77.2ml/kg). Nine patients received intraoperative transfusion with a median red blood cell transfusion volume of 14ml/kg (range 10.1-58.5ml/kg). The median intraoperative urine output was 2ml/kg/h (range 0.09-8.40ml/kg/h), and half of the patients received intraoperative diuretics. Cisplatin was used during HIPEC for eight surgeries. Acute kidney injury was observed in two patients, one of whom required short-term dialysis. Epidural infusions were used in eight cases for a median of 4days (range 3-5days). Postoperative intravenous opioid use (morphine equivalent) was 0.67mg/kg/day (range 0.1-9.2mg/kg/day) administered for a median of 11days (range 2-35days). Cytoreduction and HIPEC for DSRCT are associated with significant perioperative fluid requirements and potentially challenging pain management. Renal protective strategies should be considered for reduction of cisplatin-associated nephrotoxicity. Further investigation for a more effective, less systemically toxic HIPEC agent is warranted.

Abstract CT006: Intraperitoneal radioimmunotherapy for desmoplastic small round cell tumor: Results of a phase I study (NCT01099644)

Abstract Background / Objectives: Desmoplastic small round cell tumor (DSRCT), a rare sarcoma of adolescents and young adults, has a long-term survival of <20% despite aggressive multimodality therapy, warranting a search for novel treatments. The murine monoclonal IgG1 antibody 8H9 recognizes cell surface antigen 4Ig-B7H3 and binds to 96% of DSRCTs with restricted normal tissue reactivity. DSRCT recurrences often present as multifocal peritoneal implants. We hypothesized that intraperitoneal (IP) radioimmunotherapy (RIT) by virtue of prolonged residence time and slow transfer to the circulation, may selectively target IP DSRCT. Design / Methods: We conducted a phase I study of radioiodinated 8H9 to evaluate toxicity, pharmacokinetics, biodistribution and efficacy. Cohorts of 3-6 patients were treated with escalated doses of IP 131I-8H9. A prior dose of 2mCi 124I-8H9 IP was used to acquire PET images and biodistribution data. Toxicity was monitored clinically and biochemically. Pharmacokinetics was studied using serial blood draws. Results: Forty-one DSRCT patients were treated at doses of 30-90mCi/m2. Maximum tolerated dose was not reached; there were no dose-limiting toxicities. Major adverse events (n=1 each) were transient: grade 3 transaminitis, neutropenia, and thrombocytopenia. Blood and peritoneal half-times were 32.5h and 14.6h respectively. Mean projected absorbed doses to blood, kidney, liver, lung and spleen were 0.7,1.72,1.92,0.64 and 1.03 rad/mCi 131I-8H9 respectively (n=12 patients analyzed). Dehalogenation was insignificant: >80% blood 131I remained protein-bound 66h post-RIT. Recommended phase II dose was 80mCi/m2. External beam intensity-modulated whole-abdominopelvic radiotherapy (WAP-IMRT) to 3000cGy was administered after protocol therapy to 25 patients without unexpected adverse events. Median progression-free survival (PFS) from RIT for first remission patients (n=21) undergoing gross total resection followed by RIT and whole-abdominal radiotherapy was 17.9±1.7 months. Of these, 19 and 13 patients are PF and overall survivors respectively at a median of 13 months post-RIT. In contrast patients with gross residual disease pre-RIT or those receiving RIT in ≥2nd remission (n=20) had median PFS of 8.1±3.5 months (p<0.05 for PFS and OS). Conclusions: 124I-8H9-directed radioimmuno-PET successfully determined biodistribution, whole-body and organ exposure. 131I-8H9 IP RIT had a satisfactory safety profile and appears to have activity against micro-metastatic DSRCT. A phase II trial combining IP RIT and WAP-IMRT will commence shortly. Citation Format: Shakeel Modak, Jorge Carrasquillo, Michael LaQuaglia, Zanzonico Pat, Todd Heaton, Nai-Kong Cheung, Neeta Pandit-Taskar. Intraperitoneal radioimmunotherapy for desmoplastic small round cell tumor: Results of a phase I study (NCT01099644) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT006.

Les tumeurs desmoplastiques à petites cellules rondes de l’enfant, de l’adolescent et du jeune adulte

Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma that typically affects pediatric and young adult patients with a median age in the general and in the pediatric population of 24.6 years (range 4-58 years) and 15.0 years (range 0-21 years) respectively, with a strong male predominance. This tumor is characterized by a specific t(11;22)(p13;q12) that results in fusion of EWS and WT1 genes which can be demonstrated by RT-PCR or by FISH. DSRCT most frequently presents as an intra-abdominal primary mass associated with peritoneal seeding and a highly aggressive pattern of spread. Generally, all tumors showed the typical histologic findings of variably sized clusters of poly-phenotypic small, round, or spindled cells lying in a desmoplastic stroma. Treatment of this malignancy remains a challenge. The combination of polychemotherapy regimens and aggressive surgery followed by whole abdomen radiation therapy represents nowadays a classical protocol for DSRCT. The survival rate of DSRCT patients is still disappointing around 20%. However, the survival of patients who had complete resection of the tumor appears better. Hopes are turning to targeted therapeutics against this simple genomic sarcoma. Authors summarize medical knowledge of this rare tumor.

Clinical Activity of Pazopanib in Patients with Advanced Desmoplastic Small Round Cell Tumor.

Desmoplastic small round cell tumor (DSRCT) is an aggressive, often fatal soft tissue sarcoma that lacks an optimal salvage regimen. We retrospectively reviewed data from 29 pretreated DSRCT patients who received pazopanib at MD Anderson Cancer Center after failure of standard chemotherapies. Medical records of patients treated from January 2012 to December 2016 were reviewed and regression analyses were performed. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and differences in survival were assessed by a log-rank test. A landmark statistical analysis was used to assess OS at a predefined 12-week time point following pazopanib initiation. The mean age at pazopanib treatment was 27.5 years (range, 6.3-50.1 years). According to RECIST 1.1 criteria, 16 patients (55%) had stable disease, 1 patient (3%) had partial response, 1 patient (3%) had complete response, and 11 patients (38%) had progressive disease. Estimated median PFS was 5.63 months (95% confidence interval [CI]: 3.23-7.47). Median OS was 15.7 months (95% CI: 10.3-32.4). As of December 2016, 11 patients (38%) were still alive, with a median follow-up time of 16.8 (range 3.8-30.1) months. Doses between 400 and 800 mg were included. Pazopanib was well tolerated and 23 (79%) of the patients continued it until progression or death, 4 discontinued because of side effects, and 2 were still on pazopanib at the time of data analysis. In the largest study conducted to date in DSRCT, pazopanib was well tolerated and clinically active in heavily pretreated patients who otherwise lack good treatment options. Desmoplastic small round cell tumor (DSRCT) is a rare, extremely aggressive soft tissue sarcoma subtype that most commonly occurs in adolescent and young adult males. No DSRCT-specific therapies exist, and for lack of a better treatment approach, current therapies have relied upon U.S. Food and Drug Administration-approved drugs like pazopanib that exhibit clinical activity in other sarcoma subtypes. This article describes the largest experience to date using pazopanib as salvage treatment in heavily pretreated DSRCT patients. Pazopanib was well tolerated and clinically active, surpassing predefined metrics proposed by the European Organization for Research and Treatment of Cancer indicative of "active" sarcoma drugs (5.63 months progression-free survival [PSF], with 62% of the study population achieving progression-free survival at 12 weeks).

Desmoplastic small round cell tumor of the abdomen and pelvis: clinicopathological characters of 12 cases.

Purpose. To study the clinical, radiological, and pathological characteristics of abdominal desmoplastic small round cell tumor (DSRCT) and investigate the optimal therapy modalities. Patients and Methods. A retrospective cohort study was performed on 12 abdominal DSRCT patients; all pathological, radiological, and prognostic data were analyzed. There were 3 patients (25%) with metastatic disease at presentation. In all 12 cases, 6 cases underwent operation and adjuvant chemotherapy (group 1, 6/12, 50%). The other 6 cases were diagnosed by fine needle aspiration or exploratory laparotomy biopsy (group 2, 6/12, 50%); all cases received four to six courses of multiple agents chemotherapy, respectively. Results. All cases were finally diagnosed as DSRCT pathologically. Among group 1, all cases underwent en bloc resection (2/6, 33%) or tumor debulking (4/6, 67%) and, following four courses of multiple agents chemotherapy, Kaplan-Meier analysis revealed that 3-year survival was 50% in group 1 versus 16.7% in group 2 (P < 0.05). Gross tumor resection was highly significant in prolonging overall survival; patients with localized solitary lesion have a better prognosis, most likely due to increased feasibility of resection. Conclusions. DSRCT is a rare malignant tumor with poor prognosis. Surgical excision with combination chemotherapy as an adjunct is mandatory for nonmetastatic cases because these modalities used in isolation may have less impact.

Intraperitoneal radioimmunotherapy (RIT) for desmoplastic small round cell tumor (DSRCT): Initial results from a phase I trial.

3033 Background: DSRCT, a rare sarcoma of adolescents and young adults usually arising from the peritoneum, is lethal in &gt;80% of patients despite aggressive multimodality therapy. Recurrences often present as multifocal peritoneal implants, making it uniquely suited for intraperitoneal (IP) targeting. We hypothesized that targeted radiotherapy may improve local control and reduce relapses. IP RIT, by virtue of prolonged residence time and slow transfer to the circulation, may selectively target IP DSRCT while minimizing organ toxicity. The anti-4Ig-B7H3 murine monoclonal antibody 8H9 binds to 96% of primary DSRCT (Med Pediatr Oncol 39:547). 131I-8H9 injected intra-Ommaya is safe (J Neurooncol 97:409). Methods: We initiated a phase I study to test the safety of IP RIT with 131I-8H9. Cohorts of 3-6 patients were treated with 131I-8H9 at escalated doses from 30mCi/m2-60mCi/m2 as a single IP injection. A tracer dose of 2mCi124I-8H9 was given IP before 131I-8H9 to acquire PET images and biodistribution data. Pharmacokinetics (PK) was studied using serial blood draws. Results: 15 heavily prior-treated patients: 13 with DSRCT, 2 with rhabdomyosarcoma received 30, 40, 50mCi/m2 131I-8H9 (3 at each dose level) or 60mCi/m2 (n=6). Dose-limiting toxicity was not seen. Three patients (n=1 each) had transient, self-limiting, possibly therapy-related grade 3 toxicities: neutropenia, hepatic transaminase elevation and thrombocytopenia. No patient required hematopoietic stem cell rescue. Blood half life was 32.5±11.5h (n=12) and mean peritoneal residence time was 14.6h (n=3). Mean absorbed dose to blood based on blood sampling was 0.56±0.21 rad/mCi (n=14). Mean absorbed doses (rad/mCi) to kidney, liver, lung and spleen were 1.72, 1.92, 0.64 and 1.03 respectively (n=3). Dehalogenation was insignificant: &gt;80% iodine remained protein-bound in blood (n=10). 6/7 DSRCT patients treated without evaluable disease remain in remission at a median of 11.1 months post 131I-8H9. Conclusions: IP 131I-8H9 was safe and 124I-8H9 provided valuable PK and dosimetry data. Since maximum tolerated dose was not reached we have expanded patient accrual to a planned dose of 90mCi/m2. Clinical trial information: NCT01099644.

The diagnosis and management of desmoplastic small round cell tumor: a review

Desmoplastic small round cell tumor (DSRCT) is a rare disease of children, adolescents and young adults, which begins in the abdominal cavity. Less than 200 cases are reported in the world literature. Because of the rarity of this disease, little is known about optimal treatment. Patients may present with dozens to hundreds of tumors studding the peritoneal cavity. Despite this presentation, it is not primarily considered metastatic but multifocal. It can metastasize to the liver or lung. Chemotherapy, radiotherapy, and surgical approaches have not been standardized. Neoadjuvant chemotherapy often yields a partial response; however, tumors may remain surgically un-resectable. An aggressive approach to treatment is required to maximize long-term remission. This review is designed to outline the evidence-based multidisciplinary approach to DSRCT. Complete surgical resection, including 1-2 mm implants, is necessary to achieve long-term disease control. Hyperthermic intraperitoneal chemotherapy using cisplatin has recently been found to be a low morbidity treatment option for DSRCT patients. Yttrium microspheres have been used successfully to treat liver metastasis from DSRCT. DSRCT is a rare tumor that requires a multidisciplinary approach which includes aggressive surgical extirpation to provide long-term disease control.

Desmoplastic Small Round Cell Tumor: A Clinical, Pathological, and Immunohistochemical Study of 18 Chinese Cases

Desmoplastic small round cell tumor (DSRCT) was first reported in 1989. Generally, DSRCT is considered to be an aggressive malignant neoplasm that mainly occurs in the abdominal cavity and has been often seen in adolescents and young male adults. In the present study, a total of 18 cases of DSRCT reported in China between October 1998 and June 2006, including one case treated by the authors, were reviewed and analyzed. Among them, 14 had tumors in the abdominal cavity; the other four cases had tumors in the left fossa orbitalis, the root of the tongue, the soft tissue behind the left eyeball, and the abdominal wall (umbilicus). Overall, the 1-year, 3-year, and 5-year survival rates were 52.36%, 27.92%, and 27.92%, respectively. The survival rate of DSRCT patients is disappointing; however, the survival of patients who had resection of the tumor or received comprehensive clinical treatment is satisfactory.

Androgen and c-Kit receptors in desmoplastic small round cell tumors resistant to chemotherapy: novel targets for therapy

Desmoplastic small round cell tumor (DSRCT) is a highly fatal, mainly peritoneal cell origin cancer which predominantly affects young adult males. This predilection in young males led us to examine the role of androgen receptors (AR), testosterone, and growth factors in the biology of DSRCT. Slides were prepared from 27 multi-institutional patients all with end-stage DSRCT. Slides were stained for AR, c-Kit, various growth factors, and drug resistance-associated proteins. Immunohistochemical (IHC) expression was scored semi-quantitatively. Western blot and MTT studies were performed to validate the IHC findings of over-expression of the AR and its functional status by stimulation of growth by dihydrotestosterone, respectively. Six patients with positive AR status were treated solely with combined androgen blockade (CAB) as used for prostate cancer. Twenty-two patients were male (81%) and five were female (19%) with a median age at diagnosis of 23. All patients had failed at least two prior multi-agent chemotherapy regimens and 44% had progressed after autologous stem cell transplant. DSRCT samples from 10 of 27 patients were >or=2+ IHC positive for AR (37%,P=0.0045) and 7 of 20 patients were >or=2+ IHC positive for c-Kit (35%, P=0.018). We found elevated IHC expression of GST-pi, MRP and thymidylate synthase in smaller subsets of patients. In vitro studies for AR by Western blot and stimulation of growth by dihydrotestosterone in MTT assays suggest that the AR in DSRCT cells is functional. Six patients with positive AR status were treated with CAB alone and three of six attained clinical benefit (1-PR, 1-MR, 1-SD) in a range of 3-4 months. The three patients who responded to CAB had normal testosterone levels before CAB, while the three who did not respond to CAB had baseline castrate levels of testosterone. DSRCT has significant IHC expression of AR and c-Kit in heavily pre-treated patients. The presence of significant AR expression in 37% suggests that these patients could possibly respond to CAB. The significance of c-Kit expression in 35% of DSRCT patients is unknown and warrants further investigation.