Identification of a distinct epigenetic subgroup with inferior PFS in intracranial mesenchymal tumors with FET::CREB fusion.

‘Intracranial mesenchymal tumor, FET‐CREB fusion‐positive’ occurs primarily in children and young adults and has previously been termed intracranial angiomatoid fibrous histiocytoma (AFH) or intracranial myxoid mesenchymal tumor (IMMT). Here we performed genome‐wide DNA methylation array profiling of 20 primary intracranial mesenchymal tumors with FET‐CREB fusion to further study their ontology. These tumors resolved into two distinct epigenetic subgroups that were both divergent from all other analyzed intracranial neoplasms and soft tissue sarcomas, including meningioma, clear cell sarcoma of soft tissue (CCS), and AFH of extracranial soft tissue. The first subgroup (Group A, 16 tumors) clustered nearest to but independent of solitary fibrous tumor and AFH of extracranial soft tissue, whereas the second epigenetic subgroup (Group B, 4 tumors) clustered nearest to but independent of CCS and also lacked expression of melanocytic markers (HMB45, Melan A, or MITF) characteristic of CCS. Group A tumors most often occurred in adolescence or early adulthood, arose throughout the neuroaxis, and contained mostly EWSR1‐ATF1 and EWSR1‐CREB1 fusions. Group B tumors arose most often in early childhood, were located along the cerebral convexities or spinal cord, and demonstrated an enrichment for tumors with CREM as the fusion partner (either EWSR1‐CREM or FUS‐CREM). Group A tumors more often demonstrated stellate/spindle cell morphology and hemangioma‐like vasculature, whereas Group B tumors more often demonstrated round cell or epithelioid/rhabdoid morphology without hemangioma‐like vasculature, although robust comparison of these clinical and histologic features requires future study. Patients with Group B tumors had inferior progression‐free survival relative to Group A tumors (median 4.5 vs. 49 months, p = 0.001). Together, these findings confirm that intracranial AFH‐like neoplasms and IMMT represent histologic variants of a single tumor type (‘intracranial mesenchymal tumor, FET‐CREB fusion‐positive’) that is distinct from meningioma and extracranial sarcomas. Additionally, epigenomic evaluation may provide important prognostic subtyping for this unique tumor entity.

Intracranial mesenchymal tumor (IMT), FET::CREB fusion-positive is a provisional tumor type in the 2021 WHO classification of central nervous system tumors with limited information available. Herein, we describe five new IMT cases from four females and one male with three harboring an EWSR1::CREM fusion and two featuring an EWSR1::ATF1 fusion. Uniform manifold approximation and projection of DNA methylation array data placed two cases to the methylation class “IMT, subclass B”, one to “meningioma-benign” and one to “meningioma-intermediate”. A literature review identified 74 cases of IMTs (current five cases included) with a median age of 23 years (range 4–79 years) and a slight female predominance (female/male ratio = 1.55). Among the confirmed fusions, 25 (33.8%) featured an EWSR1::ATF1 fusion, 24 (32.4%) EWSR1::CREB1, 23 (31.1%) EWSR1::CREM, one (1.4%) FUS::CREM, and one (1.4%) EWSR1::CREB3L3. Among 66 patients with follow-up information available (median: 17 months; range: 1–158 months), 26 (39.4%) experienced progression/recurrences (median 10.5 months; range 0–120 months). Ultimately, three patients died of disease, all of whom underwent a subtotal resection for an EWSR1::ATF1 fusion-positive tumor. Outcome analysis revealed subtotal resection as an independent factor associated with a significantly shorter progression free survival (PFS; median: 12 months) compared with gross total resection (median: 60 months; p < 0.001). A younger age (< 14 years) was associated with a shorter PFS (median: 9 months) compared with an older age (median: 49 months; p < 0.05). Infratentorial location was associated with a shorter overall survival compared with supratentorial (p < 0.05). In addition, the EWSR1::ATF1 fusion appeared to be associated with a shorter overall survival compared with the other fusions (p < 0.05). In conclusion, IMT is a locally aggressive tumor with a high recurrence rate. Potential risk factors include subtotal resection, younger age, infratentorial location, and possibly EWSR1::ATF1 fusion. Larger case series are needed to better define prognostic determinants in these tumors.

Mesenchymal tumors of the central nervous system (CNS) include numerous entities, with different pathological features and biological behavior. Mesenchymal non-meningothelial tumors are rare and comprise neoplasms that are exclusive to the CNS or show peculiar features when occurring in the CNS compared with other sites. Within this group there are three new entities, classified on the basis of specific molecular alterations and included in the 5th edition of the WHO Classification of CNS Tumors: primary intracranial sarcoma; DICER1-mutant; CIC-rearranged sarcoma; intracranial mesenchymal tumor, FET::CREB fusion-positive. These tumors often show variable morphology, making diagnosis very challenging, although the implementation of molecular techniques has led to better characterization and more precise identification of these entities. However, many molecular alterations have yet to be discovered and some recently reported CNS tumors are currently missing an appropriate classification. Herein, we report the case of a 43-year-old man who presented with an intracranial mesenchymal tumor. Histopathological examination showed a wide spectrum of peculiar morphological features and a non-specific immunohistochemical profile. Whole transcriptome sequencing revealed the presence of a novel genetic rearrangement involving COX14 and PTEN genes, which has never been reported before in any other neoplasm. The tumor did not cluster in any defined methylation class of the brain tumor classifier, but resulted in a calibrated score of 0.89 for the methylation class “Sarcoma, MPNST-like”, when analyzed by the sarcoma classifier. Our study is the first to report about this tumor with unique pathological and molecular features, characterized by a novel rearrangement between COX14 and PTEN genes. Other studies are necessary in order to define it as a new entity or as a novel rearrangement involving recently described and incompletely characterized CNS mesenchymal tumors.

Introduction: Despite recent incremental advances, patients with small-cell lung cancer (SCLC) continue to have a poor prognosis, with a median overall survival (OS) of 12-20 months in limited-stage disease (LS-SCLC) and approximately 12 months in extensive-stage disease (ES-SCLC). In an attempt to improve the detection and monitoring of SCLC, assays of circulating tumor DNA (ctDNA) via blood-based next-generation sequencing (NGS) have been validated. In this study, we used a blood-based 14 gene SCLC ctDNA NGS panel to evaluate the prognostic significance of the diagnostic maximum ctDNA variant allele frequency (VAF), diagnostic mean ctDNA VAF, and time to ctDNA clearance while on first-line therapy. Design: In our previous work, we developed a ctDNA assay to sequence 14 genes (TP53, RB1, BRAF, KIT, NOTCH1-4, PIK3CA, PTEN, FGFR1, MYC, MYCL1, and MYCN) that are commonly mutated in SCLC. A total of 104 plasma samples were analyzed from a cohort of 14 patients with LS-SCLC who completed definitive chemoradiation (n=13) or surgical resection (n=1) and had an end-of-treatment blood collection within nine weeks (mean 10.5 days, range 0-63 days) of completion of definitive initial therapy. We used a Cox Proportional Hazards model to estimate the hazard ratio (HR) for progression-free survival (PFS) or death based on the diagnostic maximum ctDNA VAF, diagnostic mean ctDNA VAF, and time to ctDNA clearance on first-line therapy. Results: In our 14-patient cohort, we did not observe any association between progression or death and maximum diagnostic ctDNA VAF (PFS HR: 1.01, CI 0.97-1.05; OS HR: 1, CI 0.95-1.04) or mean diagnostic ctDNA VAF (PFS HR: 1.01, CI 0.94-1.08; OS HR: 0.99, CI 0.91-1.07). Of the specific mutations representing the maximum diagnostic ctDNA VAF, TP53 represented 14.2% (n=2), while the remaining included RB1 associated mutations (n=5), PIK3CA (n=1), MYCL1 amplification (n=1), or no ctDNA at diagnosis (n=5). Among patients with clearance of ctDNA during first-line therapy (n=9), delayed time to ctDNA clearance was associated with inferior PFS (HR 1.1, CI 1.01-1.19) and OS (HR 1.07, CI 1.01-1.15), with median time to clearance of 63 days (range 29-92 days). Notably, 3 patients cleared ctDNA on their first on-treatment draw at approximately 30 days (29, days, 29 days, and 32 days). These patients have had no evidence of relapse and all remain alive since the start of first-line treatment (1467, 965, and 383 days of follow-up). Of the patients who had disease recurrence, the median time to clearance on first-line therapy was 65 days and median time to progression was 249 days, with all but 1 patient succumbing to their disease (median OS 437 days). Conclusion: In patients with LS-SCLC, prolonged time to ctDNA clearance during first-line therapy is associated with inferior PFS and OS. Larger patient cohorts are needed to validate this finding. Citation Format: Christopher Cann, Prasad Kopparapu, Yingjun Yan, Anel Muterspaugh, Heidi Chen, Zhiguo Zhao, Sally York, Leora Horn, Kristen Ancell, Kenneth Wyman, Caterina Bertucci, Tristan Shaffer, Lauren Hodson, Kavita Garg, Seyed Ali Hosseini, Lee Lim, Christine M. Lovly, Wade Iams. Prolonged time to clearance of circulating-tumor DNA from patients with limited-stage small-cell lung cancer is associated with inferior progression-free and overall survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B20.

59 Background: In mCSPC, baseline CTC counts have been shown to correlate with PSA responses and progression free survival (PFS) in small studies in the context of androgen deprivation therapy (ADT) without modern intensification with docetaxel or novel hormonal therapy. Similar correlation of CTC count with PSA responses and PFS was recently reported from an ongoing phase 3 trial in mCSPC setting (SWOG1216) without reporting the association in the context of ADT intensification. Furthermore, none of these studies correlated CTCs with overall survival (OS). Herein we evaluated whether CTCs were associated with outcomes including OS in a real world mCPSC population treated with intensified as well as non-intensified ADT. Methods: Eligibility criteria: new mCSPC receiving ADT with or without intensification and enumeration of baseline CTCs by FDA cleared Cell Search CTC assay. The relationship between CTC counts (categorized as: 0, 1-4, and ≥5/7.5 ml) and both PFS and OS was assessed in the context of Cox proportional hazards models, both unadjusted and adjusted for age, Gleason, PSA at ADT initiation, de novo vs. non-de novo status, and ADT intensification vs. non-intensification therapy. Results: Overall 99 pts were identified. Baseline characteristics are summarized in Table. In unadjusted analyses, CTC counts of ≥5 as compared to 0 were strongly associated with inferior PFS (hazard ratio [HR] 3.38, 95% CI 1.85-6.18; p &lt; 0.001) and OS (HR 4.44 95% CI 1.63-12.10; p = 0.004). In multivariate analyses, CTC counts of ≥5 as compared to 0 continued to be associated with inferior PFS (HR 5.49, 95% CI 2.64-11.43; p &lt; 0.001) and OS (HR 4.00, 95% CI 1.31-12.23; p = 0.015). Within the ADT intensification subgroup also, high CTC counts were associated with poor PFS and OS. For PFS, the univariate HR for CTC ≥5 vs. 0 was 4.87 (95% CI 1.66-14.30; p = 0.004) and multivariate HR for CTC ≥5 vs. 0 was 7.43 (95% CI 1.92-28.82; p = 0.004). For OS, the univariate HR for CTC ≥5 vs. 0 was 15.88 (95% CI 1.93-130.58; p = 0.010) and multivariate HR for CTC ≥5 vs. 0 was 24.86 (95% CI 2.03-304.45; p = 0.012). Conclusions: To best of our knowledge this is the first study to show that high baseline CTC counts are strongly associated with inferior PFS as well as OS in pts with newly diagnosed mCSPC, even in those who received intensified ADT therapy. Identifying these pts at highest risk of progression and death can help with counselling and prognostication in clinics as well as design and enrollment in future clinical trials. [Table: see text]

Intracranial mesenchymal tumors with FET‐CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET‐CREB fusion by next‐generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4–70). Tumors were uniformly extra‐axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1‐ATF1 fusion, seven had EWSR1‐CREB1, four had EWSR1‐CREM, and one had FUS‐CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1‐CREB1 fusions more often featured stellate/spindle cell morphology, mucin‐rich stroma, and hemangioma‐like vasculature compared to tumors with EWSR1‐ATF1 fusions that most often featured sheets of epithelioid cells with mucin‐poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression‐free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1‐ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET‐CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma‐like neoplasms.

Intracranial mesenchymal tumors with female expressed transcript::cyclic AMP responsive element binding protein (FET::CREB) fusion, characterized by Ewing sarcoma breakpoint region 1/EWS RNA binding protein 1 (EWSR1) rearrangements, represent a rare and complex category of neoplasms with varied morphologies and significant diagnostic challenges. These tumors commonly occur in young adults, presenting as dural-based masses with solid and cystic components on radiological imaging, often mimicking meningioma. Histopathologically, they exhibit a spectrum of features, including spindle, stellate, and epithelioid cells within myxoid or collagenous stroma, occasionally with hemangioma-like vasculature or chronic inflammatory infiltrates. Immunohistochemistry typically reveals strong positivity for cluster of differentiation 99 (CD99) and epithelial membrane antigen (EMA), with variable expression of Desmin, S100, and MUCIN 4 (MUC4). Molecular studies confirm EWSR1 rearrangements via fluorescence in situ hybridization (FISH), while RNA sequencing further elucidates specific fusion partners, such as cyclic AMP response element binding protein (CREB)1 or ATF1. Differential diagnosis includes solitary fibrous tumors, inflammatory myofibroblastic tumors, and chordoid meningiomas, necessitating thorough morphological and immunohistochemical analysis. Emerging genomic profiling divides these tumors into two epigenetic subgroups with distinct molecular and clinical profiles, influencing prognosis and progression-free survival. This case series highlights five instances of such tumors, underscoring the importance of recognizing their unique histopathological and molecular characteristics for accurate diagnosis. While the study employed FISH for cost-effective analysis, the absence of RNA sequencing limits identification of fusion partners. Overall, the study contributes valuable insights into these rare tumors, advancing understanding of their pathology and potential clinical implications.

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Intracranial mesenchymal tumor, FET-CREB fusion positive, is a newly recognized and rare CNS tumor that occurs primarily in children and young adults. It is regarded as the intracranial variant of angiomatoid fibrous histiocytoma. Extracranial angiomatoid fibrous histiocytomas are typically located in the extremities and usually discernible on a 18 F-FDG PET/CT scanning. We present a 50-year-old man with recurrence of a primary intracranial mesenchymal tumor with equivocal 18 F-FDG PET/CT findings but with subsequent highly increased metabolic activity using 18 F-FET PET/CT confirming tumor recurrence. This case highlights the importance of 18 F-FET PET/CT, as opposed to 18 F-FDG, in the clinical evaluation of this rare intracranial mesenchymal tumor.

e20041 Background: Older adults are underrepresented in clinical trials in multiple myeloma (MM), as are the risk prognostication schema derived from them, which limits their generalizability to this age group. Despite appropriate fitness, older adults may not be offered the same therapies as their younger counterparts. In this study, we compared disease characteristics and their associations with outcomes in older and younger adults with MM. Methods: We obtained data for newly diagnosed MM patients from the MM Research Foundation CoMMpass registry (version IA16), a prospective observational study with highly annotated clinical data, cytogenetics, and longitudinal outcomes. Chi-square or Fisher’s exact test were used for comparisons of categorical variables. Progression free survival (PFS) and overall survival (OS) curves were constructed using the Kaplan–Meier method and compared with the log-rank test. Cox proportional hazard models were computed to estimate hazard ratio (HR) and 95% confidence interval (CI) for association between pre-treatment variables and outcomes. Results: 1,143 patients were analyzed, including 853 patients (pts) under age 70 years (&lt; SEV) and 290 pts age 70+ years (SEV+). SEV+ had a higher frequency of ISS score 3 (p &lt; 0.001), lower estimated glomerular filtration rate (median 57.6 vs 74.7 mL/min/1.73m2, p &lt; 0.001), and worse ECOG performance status (PS) (p = 0.01). Of the cytogenetic abnormalities analyzed [del17p, gain1q, t(4;14), t(8;14), t(14;16), t(14;20), and hyperdiploidy], SEV+ had higher frequency of gain1q (42% vs 33%, p = 0.02) and t(14;20) (3% vs 1%, p = 0.03) compared with younger adults. SEV+ received less proteasome inhibitor + immunomodulatory imide triplet induction therapy (27% vs 55%, p &lt; 0.001) and less frontline autologous stem cell transplant (ASCT) (22% vs 59%, p &lt; 0.001). SEV+ were less likely to achieve &gt;complete response to induction therapy compared to &lt; SEV (32% vs 18%, p &lt; 0.001). SEV+ had worse PFS (HR 1.8, 1.6-2.2, p &lt; 0.001) and OS (2.3, 1.8-2.9, p &lt; 0.001) compared to &lt; SEV. On multivariate analysis, increasing ISS, gain1q, high risk gene expression profiling (UAMS70), and lack of triplet induction with frontline ASCT were associated with both poorer PFS and OS in &lt; SEV. For SEV+, multivariate analysis revealed that increasing ISS, t(14;16), and lack of triplet+ASCT were associated with inferior PFS, while age, male sex and increasing ISS were associated with inferior OS. Conclusions: Older adults have a greater prevalence of ISS 3, gain1q, and t(14;20) compared with younger adults but only ISS translates into inferior PFS or OS within this group. Increased access to triplet induction therapy and expanding access to frontline ASCT among older adults may help to improve outcomes in this growing subset of patients.

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