Soft Tissue Leiomyosarcoma Research Articles

The Impact of Li-Fraumeni and Germline Retinoblastoma Mutations on Leiomyosarcoma Initiation, Outcomes, and Genetic Testing Recommendations.

Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous, occurring mostly in sporadic but also syndromic settings. The role of pathogenic germline variants (PGV) as LMS drivers and their impact on outcomes remains uncertain. We performed a comprehensive clinicopathologic and molecular analysis using a tumor-normal DNA next-generation sequencing assay (Memorial Sloan Kettering-Integrated Mutational Profiling of Actionable Cancer Targets) of germline-associated LMS compared with sporadic LMS. Among 285 LMS [120 soft-tissue LMS (STLMS) and 165 uterine LMS (ULMS)] with germline testing, 78 (27%, 43 STLMS and 35 ULMS) cases harbored PGV, with 35/78 (45%) of PGV carriers showing biallelic inactivation of the corresponding gene in the tumor (26 STLMS and nine ULMS). The most frequent germline predispositions were TP53 (Li-Fraumeni syndrome; 17 patients, 16 in STLMS) and RB1 (retinoblastoma; 13 patients, 11 in STLMS). Germline TP53 and somatic RB1 alterations often co-occurred in the tumor andvice versa. Other biallelically inactivated PGV were enriched in DNA damage repair-related genes: CHEK2, MSH2, MSH6, RAD51D, BRCA2, and FANCA. Monoallelic PGV were mostly in ULMS and associated with co-occurring TP53 and RB1 somatic alterations. Patients with STLMS with biallelic but not monoallelic PGV were significantly younger than patients with sporadic STLMS (median ages 38 vs. 52 vs. 58 years). No differences in disease-specific or progression-free survival were observed in germline-associated versus sporadic LMS regardless of biallelic status. Although patients with ULMS had a relatively low proportion of PGV, a high percentage of patients with STLMS with PGV had tumor biallelic status, indicating that PGV drive tumorigenesis in these individuals. These findings have significant implications for genetic testing recommendations.

Soft-tissue leiomyosarcoma on the parietal area with angiosarcoma

Soft-tissue leiomyosarcoma on the parietal area with angiosarcoma

Characterizing TP53 mutations in bone and soft tissue sarcoma.

e23521 Background: Tumor protein P53 (TP53) is the most frequently mutated gene in cancer and most mutations inactivate wild type TP53 activity through heterogenous mechanisms. Whether different variants of mutant TP53 have different biologic potencies or clinical outcomes remain unclear. This ongoing study aims to characterize the spectrum of TP53 mutations in patients with bone and soft tissue sarcoma. Methods: We retrospectively identified and analyzed patients with bone and soft tissue sarcoma who underwent MSK-IMPACT (Memorial Sloan Kettering Cancer Center - Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing panel and had at least one mutation in the TP53 gene at Memorial Sloan Kettering Cancer Center. Mutations in the TP53 gene were categorized into the following sub-types: fusion, missense, splice site, or protein-truncating. Hotspots were defined as variants with frequency of 10 or greater. We queried the missense variants for the 800 most frequent variants recorded in the International Agency for Research on Cancer R20 (IARC), which were structurally characterized based on their impact on TP53 protein and rescue potencies with arsenic trioxide (ATO) in vitro (Song et al. Sci Transl Med. 2023). Results: We identified a total of 1257 patients with bone and soft tissue sarcoma who had at least one mutation in TP53. 92.5% of patients had only 1 mutation in TP53. In total, 1363 mutations were detected with 541 variants identified across all sarcoma subtypes. Most TP53 mutations were identified in soft tissue leiomyosarcoma (18.05%), uterine leiomyosarcoma (12.84%), sarcoma not otherwise specified (15.62%), undifferentiated pleomorphic sarcoma (12.11%), and osteosarcoma (7.78%). Of the 541 variants identified, the most frequent alterations were intragenic fusion (6.23%), R175H missense (2.93%), R248Q missense (2.27%), R273H missense (2.13%), and R213* protein-truncating (2.05%) mutations. Of the 800 most frequent missense variants in IARC R20 database, 233 missense variants were detected representing 52% of all mutations detected. Structural or likely structural mutations represented most of the identified missense mutations (77.46%). These mutations were clustered in the following hotspots: R175H, Y220C, R282W, H179Y, and C135Y. DNA-contact mutations were clustered in the following hotspots: R248Q, R273H, R273C, and R248W. Conclusions: This analysis highlights the heterogenous landscape of TP53 mutations in bone and soft tissue sarcomas. Structural variants are prevalent in sarcoma and occur at hotspots that may represent novel drug targets in the future.

Immune infiltrate analysis to reveal distinct immune classes for leiomyosarcomas.

11546 Background: Leiomyosarcomas (LMS) are aggressive malignancies of smooth-muscle origin. Few targeted molecular options exist and immunotherapy (IO) agents against T cells have been disappointing. In this study, we examine the immune infiltrate of LMS tumors by immunohistochemistry (IHC) and gene expression. Our objective was to identify actionable targets for immunotherapy in patients with LMS. Methods: Tumor samples from a series of LMS patients were prospectively collected and banked for DNA and RNA sequencing as part of the MD Anderson Patient Mosaic. Associated clinical data for the patients were collected and maintained. IHC was performed on available separate tissue microarrays. Differential gene expression (DGE) analysis was done using the DESeq2 package for R and the Benjamini-Hochberg procedure used to control for false discovery rate. Immune cell fractions were estimated using the MCPcounter package. All gene expression analyses were repeated on The Cancer Genome Atlas (TCGA) dataset as an independent dataset. Results: A total of 104 TCGA samples and 72 samples from Mosaic from 53 patients with uterine or soft tissue LMS were included in the analysis. Tumors in the TCGA group were treatment naive. Of the samples in the Mosaic group, 61 (85%) had been previously treated with chemotherapy, 8 (11%) had been radiated, and 5 (7.5%) had been previously treated with immunotherapy. Thirty-one (43%) tumors were metastatic. Fifty-one (70%) were soft tissue LMS and 21 (30%) were uterine LMS. Four distinct immune classes were seen in both the TGCA and Mosaic: a predominantly B-cell group, a monocyte/macrophage group, a mixed infiltrate group and a group with a neutrophil signature. DGE performed between the subgroups revealed a unique gene expression pattern for tumors in the B cell and monocyte/macrophage subgroups. Interrogation of specific immune-associated genes revealed low levels of expression in the neutrophil group, suggesting this may be the most immunologically “cold” subset. Some of these results were reproduced by IHC using a TMA: the presence of a cluster of samples with B-cells and higher expression of immune checkpoints, a macrophage driven cluster, and an immunologically cold cluster. Conclusions: Analyses of LMS samples across two large datasets demonstrate the existence of 4 distinct immune classes of tumors that persist despite variation in clinical and treatment conditions: B cell, monocytic/macrophage, mixed-infiltrate and neutrophil rich. The B cell and monocytic groups have increased expression of immune markers which may be amenable to targeted therapies.

Predicting Trabectedin Efficacy in Soft Tissue Sarcoma: Inflammatory Biomarker Analysis.

Trabectedin is used as a treatment for advanced-stage soft tissue sarcomas (STSs), particularly liposarcoma and leiomyosarcoma. Aside from its direct effect on tumor cells, trabectedin can affect the immune system in the tumor microenvironment. This study aimed to evaluate whether inflammatory biomarkers predict trabectedin efficacy in STSs. We retrospectively reviewed the clinical features and outcomes of patients with STS treated with trabectedin at our institution between 2016 and 2020. The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI=neutrophil × monocyte/lymphocyte) were calculated based on the blood samples obtained prior to trabectedin treatment initiation. Analyses of overall survival (OS) and progression-free survival (PFS) were performed according to various factors. Of the 101 patients identified, 54 had L-sarcoma (leiomyosarcoma: 30; liposarcoma: 24), and 47 had other types of STSs. Elevated SIRI, NLR, PLR, LMR, and C-reactive protein (CRP) were associated with worse PFS (p<0.001, p=0.008, p=0.027, p=0.013, and p<0.001, respectively) according to the results of the univariate analysis. Multivariate analysis showed that elevated SIRI, other histology, and CRP were associated with poor PFS (p=0.007, p=0.008, and p=0.029, respectively). In addition, the multivariate analysis of OS showed that SIRI was an independent prognostic factor (hazard ratio=2.16, p=0.006). Pretreatment SIRI can be considered a biomarker for the prognostic prediction of patients with STS treated with trabectedin.

What Is the Impact of Multimodal Treatment in Patients with Leiomyosarcoma of Bone? A Multicenter Study of 35 Patients with an Ultra-Rare Tumor Entity.

Primary leiomyosarcoma of bone (LMSoB) is extremely rare, comprising only <0.7% of primary malignant bone tumors, and is therefore considered an ultra-rare tumor entity. There is currently no consensus as to whether therapeutic strategies should be based on the biological characteristics of soft tissue leiomyosarcoma or on primary tumor localization in the bone. The use of perioperative chemotherapy and its effectiveness in this rare tumor entity remains unclear. We aimed to evaluate the impact of different treatment approaches in a multicenter setting with a total of 35 patients included. The 5-year overall survival (OS) was 74%. Patients with localized disease undergoing surgery had a significantly higher 5-year OS compared to patients who did not undergo surgical treatment (82% vs. 0%, p = 0.0015). Axial tumor localization was associated with worse event-free survival (EFS) probability (p < 0.001) and OS (p = 0.0082). A high proportion of our patients developed secondary metastases. Furthermore, the perioperative chemotherapy protocols applied to our patients were not associated with an improved EFS or OS. Therefore, the benefit of perioperative chemotherapy in LMSoB needs to be further investigated, and the choice of agents still needs to be clarified.

Surgically treated pelvic liposarcoma and leiomyosarcoma: The effect of tumor size on cancer-specific survival

IntroductionIn soft tissue pelvic liposarcoma and leiomyosarcoma, it is unknown whether a specific tumor size cut-off may help to better predict prognosis, defined as cancer-specific survival (CSS). We tested whether different tumor size cut-offs, could improve CSS prediction. Materials and methodsSurgically treated non-metastatic soft tissue pelvic sarcoma patients were identified (Surveillance, Epidemiology, and End Results 2004–2019). Kaplan-Meier plots, univariable and multivariable Cox-regression models and receiver operating characteristic-derived area under the curve (AUC) estimates were used. ResultsOverall, 672 (65 %) liposarcoma (median tumor size 11 cm, interquartile range [IQR] 7–16) and 367 (35 %) leiomyosarcoma (median tumor size 8 cm, IQR 5–12) patients were identified. The p-value derived ideal tumor size cut-off was 17.1 cm, in liposarcoma and 7.0 cm, in leiomyosarcoma. In liposarcoma, according to p-value derived cut-off, five-year CSS rates were 92 vs 83 % (≤17.1 vs > 17.1 cm). This cut-off represented an independent predictor of CSS and improved prognostic ability from 83.8 to 86.8 % (Δ = 3 %). Similarly, among previously established cut-offs (5 vs 10 vs 15 cm), also 15 cm represented an independent predictor of CSS and improved prognostic ability from 83.8 to 87.0 % (Δ = 3.2 %). In leiomyosarcoma, according to p-value derived cut-off, five-year CSS rates were 86 vs 55 % (≤7.0 vs > 7.0 cm). This cut-off represented an independent predictor of CSS and improved prognostic ability from 68.6 to 76.5 % (Δ = 7.9 %). ConclusionsIn liposarcoma, the p-value derived tumor size cut-off was 17.1 cm vs 7.0 cm, in leiomyosarcoma. In both histologic subtypes, these cut-offs exhibited the optimal statistical characteristics (univariable, multivariable and AUC analyses). In liposarcoma, the 15 cm cut-off represented a valuable alternative.

Loss of the DNA Repair Gene RNase H2 Identifies a Unique Subset of DDR-Deficient Leiomyosarcomas.

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In the TCGA database, RNASEH2B homozygous deletions (HomDels) were found in 6% (5/80) of LMS cases, with a higher proportion in U-LMS (15%; 4/27) compared with ST-LMS (2%; 1/53). Using the SNiPDx targeted-NGS sequencing assay to detect biallelic loss of function in select DDR-related genes, we found RNASEH2B HomDels in 54% (19/35) of U-LMS cases with RNase H2 loss by IHC, and 7% (3/43) HomDels in RNase H2 intact cases. No RNASEH2B HomDels were detected in ST-LMS. In U-LMS patient cohort (n = 109), no significant overall survival difference was seen in patients with RNase H2 loss versus intact, or RNASEH2B HomDel (n = 12) versus Non-HomDel (n = 37). The overall diagnostic accuracy, sensitivity, and specificity of RNase H2 IHC for detecting RNA-SEH2B HomDels in U-LMS was 76%, 93%, and 71%, respectively, and it is being developed for future predictive biomarker driven clinical trials targeting DDR in U-LMS.

Retracted: Analysis of Extended Resection of Limb Soft Tissue Leiomyosarcoma.

[This retracts the article DOI: 10.1155/2021/2106972.].

Developing Novel Genomic Risk Stratification Models in Soft Tissue and Uterine Leiomyosarcoma.

Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite recent large-scale genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model. We performed comprehensive genomic profiling in a cohort of 195 soft tissue LMS (STLMS), 151 primary at presentation, and a control group of 238 uterine LMS (ULMS), 177 primary at presentation, with at least 1-year follow-up. In STLMS, French Federation of Cancer Centers (FNCLCC) grade but not tumor size predicted progression-free survival (PFS) or disease-specific survival (DSS). In contrast, in ULMS, tumor size, mitotic rate, and necrosis were associated with inferior PFS and DSS. In STLMS, a 3-tier genomic risk stratification performed well for DSS: high risk: co-occurrence of RB1 mutation and chr12q deletion (del12q)/ATRX mutation; intermediate risk: presence of RB1 mutation, ATRX mutation, or del12q; low risk: lack of any of these three alterations. The ability of RB1 and ATRX alterations to stratify STLMS was validated in an external AACR GENIE cohort. In ULMS, a 3-tier genomic risk stratification was significant for both PFS and DSS: high risk: concurrent TP53 mutation and chr20q amplification/ATRX mutations; intermediate risk: presence of TP53 mutation, ATRX mutation, or amp20q; low risk: lack of any of these three alterations. Longitudinal sequencing showed that most molecular alterations were early clonal events that persisted during disease progression. Compared with traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.

Primary leiomyosarcoma of the bone: a case report.

Primary leiomyosarcoma of the bone is rare. Histologically, it resembles leiomyosarcoma of soft tissue. Given the rarity of this entity, its diagnosis should be made only after clinical studies and workup have excluded metastasis from other sites. Herein, we describe an additional case of primary bone leiomyosarcoma. We report a 32-year-old female patient, who presented with right knee pain and was found to have a right distal femur mass by imaging studies. Biopsy showed a neoplasm composed of fascicles of spindle cells, arranged in different patterns, with significant pleomorphism. The tumor cells were positive for smooth muscle actin, focally positive for desmin and H-caldesmon. No other masses in the body were detected by imaging studies. The diagnosis of leiomyosarcoma of the bone was rendered. Given the broad diagnostic differential of primary bone leiomyosarcoma, it is important to be aware of this rare bone tumor phenotype and of its histomorphologic and immunohistochemical features for an accurate diagnosis.

Prediction of 5-year survival in soft tissue leiomyosarcoma using a machine learning model algorithm.

Leiomyosarcoma (LMS) is associated with one of the poorest overall survivals among soft tissue sarcomas. We sought to develop and externally validate a model for 5-year survival prediction in patients with appendicular or truncal LMS using machine learning algorithms. The Surveillance, Epidemiology, and End Results (SEER) database was used for development and internal validation of the models; external validation was assessed using our institutional database. Five machine learning algorithms were developed and then tested on our institutional database. Area under the receiver operating characteristic curve (AUC) and Brier score were used to assess model performance. A total of 2209 patients from the SEER database and 81 patients from our tertiary institution were included. All models had excellent calibration with AUC 0.84-0.85 and Brier score 0.15-0.16. After assessing the performance indicators according to the TRIPOD model, we found that the Elastic-Net Penalized Logistic Regression outperformed other models. The AUCs of the institutional data were 0.83 (imputed) and 0.85 (complete-case analysis) with a Brier score of 0.16. Our study successfully developed five machine learning algorithms to assess 5-year survival in patients with LMS. The Elastic-Net Penalized Logistic Regression retained performance upon external validation with an AUC of 0.85 and Brier score of 0.15.

Femoro-popliteal autogenous venous bypass in surgical treatment of soft tissue sarcomas of the lower limbs: clinical case

Femoro-popliteal autogenous venous bypass in surgical treatment of soft tissue sarcomas of the lower limbs: clinical case

Loss of the DNA repair gene RNase H2 and a unique subset of DDR-deficient leiomyosarcomas.

11549 Background: Targeting the DNA damage response (DDR)/Homologous Recombination (HR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS). Loss of RNase H2 decreases DNA repair via the Non-Homologous End-Joining (NHEJ) pathway, leading to increased double stranded breaks, replication stress, and increased cell death. Therefore, we developed an assay to screen for RNase H2 loss in STS patient samples to determine its prevalence and prognostic significance, particularly in LMS patients. Methods: RNASEH2B homozygous deletion (HomDel) calls from TCGA samples were based on the Allele-Specific Copy number Analysis of Tumors (ASCAT2) algorithm. Immunohistochemistry (IHC) of RNase H2 was performed on tissue microarrays (TMAs) of uterine (U-LMS) and soft tissue (ST-LMS) leiomyosarcoma samples from MD Anderson Cancer Center (MDACC) using a selective antibody developed by Repare Therapeutics. RNase H2 loss was defined as &lt; = 10% cells without nuclear IHC staining and scored by experienced pathologists in 2 separate cohorts. Genomic analysis was performed using SNiPDx™, a targeted-NGS assay designed to detect biallelic loss of function in select DDR related genes and whole genome sequencing (WGS). MDACC TMA samples were clinically annotated by retrospective review. Results: Using TCGA data, RNASEH2B HomDels were seen in 6% (5/80) of all LMS cases, with a higher proportion in U-LMS (15%; 4/27) as compared to ST-LMS (2%; 1/53). In a pan-tumor TMA, RNase H2 loss by IHC was found in 3.8% (32/843) of samples overall, and in 10% (9/88) of LMS samples. This proportion of RNase H2 loss was higher in a larger MDACC LMS cohort, where negative staining of RNase H2 was found in 30% (33/110) of U-LMS and 38% (39/102) of ST-LMS cases. 30 MDACC LMS cases (15 U-LMS and 15 ST-LMS) were analyzed for RNASEH2B HomDels by SNiPDx. In U-LMS, RNASEH2B HomDels were detected in 64% (7/11) of RNase H2 IHC loss cases vs. 0% (0/3) in RNase H2 IHC intact cases. No RNASEH2B HomDels were detected in ST-LMS cases (10 IHC loss, 5 intact). The median overall survival (mOS) of MDACC U-LMS patients (n = 109) was 4.3 years. No significant mOS difference was seen in RNase H2 IHC intact cases versus loss (mOS 4.4 v 3.3 years, p = 0.54). In a separate cohort, 45 U-LMS samples were screened by IHC; 22% (10/45) had RNase H2 loss. RNASEH2B HomDels were detected in 70% (7/10) of RNase H2 IHC loss cases using SNiPDx and confirmed using WGS. In contrast, RNASEH2B HomDels were detected in 3% (1/33) of RNase H2 IHC intact cases. In the combined U-LMS cohort with IHC and SNiPDx results (n = 71), the diagnostic accuracy, sensitivity and specificity of RNase H2 IHC for detecting RNASEH2B HomDels was 76%, 93% and 71% respectively. Conclusions: RNase H2 loss via RNASEH 2B HomDels is prevalent in U-LMS and is unique from other DDR pathway alterations. RNase H2 IHC is an effective screening tool and is being developed for future clinical trials targeting DDR in LMS.

Targeting the Molecular and Immunologic Features of Leiomyosarcoma.

Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. The LMS immune microenvironment is highly infiltrated with tumor-associated macrophages and tumor-infiltrating lymphocytes, which may represent promising biomarkers. This review provides an overview of the clinical and pathologic behavior of both soft tissue and uterine LMS and summarizes the genomic and immune characteristics of these tumors and how they may provide opportunities for the development of biomarker-based immune therapies.

High-Grade Sarcomas with Myogenic Differentiation Harboring Hotspot PDGFRB Mutations

PDGFRB-activating mutations have been reported in pediatric myofibroma and myofibromatosis. However, recurrent gain-of-function PDGFRB mutations have not been documented in sarcomas with myogenic differentiation. Driven by occasional sarcomas harboring PDGFRB mutations, we investigated their prevalence and clinicopathologic and genomic features in a large cohort of sarcomas. An institutional targeted DNA next-generation sequencing database was searched for sarcomas with myogenic differentiation harboring hotspot PDGFRB gene alterations. Among 3300 patients with sarcomas, 21 (0.6%) patients were identified (17 women, 4 men) with an age range of 35 to 88 years. The site distribution included 13 gynecologic tract (12 uteri, 1 vagina), 4 bone and soft tissue, and 4 viscera. All except 1 were high grade. Most patients were diagnosed as sarcomas with myogenic differentiation based on partial staining for 1 or more muscle markers, whereas 6 were labeled as leiomyosarcoma (LMS). Most tumors showed monomorphic spindle morphology, with either heterogeneous features of myofibroblastic and smooth muscle differentiation or an undifferentiated phenotype. Hormone receptors were negative in all uterine cases. PDGFRB immunostaining in all cases tested was strong and diffuse, whereas PDGFRA was negative/focal. The most frequent PDGFRB mutations were exon 12 (43%), exon 14 (N666K/S/T) (38%), and exon 18 (D850Y/H/V or insertion/deletion) (19%). The most frequent co-existing genetic alterations (26% to 37%) occurred in CDKN2A/B, TP53, TERT, and MED12. Moreover, PDGFRB-mutant sarcomas had an overall distinct genomic landscape compared with both uterine and soft tissue LMS control groups. These tumors were associated with a highly aggressive clinical course, with frequent distant metastases (81%) and death (76%), regardless of anatomic location, and worse overall survival compared with the 2 LMS control groups. This is the first study documenting recurrent hotspot PDGFRB alterations in high-grade sarcomas, which show a predilection for uterine location and myogenic differentiation that fall short of the diagnostic criteria for LMS. Further studies are needed to investigate the therapeutic potential of kinase inhibitors in this group of tumors.

Molecular subtypes of leiomyosarcoma: Moving toward a consensus

Molecular subtypes of leiomyosarcoma: Moving toward a consensus

Abstract PR012: Targeted sequencing of 2,138 bone and soft tissue sarcomas reveals commonly altered pathways, subtype-independent genetic clusters, and potential therapeutic targets

Abstract A hallmark of sarcomas is genetic, biologic, and clinical heterogeneity, which is a challenge for preclinical development of therapeutic targets, clinical trial design, and patient care. Because sarcomas comprise over 100 subtypes, a broad comparative genetic analysis of subtypes has been lacking and sarcoma genetic studies have by necessity focused on one or a few subtypes. We will report the results of a comprehensive analysis of somatic genetic alterations detected by a targeted sequencing platform in a single institution cohort of 2,138 patient-specific samples of soft tissue and bone sarcoma representing 45 distinct pathological entities. We determined subtype-specific mutation and copy number (arm and gene level) events with a focus on pathways in which there are therapeutic targets under clinical or preclinical investigation. The most commonly altered pathways are cell cycle control, TP53, PI3K, receptor tyrosine kinase/RAS, and epigenetic regulators (e.g. &amp;gt;40% of uterine leiomyosarcoma [n=165], undifferentiated pleomorphic sarcoma [UPS, n=145] and pleomorphic liposarcoma [n=22]). Subtype-specific associations in rare subtypes include TERT amplification in 41% of intimal sarcoma (n=18) and alterations in chromatin remodeling and histone modifying complexes in uterine adenosarcoma (43% and 36%, respectively; n=14). Epigenetic pathway alterations in common sarcomas were also noted, including an increased frequency of oncogenic alterations in epigenetic regulators in dedifferentiated liposarcoma (DDLS; n=167) (25%) vs. well differentiated liposarcoma (8%; n=48). We evaluated rates of whole genome doubling (WGD), which in subtypes such as UPS and osteosarcoma (n=129) were &amp;gt;45%, which is more frequent than many carcinomas. WGD associated with worse overall survival in metastatic (p=0.042) but not primary samples (p=0.391). Among specific subtypes, WGD was associated with worse overall survival in metastatic UPS (p=0.022). Unsupervised clustering of samples based on genetic features revealed that in some cases sarcomas are more similar to individual tumors of distinct histology than to other sarcomas of the same subtype. For example, UPS and soft tissue leiomyosarcoma (n=125) segregated into multiple genetic clusters (high entropy) compared to others with low entropy (DDLS), which could have implications for future clinical trial interpretation and/or design. We also determined the subtype-specific rate of tumor mutation burden, which was overall low compared to many carcinomas, but notably varied between and within subtypes, with some having a long tail in the upper range of the distribution. Lastly, we assessed targetable alterations on a subtype-specific basis. Together with other ‘multiomic’ approaches, we anticipate this work will motivate preclinical studies of subtype-specific sarcoma biology and potential therapeutic targets and will inform efforts to interpret outcomes in sarcoma clinical trials with respect to underlying genetic subtypes. Citation Format: Benjamin A. Nacev, Francisco Sanchez-Vega, Shaleigh Smith, Cristina Antonescu, Evan Rosenbaum, Hongyu Shi, Cerise Tang, Nicholas Socci, Satshil Rana, Rodrigo Gularte-Merida, Ahmet Zehir, Mrinal Gounder, Timothy Bowler, Anisha Luthra, Bhumika Jadeja, Azusa Okada, Jonathan Strong, Jake Stoller, Jason Chan, Ping Chi, Sandra D'Angelo, Mark Dickson, Ciara Kelly, Mary Louise Keohan, Sujana Movva, Katherine Thornton, Paul Meyers, Leonard Wexler, Emily Slotkin, Julia Glade Bender, Neerav Shukla, Martee Hensley, John Healey, Michael La Quaglia, Kaled Alektiar, Aimee Crago, Sam Yoon, Brian Untch, Sarah Chiang, Narasimhan Agaram, Meera Hameed, Michael Berger, David Solit, Nikolaus Schultz, Marc Ladanyi, Samuel Singer, William Tap. Targeted sequencing of 2,138 bone and soft tissue sarcomas reveals commonly altered pathways, subtype-independent genetic clusters, and potential therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR012.

Surgical resection of chest wall sarcomas: an analysis of survival and predictors of outcome at an Australian multidisciplinary sarcoma service.

Chest wall sarcomas are a rare group of tumours. Surgical resection is considered the mainstay of curative treatment, however, resection and reconstruction of chest wall defects presents complex issues for the clinician. A retrospective analysis of 59 patients undergoing surgical management of chest wall sarcoma between December 1996 and July 2020 was conducted across a multidisciplinary sarcoma service in Melbourne, Australia. Patient demographics, pathologic data, and long-term outcomes were recorded. Mean age at surgery was 48.4 years (SD 18.3), and 66.1% were male. Median follow-up was 29 months (IQR 11.8, 51.0months). Fifty-one patients presented with primary tumours, while the others had secondary tumours resected. Most tumours arose in bone (72.9%) as opposed to soft tissues (27.1%). Chondrosarcoma was the most common histologic subtype (50.8%). The most common reconstructive techniques involved the use of mesh (79.7%) or mesh supplemented with bone cement (33.9%). Overall survival at 1 and 5 years was 92% and 70%, respectively. Seven patients died of metastatic sarcoma during the follow up period with a median survival time of 27 months. Twelve patients had evidence of disease recurrence during the follow-up period. Stage 4 disease, soft tissue tumours, secondary tumours, leiomyosarcoma and UPS subtypes, and plating reconstruction were associated with increased disease recurrence. The results suggest that outcomes for chest wall sarcoma are similar to extremity sarcomas and may be treated in a similar manner. Patients requiring adjuvant radiotherapy and those who develop disease-recurrence are more likely to have worse overall survival outcome despite complete surgical resection.

Clinicopathologic and molecular analyses of cutaneous leiomyosarcoma: A retrospective, multicenter study of 79 cases

To the Editor: Cutaneous leiomyosarcoma (cLMS) is a rare skin sarcoma reported to have a good prognosis.1Winchester D.S. Hocker T.L. Brewer J.D. et al.Leiomyosarcoma of the skin: clinical, histopathologic, and prognostic factors that influence outcomes.J Am Acad Dermatol. 2014; 71: 919-925https://doi.org/10.1016/j.jaad.2014.07.020Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar In this large, retrospective, and multicenter study of cLMS (confined to the dermis or involving the subcutis layers), conducted from January 2000 to June 2019, we aimed to better define its clinicopathologic features and prognostic factors. Statistical analyses combined the Kaplan-Meier method (to estimate overall survival and progression-free survival) and the log-rank test (to identify prognostic factors). We also performed molecular analyses using whole-genome copy number analyses as well as targeted DNA and RNA sequencing. Seventy-nine patients were included (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/sjk9p9rgtz/1). Most cases occurred in the lower portion of the limbs (n = 29 [36.7%]) and showed subcutis invasion (n = 35 [44.3%]) and a low histologic grade (grade I, n = 49, [62.0%]) according to the Fédération Nationale des Centres de Lutte Contre le Cancer2Coindre J.M. Trojani M. Contesso G. et al.Reproducibility of a histopathologic grading system for adult soft tissue sarcoma.Cancer. 1986; 58: 306-309https://doi.org/10.1002/1097-0142(19860715)58:2<306::aid-cncr2820580216>3.0.co;2-7Crossref PubMed Google Scholar grading system. The margin status was R0 in 59 cases (74.7%, ie, complete surgical resection, without residual tumor). Recurrence occurred in 12 patients (15.2%), whereas regional or distant metastasis occurred in 7 patients (8.9%). Eight patients died, 6 of them because of metastatic cLMS. The median overall survival and progression-free survival was 38.8 (range, 4.9-73.9) and 25.2 months (range, 2.8-66.1), respectively. The estimated 24-month overall survival and progression-free survival rates were 92% and 77%, respectively. There was no significant association between outcomes and clinical parameters (age, sex, tumor location, and tumor size). However, the margin sizes were wider in the population without relapse (n = 33, margin size = 1.80 cm) than in the population with relapse (n = 9, margins size = 1.06 cm, P = .03). Conversely, an intermediate or high Fédération Nationale des Centres de Lutte Contre le Cancer grade (II-III) was significantly associated with a higher risk of recurrence or metastasis (hazard ratio, 4.8; 95% CI, 1.6-14.6; P = .01). There was no prognostic association with other histologic factors; the hazard ratio of the recurrence/metastasis of subcutis invasion was 7.4 (95% CI, 0.9-58.2; P = .06). Subcutis invasion (n = 35) was observed in 51% of cases with grade I versus 40% of cases with grade II/III cLMS. Eleven cases were molecularly explored, showing heterogeneous profiles (Supplementary Table II, available via Mendeley at https://data.mendeley.com/datasets/8t7hcb8jw7/1): 4 cases presented with >10 segmental copy number alterations (CNAs) (case numbers, 1-4), 3 cases presented with only 1 CNA (case numbers, 5-7). The recurrent abnormalities were the deletion of the RB1 (n = 5) or TP53 gene (n = 4) and the amplification of MYOCD (n = 2). Four cases presented with no CNA (case numbers, 8-11). TP53 mutations were identified, but no fusion gene was identified. The limitation of this study is its retrospective design; nevertheless, the following data deserve to be highlighted. cLMS has a good prognosis, with the 5-year survival rate ranging from 86% (in our series) to 92% (Surveillance, Epidemiology, and End Results Database). However, recurrence/metastasis may have occured.1Winchester D.S. Hocker T.L. Brewer J.D. et al.Leiomyosarcoma of the skin: clinical, histopathologic, and prognostic factors that influence outcomes.J Am Acad Dermatol. 2014; 71: 919-925https://doi.org/10.1016/j.jaad.2014.07.020Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar,3Wong G.N. Webb A. Gyorki D. et al.Cutaneous leiomyosarcoma: dermal and subcutaneous.Australas J Dermatol. 2020; 61: 243-249https://doi.org/10.1111/ajd.13307Crossref PubMed Scopus (5) Google Scholar Few previous studies correlated prognosis with clinicohistologic parameters.3Wong G.N. Webb A. Gyorki D. et al.Cutaneous leiomyosarcoma: dermal and subcutaneous.Australas J Dermatol. 2020; 61: 243-249https://doi.org/10.1111/ajd.13307Crossref PubMed Scopus (5) Google Scholar We reported for the first time that Fédération Nationale des Centres de Lutte Contre le Cancer grading is the most important prognostic factor. Therefore, cLMS of grade II/III should be managed with wider local excision, as already suggested, and we recommend margins of 2 cm.4Kazlouskaya V. Lai Y.C. Khachemoune A. Leiomyosarcoma of the skin: review of the literature with an emphasis on prognosis and management.Int J Dermatol. 2020; 59: 165-172https://doi.org/10.1111/ijd.14705Crossref PubMed Scopus (9) Google Scholar Our study was the first to explore pan-genomic CNAs as well as targeted mutations and fusion genes. Patients with cLMS with a complex genomic quantitative profile (case numbers, 1-4, which showed subcutaneous extension) share some molecular features described in patients with deep soft tissue leiomyosarcoma: TP53 and RB1 alterations and MYOCD amplification.5Dry S.M. Fröhling S. Leiomyosarcoma. WHO Classification of Soft Tissue and Bone Tumours.5th ed. IARC, 2019: 195-197Google Scholar Patients with cLMS with such molecular features might have a pejorative prognosis, which should be confirmed in a larger cohort. None disclosed.