Endometrial Stromal Sarcoma Research Articles

Pan-TRK immunohistochemistry in gynaecological mesenchymal tumours: diagnostic implications and pitfalls.

NTRK-rearranged sarcomas of the female genital tract mainly occur in the uterus (more commonly cervix than corpus) and are characterized by a "fibrosarcoma-like" morphology and NTRK gene rearrangements. These neoplasms may exhibit histological overlap with other entities and can present diagnostic difficulties without molecular confirmation. Pan-TRK immunohistochemistry was developed to identify tumours harbouring NTRK rearrangements. The aim of this study was to characterize pan-TRK immunohistochemical expression in a large cohort of gynaecological mesenchymal neoplasms and investigate the utility of pan-TRK immunohistochemistry todistinguish NTRK-rearranged sarcoma from its mimics. A total of 473 gynaecological mesenchymal tumours (461 without known NTRK fusions and 12 NTRK-rearranged sarcomas) were selected. Pan-TRK immunohistochemistry (EPR17341, Abcam) was performed on whole tissue sections and tissue microarrays. Molecular interrogation of pan-TRK positive tumours was performed by RNA sequencing or fluorescence in situ hybridization (FISH). Of the 12 NTRK-rearranged sarcomas, 11 (92%) exhibited diffuse (≥70%) cytoplasmic pan-TRK staining with moderate/marked intensity, while the other wasnegative. Eleven (2.4%) additional tumours also exhibited pan-TRK immunohistochemical expression: three low-grade endometrial stromal sarcomas, seven high-grade endometrial stromal sarcomas, and an undifferentiated uterine sarcoma. Molecular confirmation of the absence of NTRK rearrangements was possible in nine of these tumours. Of these nine neoplasms, seven exhibited focal/multifocal (<70%) pan-TRK cytoplasmic staining with weak/moderate intensity. Even though pan-TRK immunohistochemical expression is not entirely sensitive or specific for NTRK-rearranged sarcomas, these neoplasms tend to exhibit diffuse staining of moderate/strong intensity, unlike its mimics. Pan-TRK should be performed in monomorphic uterine (corpus and cervix) spindle cell neoplasms that are negative for smooth muscle markers and hormone receptors and positive for CD34 and/ or S100. Ultimately, the diagnosis requires molecular confirmation.

Targeted RNA Sequencing Highlights a Diverse Genomic and Morphologic Landscape in Low-grade Endometrial Stromal Sarcoma, Including Novel Fusion Genes.

Low-grade endometrial stromal sarcoma (LGESS) represents a morphologically and genetically heterogenous mesenchymal neoplasm. Previous work has shown that approximately half of LGESS are characterized by JAZF1::SUZ12 gene fusions, while a smaller proportion involves rearrangement of other genes. However, a subset of cases has no known genetic abnormalities. To better characterize the genomic landscape of LGESS, we interrogated a cohort with targeted RNA sequencing (RNA-Seq). Cases previously diagnosed as low-grade endometrial stromal neoplasia (n=51) were identified and re-reviewed for morphology and subjected to RNA-Seq, of which 47 were successfully sequenced. The median patient age was 49 years (range: 19 to 85). The most commonly detected fusions were JAZF1::SUZ12 (n=26, 55%) and BRD8::PHF1 (n=3, 6%). In addition to the usual/typical LGESS morphology, some JAZF1::SUZ12 fusion tumors showed other morphologies, including fibrous, smooth muscle, sex-cord differentiation, and myxoid change. Novel translocations were identified in 2 cases: MEAF6::PTGR2 and HCFC1::PHF1 . Ten tumors (21%) had no identifiable fusion, despite a similar morphology and immunophenotype to fusion-positive cases. This suggests that a subset of cases may be attributable to fusion products among genes that are not covered by the assay, or perhaps altogether different molecular mechanisms. In all, these findings confirm that RNA-Seq is a potentially useful ancillary test in the diagnosis of endometrial stromal neoplasms and highlight their diverse morphology.

A Retrospective Study Of 20 Cases Of Uterine Sarcoma In A Single Institute Over 10 Year Period

Objective: Uterine sarcomas are rare tumors arising from mesenchyme of uterus and th are diagnosed late because of confusing clinical and radiological presentation as urerine fibroids .In post hysterectomy pateints uterine sarcomas can present as pelvic or abdominal tumors causing confusion with tumors of bladder , bowel or other abdominal/pelvic malignancies. Histopathological examination and immuno histochemistry aids in diagnosis of uterine sarcoma and proper management of pateints. Hence 20 cases are studied in detail for better understanding of this rare entity. Methods: A retrospective study of 20 cases of uterine sarcoma was done. Details of patient are collected from departments of surgical oncology, medical oncology, pathology, radiology and outpatient records. Results: Uterine sarcomas are rare tumors and are usually diagnosed late. Most common types of uterine sarcoma are endometrial stromal sarcoma. leimyosarcoma, undifferentiated uterine sarcoma and adenosarcoma Abnormal uterine bleeding is the most common complaint and there are no specific complaints or radiological findings.Endometrial stromal sarcomas are known for their indolent course,in our study 6 pateints had hysterectomy in the past and years later presented as pelvic or abdominal masses causing diagnostic dilemma .Histopathology and immunohistochemistry aids in diagnosis and timely management of uterine sarcomas. Conclusion: In 20 cases of uterine sarcoma, patients presented with complaints of abnormal uterine bleeding, pain abdomen, mass per abdomen, hematuria and constipation, radiological findings revealed either fibroid uterus or degenerated fibroid or ovarian cyst or bladder tumor or bowel tumor or retroperitoneal tumor in none of the cases uterine sarcoma was in list of differential diagnosis. Diagnosis was made only after histopathological examination and immuno histochemistry. Cases of Uterine sarcomas diagnosed at early stage through proper suspicion for this rare tumor and confirmation with histopathology and immunohistochemistry have better survival and quality of life compared to cases which are mis managed. Hence study was done.

Correlation between malignant peritoneal cytology and survival in patients with uterine leiomyosarcoma and endometrial stromal sarcoma

ObjectiveThis study aimed to examine the correlation between malignant peritoneal cytology and overall survival among patients with uterine leiomyosarcoma and endometrial stromal sarcoma.MethodsPatients with uterine leiomyosarcoma and endometrial stromal sarcoma...

Diagnostic des sarcomes utérins et tumeurs mésenchymateuses utérines rares à potentiel de malignité. Référentiels du Groupe Sarcome Français et des Tumeurs Rares Gynécologiques

The landscape of uterine sarcomas is becoming more complex with the description of new entities associated with recurrent driver molecular alterations. Uterine sarcomas, in analogy with soft tissue sarcomas, are distinguished into complex genomic and simple genomic sarcomas. Leiomyosarcomas and undifferentiated uterine sarcomas belong to complex genomic sarcomas group. Low-grade and high-grade endometrial stromal sarcomas, other rare tumors associated with fusion transcripts (such as NTRK, PDGFB, ALK, RET ROS1) and SMARCA4-deficient uterine sarcoma are considered simple genomic sarcomas. The most common uterine sarcoma are first leiomyosarcoma and secondly endometrial stromal sarcomas. Three different histological subtypes of leiomyosarcoma (fusiform, myxoid, epithelioid) are identified, myxoid and epithelioid leiomyosarcoma being more aggressive than fusiform leiomyosarcoma. The distinction between low-grade and high-grade endometrial stromal sarcoma is primarily morphological and immunohistochemical and the detection of fusion transcripts can help the diagnosis. Uterine PEComa is a rare tumor, which is distinguished into borderline and malignant, according to a risk assessment algorithm. Embryonal rhabdomyosarcoma of the uterine cervix is more common in children but can also occur in adult women. Embryonal rhabdomyosarcoma of the uterine cervix is almost always DICER1 mutated, unlike that of the vagina which is wild-type DICER1, and adenosarcoma which can be DICER1 mutated but with less frequency. Among the emerging entities, sarcomas associated with fusion transcripts involving the NTRK, ALK, PDGFB genes benefit from targeted therapy. The integration of molecular data with histology and clinical data allows better identification of uterine sarcomas in order to better treat them.

High-Grade Endometrial Mesenchymal Sarcoma: Current Status and Future Trends

Endometrial Stromal Sarcoma (ESS) is a rare gynecological malignancy originating from endometrial stromal tissue. Representing only a tenth of uterine malignant tumors, ESS is categorized into Low-Grade (LGESS) and High-Grade (HGESS) based on nuclear division. Interestingly, prognostic studies have found no strong correlation between ESS prognosis and nuclear division activity. Undifferentiated Uterine Sarcoma (UUS) represents a spectrum of tumors with varied morphological, clinical, and prognostic features, and lacks a standardized naming convention. In 2014, the World Health Organization grouped ESS into LGESS, HGESS, and UUS based on clinical and pathological attributes. HGESS, despite its rarity, is notorious for its poor prognosis and low survival rate. Its early detection is complicated due to its asymptomatic presentation and ambiguous pathogenesis, leading to debates over treatment approaches. This article delves into the recent research developments concerning HGESS.

Next generation sequencing reveals a high prevalence of pathogenic mutations in homologous recombination DNA damage repair genes among patients with uterine sarcoma

ObjectiveInvestigate the incidence of homologous recombination DNA damage response (HR-DDR) genomic alterations among patients with uterine sarcoma. MethodsThe American Association for Cancer Research GENIE v13.0 database was accessed and patients with uterine leiomyosarcoma, adenosarcoma, undifferentiated uterine sarcoma, high-grade endometrial stromal sarcoma, low-grade endometrial stromal sarcoma, and endometrial stromal sarcoma not otherwise specified were identified. We determined the incidence of pathogenic alterations in the following genes involved in HR-DDR: ATM, ARID1A, ATRX, BAP1, BARD1, BLM, BRCA2, BRCA1, BRIP1, CHEK2, CHEK1, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, WRN. Data from the OncoKB database, as provided by cBioPortal, was utilized to determine the presence of pathogenic genomic alterations. ResultsA total of 509 patients contributing with 525 samples were identified. Median patient age at sample collection was 56 years while the majority were White (80.7%). The most common histologic subtype was leiomyosarcoma (63.8%) followed by adenosarcoma (12.3%). The overall incidence of HR-DDR genomic alterations was 28.2%. The most commonly altered genes were ATRX (18.2%), BRCA2 (4%), and RAD51B (2.6%). The highest incidence of HR-DDR genomic alterations was observed among patients with leiomyosarcoma (35.4%), adenosarcoma (27%) and undifferentiated uterine sarcoma (30%), while those with low-grade endometrial stromal sarcoma had the lowest (2.9%) incidence. ConclusionsApproximately 1 in 3 patients with uterine sarcoma harbor a pathogenic alteration in HR-DDR genes. Incidence is high among patients with uterine leiomyosarcoma and adenosarcoma.

Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer.

Japan's health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne® CDx or OncoGuide™ NCC Oncopanel between November 2019 and October 2022. Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with other). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients' prognosis and performance status should be considered before performing the test.

Sarcoma estromal endometrial extrauterino primario de bajo grado

Endometriosis is a common benign lesion whose importance lies in the associated symptomatology and the possibility of malignant transformation. Endometrial stromal sarcoma is a rare tumor, accounting for only 0.2% of all female genital tract tumors. Primary extrauterine endometrial stromal sarcomas are even rarer, are frequently associated with endometriosis, and have been reported in the ovaries, fallopian tubes, pelvic cavity, abdominal cavity, and retroperitoneum in the absence of uterine pathology. We describe a case of a female patient who consulted for dysmenorrhea, dysuria, and dyschezia. Pelvic magnetic resonance showed a heterogeneous tumor in the left adnexa compatible with endometrioma. Histopathological findings and immunohistochemical staining were consistent with the diagnosis of primary low-grade extrauterine endometrial stromal sarcoma. The patient underwent total hysterectomy, bilateral oophorosalpingectomy, total omentectomy, and pelvic and para-aortic lymph node resection.

High-grade endometrial stromal sarcoma displaying immunohistochemical expression of BCOR—A report of two cases of a novel tumor entity

ABSTRACT Several defining molecular alterations have recently been identified underlying high-grade endometrial stromal sarcomas, such as YWHAE: NUTM2A/B fusions, ZC3H7B: BCOR fusions, and BCOR internal tandem duplication (ITD). BCOR is a useful immunohistochemical marker for identifying these tumors. A 37-year-old lady was presented with a 10-cm-sized tumor in the pouch of Douglas, involving the vaginal vault, bilateral adnexa, and peritoneum. A 53-year-old lady with a prior hysterectomy was presented with a 12-cm-sized tumor in the vault with abdominal deposits. Histopathological examination of both tumors revealed atypical cells comprising oval to spindle-shaped nuclei, a variable amount of myxoid stroma, and mitotic figures exceeding 10/10 high power fields. Immunohistochemically, the former tumor was diffusely positive for CD10, and the second tumor displayed patchy staining. Both tumors were positive for BCOR. Estrogen receptor (ER) showed variable staining in both tumors. By fluorescence in-situ hybridization (FISH), both tumors lacked YWHAE gene rearrangement. Both tumors had an aggressive clinical course, including extensive involvement This constitutes the first report of BCOR-positive high-grade sarcomas involving the female genital tract from our subcontinent. BCOR is a useful immunostain for identifying these relatively aggressive tumors. The differential diagnoses and the prognosis of these ultra-rare tumors are discussed herewith.

Clinical features of uterine sarcomas presenting mainly with uterine masses: a retrospective study

BackgroundUterine sarcomas are uncommon mesenchymal tumors of the uterus. The clinical problem is that the features of uterine sarcomas can sometimes mimic uterine fibroids. This study aims to investigate the clinical characteristics of patients with uterine sarcomas who were preoperative presenting mainly with uterine masses.MethodsA retrospective analysis of patients who underwent gynecological surgery for uterine sarcomas at the Obstetrics & Gynecology Hospital of Fudan University, between January 2016 and December 2021.ResultsOver the 5-year period, 277 patients were final diagnosed of uterine sarcomas. A total of 162 patients were preoperatively diagnosed as uterine fibroids for surgical treatment, the majority of whom were diagnosed of uterine leiomyosarcoma (uLMS) (49/162) and low-grade endometrial stromal sarcoma (LG-ESS) (100/162). Ninety people underwent total hysterectomy and bilateral salpingo-oophorectomy (TH + BSO), while 72 underwent myomectomy followed by supplemental TH + BSO. The group with direct hysterectomy had a higher average age than the group with prior myomectomy (47.20 ± 8.94 vs. 40.86 ± 5.88, p < 0.001). Among patients preoperatively diagnosed as uterine fibroids, patients with uLMS had a higher proportion of previous myomectomy (26.53% vs. 5.00%, p < 0.001), a larger uterine mass diameter on ultrasound (8.38 ± 3.39 cm vs. 6.41 ± 1.92 cm, p < 0.001), and richer hypervascularity (34.69% vs. 18%, p = 0.024) compared with LG-ESS.ConclusionsAnalysis of our data showed that a large proportion of uterine sarcomas, especially uLMS and LG-ESS, present mainly with uterine masses. Ultrasound features including a large uterine mass diameter and rich hypervascularity, and with a history of myomectomy may alert clinicians in suspicion of uLMS when compared with LG-ESS.

Clinical characteristics and prognostic factors of endometrial stromal sarcoma and undifferentiated uterine sarcoma confirmed by central pathologic review: A multi-institutional retrospective study from the Japanese Clinical Oncology Group

ObjectivesLow-grade and high-grade endometrial stromal sarcomas (LGESS and HGESS) and undifferentiated uterine sarcomas (UUS) are rare tumors whose pathological classification and staging system have changed recently. These tumors are reported to contain fusion genes. We aimed to clarify the genetic background, clinical features, prognostic factors, and optimal therapy of these tumors using a new classification and staging system. MethodsWe analyzed the clinical features and prognostic information of 72 patients with LGESS, 25 with HGESS, and 16 with UUS using central pathological review. Estrogen and progesterone receptors (PgRs) were examined by immunohistochemistry. JAZF1–SUZ12 and YWHAE-NUTM2A/B gene fusions were tested using real-time polymerase chain reaction. ResultsThe 5-year overall survival (OS) rates of LGESS, HGESS, and UUS were 94%, 53%, and 25%, respectively. In LGESS, stage IV, incomplete surgery, and absence of PgR were associated with poor OS. The presence of JAZF1-SUZ12 fusion gene was not associated with OS. In HGESS, the relationship between stage and prognosis was unclear. None of the 3 patients with YWHAE-NUTM2A/B fusion gene died during follow-up. Adjuvant chemotherapy was associated with a favorable OS. Incomplete resection of UUS was associated with poor OS; however, residual tumors frequently occurred. Although most patients underwent adjuvant chemotherapy, their prognosis was extremely poor even in stage I disease. ConclusionsPrognosis of LGESS is generally good; however, stage IV, incomplete surgery, and PgR-negative tumors are associated with poor prognosis. Adjuvant chemotherapy may be useful for HGESS. Prognosis of UUS is extremely poor, even with adjuvant chemotherapy.

Metastatic Low-Grade Endometrial Stromal Sarcoma of Uterus Presenting as Urothelial Tumor: Case Report and Brief Review of Literature

Metastatic Low-Grade Endometrial Stromal Sarcoma of Uterus Presenting as Urothelial Tumor: Case Report and Brief Review of Literature

A Case of Uterine Tumor Resembling Ovarian Sex Cord Tumor With Prominent Myxoid Features.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor with low malignant potential that commonly occurs in middle age. Although more than 100 cases have been reported to date, myxoid morphology is not well documented. Here, we present a 75-yr-old woman with abnormal vaginal bleeding, with an 8-cm mass in the uterine corpus detected by irregular, high-intensity signaling on T2-weighted imaging. The uterine mass had a glistening mucinous appearance on gross examination. Microscopically, most of the tumor cells were floating in the myxoid stroma. The tumor cells formed clusters or nests with abundant cytoplasm, while some exhibited trabecular or rhabdoid appearances. Immunohistochemically, tumor cells were positive for pancytokeratin (AE1/AE3), α-smooth muscle actin, CD10, progesterone receptor, and some sex cord markers such as calretinin, inhibin, CD56, steroidogenic factor-1. Electron microscopy demonstrated epithelial and sex cord differentiation. This tumor was negative for JAZF1-JJAZ1 fusion gene that is frequently found in low-grade endometrial stromal sarcoma. Fusion genes related to UTROSCT, including NCOA2/3, were not detected by reverse transcription polymerase chain reaction. The present case suggests that UTROSCT should be included in the differential diagnosis of myxoid uterine tumors.

The KAT6B::KANSL1 Fusion Defines a New Uterine Sarcoma With Hybrid Endometrial Stromal Tumor and Smooth Muscle Tumor Features

Neoplasms harboring a KAT6B/A::KANSL1 fusion were initially reported as benign (leiomyomas) and malignant (leiomyosarcomas, low-grade endometrial stromal sarcomas [LG-ESSs]) uterine neoplasms. However, they may represent an emerging entity characterized by clinical aggressiveness contrasting with a rather reassuring microscopic appearance. Here, we aimed to confirm that this neoplasm is a distinct clinicopathologic and molecular sarcoma and identify criteria that should alert pathologists and lead to KAT6B/A::KANSL1 fusion testing in routine practice. Therefore, we conducted a comprehensive clinical, histopathologic, immunohistochemical, and molecular study, including array comparative genomic hybridization, whole RNA-sequencing, unsupervised clustering, and cDNA mutational profile analyses of 16 tumors with KAT6B::KANSL1 fusion from 12 patients. At presentation, patients were peri-menopausal (median, 47.5 years), and the primary tumors were located in the uterine corpus (12/12, 100%), with an additional prevesical location in 1 (8.3%) of 12 cases. The relapse rate was 33.3% (3/9). All tumors (16/16, 100%) showed morphologic and immunohistochemical features overlapping between leiomyoma and endometrial stromal tumors. A whirling recurrent architecture (resembling fibromyxoid-ESS/fibrosarcoma) was found in 13 (81.3%) of 16 tumors. All tumors (16/16, 100%) exhibited numerous arterioliform vessels, and 13 (81.3%) of 18 had large hyalinized central vessels and collagen deposits. Estrogen and progesterone receptors were expressed in 16 (100%) of 16 and 14 (87.5%) of 16 tumors, respectively. Array comparative genomic hybridization performed on 10 tumors classified these neoplasms as simple genomic sarcomas. Whole RNA-sequencing on 16 samples and clustering analysis on primary tumors found that the KAT6B::KANSL1 fusion always occurred between exons 3 of KAT6B and 11 of KANSL1; no pathogenic variant was identified on cDNA, all neoplasms clustered together, close to LG-ESS, and pathway enrichment analysis showed cell proliferation and immune infiltrate recruitment pathway involvement. These results confirm that the sarcomas harboring a KAT6B/A::KANSL1 fusion represent a distinct clinicopathologic entity, close to LG-ESS but different, with clinical aggressiveness despite a reassuring morphology, for which the KAT6B/A::KANSL1 fusion is the molecular driver alteration.

Prognostic factors, oncological treatment and outcomes of uterine sarcoma: 10 years’ clinical experience from a tertiary care center in Pakistan

BackgroundUterine sarcoma is an uncommon aggressive malignancy. Optimal management and prognostic factors have yet to be well recognized due to their rarity and various histological subtypes. This study aims to investigate these patients' prognostic factors, treatment modalities, and oncological outcomes.MethodsA single-center retrospective cohort study was conducted on all patients diagnosed with uterine sarcoma and treated from January 2010 to December 2019 in a tertiary-care hospital in Pakistan. The data were analyzed using STATA software and stratified on the histological subtype. Survival rates were estimated using the Kaplan–Meier method. Crude and adjusted hazard ratios with 95% CI were estimated using univariate and multivariate analysis.ResultsOf the 40 patients, 16(40%) had uterine leiomyosarcoma (u-LMS), 10(25%) had high-grade endometrial stromal sarcoma (HGESS), 8(20%) had low-grade endometrial stromal sarcoma (LGESS) and 6(15%) had other histological subtypes. The median age of all patients was 49 (40–55.5). Thirty-seven (92.5%) patients underwent primary surgical resection, and 24 (60%) patients received adjuvant systemic chemotherapy. The survival plots showed the overall population's DFS of 64 months and the OS of 88 months (p-value = 0.001). The median DFS in all patients was 12 months, and the median OS was 14 months (p-value = 0.001). A small but significant DFS benefit was found in patients who received adjuvant systemic chemotherapy, 13.5 versus 11 months (p-value = 0.001). Multivariate Cox-regression analysis revealed that large tumor size and advanced FIGO stage were substantial factors associated with decreased survival.ConclusionUterine sarcomas are rare malignancies with poor prognosis. Multiple factors, including tumor size, mitotic count, stage of the disease, and myometrial invasion, impact survival outcomes. Adjuvant treatment may decrease the recurrence rate and improve DFS but do not affect OS.

Metronomic dosing of selinexor in select soft tissue sarcomas (STS).

11557 Background: Selinexor (S) is a first-in-class, oral, selective inhibitor of nuclear export (SINE). S has a demonstrated anti-tumor activity in STS. However, the use of S can be associated with toxicities, such as nausea, anorexia and fatigue. A modified dosing schedule may improve the tolerability of S without compromising its efficacy. Methods: We evaluated S when given metronomically in patients (pts) with advanced metastatic leiomyosarcoma, endometrial stromal sarcoma, and malignant peripheral nerve sheath tumors. S was administered daily for 4-days in a row followed by 3-days break, repeated weekly in a 28-days cycle. Dose levels (DL) were escalated using a 3+3 design to determine maximum tolerated dose. DL included 2.5mg (DL1), 5mg (DL2), 7.5mg (DL3), 10 mg (DL4), 12.5 mg (DL5), 15 mg (DL6) and 17.5 mg (DL7). S was administered until unacceptable toxicities or disease progression. Imaging was performed every 8 weeks. Primary objectives were safety and tolerability as well as the determination of the recommended phase II dose. Secondary objectives were anti-tumor activity, toxicity profile, and pharmacokinetics (PK) profile. Results: Twenty-five pts (22 females/3 males, median age 59 years [range 35-84]) were enrolled at different DL (3, 3, 4, 6, 6, 3 pts at DL1 to DL6 respectively). The most common adverse events (AE) of any grade were constipation (n = 11, 50%), nausea (n = 11, 50%), and dysgeusia (n = 10, 45%). Eight (36%) pts experienced G3/4 AE while on trial; most were hematological toxicities seen in 3 (14%) pts (anemia, neutropenia, and leukopenia, n = 1 each). Non-hematological G3/4 AE were seen in 5 (23%) pts (Including: colonic obstruction, atrial fibrillation, and spinal cord compression, n = 1 each). Two Dose limiting toxicities were experienced, at DL4 (thrombocytopenia) and DL5 (transaminitis). Twenty-two pts were evaluable for response; 10 (45%) pts had stable disease (SD) as best response. Eight pts with SD had disease stability of &gt; 4 months. Twelve pts (55%) had progressive disease. Median progression-free survival was 2.4 months (95% CI 1.7-5.3 months). PK data is awaiting final analysis. Conclusions: Metronomic S demonstrated tolerability in selected sarcoma pts. Signs of potential clinical benefit was seen in the form of SD. Further data comparison with historical controls and PK analysis are needed to put this finding into perspective. Clinical trial information: NCT04811196 .

Efficacy of combination lurbinectedin (LURBI) + doxorubicin (DOX) from the phase 1B soft-tissue sarcoma (STS) lead-in to a randomized phase 2 trial in leiomyosarcoma (LMS).

11507 Background: Single agent or combination chemotherapy, typically Dox- or gemcitabine-based, are standard 1st- and 2nd-line therapies in patients (pts) with metastatic LMS; however, objective response rates (ORR), progression-free, and overall survival (PFS/OS) remain inadequate. Lurbi (PharmaMar S.A. / Jazz Pharmaceuticals) binds to DNA inhibiting transcription and inducing double strand breaks leading to apoptosis and delaying S/G2 progression. In a prior pilot study, we showed Lurbi+Dox is well-tolerated, with signs of activity, particularly in LMS. We designed this phase 1b to optimize dosing to lead into a randomized (1:1) phase 2 trial of Dox+/-Lurbi in anthracycline-naïve LMS. Herein we provide updated efficacy and tolerability data for this Phase 1b cohort. Methods: Pts &gt; 18 yrs with locally advanced/metastatic, unresectable non-GIST STS (Phase 1b only) w/o prior anthracycline or Lurbi/trabectedin, ECOG PS &lt; 3, RECIST 1.1 measurable, and normal organ function were eligible. The phase 1b followed a 3+3 design. Dosing included fixed Lurbi (3.2 mg/m2 d1) with two Dox dose levels (DL; DL1: 25 mg/m2 d1; DL2 25 mg/m2 d1+8). All pts received GCSF prophylaxis. Tumor assessments were every 2 cycles. DL1 was chosen as RP2D and the phase 2 trial began accrual in Aug 2022 aiming to enroll 50 LMS pts randomized 1:1 (stratified by uterine LMS [uLMS]] v. other LMS) with PFS as primary endpoint. Pts progressing on Dox are allowed to cross to Lurbi monotherapy. Results: 10 patients were enrolled in Phase 1b. Histologies included 5 LMS (4 uLMS) and 1 each of myxofibrosarcoma (myxFS), undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), endometrial stromal sarcoma (ESS), and solitary fibrous tumor (SFT). With a median follow-up of 344 days, 5/10 pts remain on treatment with median PFS of 357 days (95%CI 175-ND). 6 pts demonstrated partial response (PR; 5 confirmed), 3 with stable disease (SD), and 1 with progressive disease (PD, Table). Median time to PR was 81 days (range 46-207). Duration of response was over 132 days in all responders with 3 still on treatment. Treatment-related AEs were typical for Dox/Lurbi, including nausea, fatigue, and reversible LFT elevations/cytopenias. Updated safety and response data will be provided at the time of the meeting. Conclusions: Lurbi+Dox is well-tolerated with efficacy in STS including 6/10 pts achieving PR, 9/10 pts staying on treatment for &gt;120d, and 6/10 pts &gt;200d. The randomized phase 2 study is currently enrolling. Clinical trial information: NCT05099666 . [Table: see text]

3D genomics identify alternate mechanisms of homologous recombination deficiency in uterine sarcoma.

e17624 Background: Uterine sarcomas are rare tumors with diverse morphologic appearances, genetic underpinnings, and clinical behavior. Molecular characterization of these tumors by next generation sequencing (NGS) has improved disease classification and prognostication, but its impact on therapeutic selection remains limited. Analysis of 3D genomics datasets has recently been shown to detect large complex structural variants (SV) and chromatin architecture in normal and diseased human tissues. We applied genome-wide chromosome conformation capture (Hi-C) techniques in a variety of uterine sarcomas to identify novel therapeutic targets. Methods: Formalin-fixed paraffin-embedded tissue from 48 primary or recurrent uterine sarcomas were subjected to Hi-C to identify chromosomal rearrangements. The cohort included leiomyosarcoma (LMS, n = 7), adenosarcoma (AS, n = 7), endometrial stromal sarcoma (n = 7; high grade (HGESS), n = 4; low grade (LGESS), n = 3), sarcoma not otherwise specified (n = 17; high grade (HGNOS), n = 10, low grade (LGNOS), n = 7), undifferentiated uterine sarcoma (UUS, n = 6) and heterologous sarcoma (n = 2). Tumors were previously subjected to targeted DNA (n = 10) and/or RNA (n = 26) NGS with no therapeutic targets identified and only BCOR internal tandem duplication detected in a HGESS. Results: Hi-C detected SV in 73% of uterine sarcomas (n = 35/48), including those previously negative by targeted RNA NGS (n = 25/26). Homologous recombination repair (HRR) gene alterations were detected by Hi-C in 42% of tumors (n = 20/48), including AS (n = 5/7), HGESS (n = 2/4), LGESS (n = 1/3), LMS (n = 2/7), UUS (n = 2/6), heterologous sarcoma (n = 1/2), HGNOS (n = 3/10) and LGNOS (n = 1/7). SV included gene (gene to gene, n = 3; gene to non-coding DNA, n = 8) and proximity (n = 13) fusions disrupting HRR genes ( ATM, BRIP1, CDK12, CHEK1, CHEK2, NBN, PARP3, RAD51B, RAD51C, RAD51D) with enrichment for RAD51B fusions (50%, n = 10/20). Among all tumors with HRR gene alterations detected by Hi-C, only one uterine sarcoma harbored a missense ATM mutation by targeted DNA NGS (n = 1/5). Conclusions: Molecular characterization of uterine sarcomas by Hi-C may uncover HRR gene alterations not currently detectable by targeted DNA and RNA NGS. Homologous recombination deficiency (HRD) is not limited to LMS and may frequently result from SV, particularly between HRR gene to non-coding DNA in a variety of uterine sarcomas. These alternate mechanisms for HRD may serve as a potential therapeutic biomarker for HRD-targeted therapy in uterine sarcoma.

A single-arm, open-label phase 2 trial of doxorubicin plus zalifrelimab, a CTLA-4 inhibitor, with balstilimab, a PD-1 inhibitor, in patients with advanced/metastatic soft tissue sarcomas.

11501 Background: Doxorubicin (DOX) is the standard of care for unresectable soft tissue sarcomas (STS). DOX induces immunogenic cell death in numerous preclinical models. Immune checkpoint inhibitors (ICIs) including antibodies (ab) to PD-1 and CTLA-4 have shown modest activity, but most STS are immune “cold” tumors and do not respond. We hypothesized that concurrent DOX would improve immunogenicity of STS and boost efficacy of ICIs, including anti-CTLA-4 ab zalifrelimab (ZAL) and anti-PD-1 ab balstilimab (BAL). Methods: We conducted a single arm Phase 2 trial of combination DOX/ZAL/BAL for patients (pts) with advanced/metastatic STS in the 1st/2nd treatment lines without prior DOX or ICI (NCT04028063). The study was a Simon minimax 2-stage design to accrue 28 pts evaluable for primary endpoint of progression-free survival rate at 6 months (PFS6mo) by RECIST 1.1. We aimed to improve PFS6mo by 20% with DOX/ZAL/BAL over null rate of 43.4% based on average PFS of 2 prior DOX monotherapy trials. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and adverse events (AEs). All pts received up to 6 DOX cycles with concurrent ZAL/BAL; pts on stage 1 began DOX at cycle 2 with ZAL/BAL at cycle 1, pts on stage 2 began DOX/ZAL/BAL at cycle 1. Imaging was obtained prior to the first dose of DOX (baseline), and then every 6 weeks (wks) to 6 mo, and thereafter every 9 wks. Tumor biopsies/peripheral blood were obtained at baseline, on-treatment, and progression for immune profiling. Results: 35 patients were accrued as of 1/25/23. 25 pts are currently evaluable for primary endpoint of PFS6mo and 28 for efficacy (at least one post-treatment scan). PFS6mo is estimated at 52% (95%CI 31-72), with mPFS of 25.6 wks (24.0-44.9). ORR was 36% (19-56), and DCR was 86% (67-96). Median DOR was 12.8 wks (range 6 – 105). Most pts with PR who progressed did so on BAL after DOX completion. Responses were observed in pts with intimal sarcoma, angiosarcoma, MPNST, LPS, LMS, endometrial stromal sarcoma, UPS, and sclerosing epithelioid fibrosarcoma. Improved outcomes were observed in stage 1 pts compared to stage 2 pts, including PFS6mo (56.3% v. 25.0%), mPFS (31.7 v. 25.3 wks), ORR (56% v. 8.3%), and DCR (94% v. 75%). Toxicity was as expected with grade 3/4 TRAEs in 48% of 31 evaluable pts, primarily DOX-related hematologic AEs, and immune-related AEs requiring steroids in 19% of pts. Conclusions: Combination DOX/BAL/ZAL led to meaningful efficacy, including favorable PFS6mo and responses in several STS subtypes unlikely to respond to DOX or ICI monotherapy. Further investigation is required to determine if the stage 1 priming dose of ZAL/BAL prior to DOX improved clinical outcomes. An ongoing cohort is exploring a next-generation CTLA-4 inhibitor, botensilimab in combination with DOX +/- BAL. Clinical trial information: NCT04028063 .