Gynecologic Carcinosarcomas Research Articles

A phase Ib/II single-arm study of cabozantinib plus dostarlimab among women with recurrent gynecologic carcinosarcoma

A phase Ib/II single-arm study of cabozantinib plus dostarlimab among women with recurrent gynecologic carcinosarcoma

Mesothelin expression in gynecologic carcinosarcoma: clinicopathological significance and correlation with HER2 expression.

This study aimed to evaluate mesothelin (MSLN) expression and determine its clinical significance and correlation with human epidermal growth factor receptor 2 (HER2) expression in gynecological carcinosarcoma. We retrospectively evaluated patients with uterine carcinosarcoma (UCS) and ovarian carcinosarcoma (OCS) who underwent surgery between 1997 and 2019. Immunohistochemical staining of formalin-fixed, paraffin-embedded specimens for MSLN (clone SP74) and HER2 (clone 4A5) was also performed. MSLN was scored using the H-score and 4-tired scoring system (0-3+). MSLN positivity was defined as any positive cell at any intensity, while high MSLN expression was defined as an intensity of ≥2+ in ≥30% of tumor cells. HER2 expression was scored according to modified 2018 American Society of Clinical Oncology/College of American Pathologists criteria. A total of 128 patients were recruited, including 119 with UCS and 9 with OCS. All cases in UCS exhibited MSLN positivity, and 33.9% showed high-MSLN expression. Clinicopathological characteristics were not significantly associated with high or low-MSLN expression. However, the high-MSLN group showed more prolonged overall survival (OS) than the low-MSLN group (not assessed vs. 36.8 months; hazard ratio=0.48, 95% confidence interval=0.26-0.89, p=0.016). HER2-high patients had higher MSLN expression than HER2-negative patients. In high-MSLN and low-MSLN expression groups, HER2 status did not affect OS. OCS showed 100% MSLN positivity, with 66.6% high-MSLN. MSLN expression is widely observed in gynecological carcinosarcomas. Moreover, high-MSLN expression is a favorable prognostic factor for UCS. MSLN could be a promising therapeutic target for UCS, even in the era of anti-HER2 therapy.

Racial and Ethnic Disparities in Gynecologic Carcinosarcoma: A Single-Institution Experience.

We aimed to determine the incidence, treatment regimen, and treatment outcomes (including progression-free survival and overall survival) of gynecologic carcinosarcoma, a rare, aggressive, and understudied gynecologic malignancy. This retrospective review included all patients with gynecologic cancers diagnosed and treated at a single tertiary care comprehensive cancer center between January 2012 and May 2021. A total of 2116 patients were eligible for review, of which 84 cases were identified as carcinosarcoma: 66 were uterine (5.2% of uterine cancers), 17 were ovarian (3.6% of ovarian cancers), 1 was cervical (0.28% of cervical cancers), and 1 was untyped. Of the patients, 76.2% presented advanced-stage disease (stage III/IV) at the time of diagnosis. Minority patients were more likely to present with stage III/IV (p < 0.0001). The majority of patients underwent surgical resection followed by systemic chemotherapy with carboplatin and paclitaxel. The median PFS was 7.5 months. Of the patients, 55% were alive 1 year after diagnosis, and 45% were alive at 5 years. In the studied population, minorities were more likely to present with more advanced disease. The rate of gynecologic carcinosarcomas was consistent with historical reports.

Gynecological carcinosarcomas: Overview and future perspectives

Gynecologic carcinosarcoma (CS) are rare and aggressive tumors composed of high-grade carcinoma and sarcoma. Carcinosarcoma account for less than 5% of uterine and ovarian carcinoma and patients have poor outcome with a 5-year overall survival of less than 30%. In early-stage setting, the treatment mainstay is surgery and adjuvant chemoradiotherapy or adjuvant chemotherapy in uterine (UCS) and ovarian CS (OCS), respectively. In metastatic or advanced stage disease, chemotherapy is the rule with a lower response rate and poorer prognosis compared to other high-grade carcinomas. Although very few treatment options are available, CS are often excluded from the clinical trials precluding therapeutic improvement. However, recent molecular advances are paving the way for new therapeutic strategies. In the current proposal, we extensively review the uterine and ovarian carcinosarcomas including epidemiology, pathology, genomic landscape, as well as current therapies and future perspectives.

Gynecologic carcinosarcomas: Exploring the disease in different racial groups (2232)

Gynecologic carcinosarcomas: Exploring the disease in different racial groups (2232)

Germline drivers of gynecologic carcinosarcoma (2274)

Germline drivers of gynecologic carcinosarcoma (2274)

Folate receptor alpha is widely expressed and a potential therapeutic target in uterine and ovarian carcinosarcoma

ObjectiveFolate receptor alpha (FRα), which is expressed in various cancers, is a potential therapeutic target. However, its expression and clinical significance in uterine (UCS) and ovarian carcinosarcoma (OCS) remain to be elucidated. MethodsThis retrospective study included patients with gynecologic carcinosarcoma who underwent primary surgery between 1997 and 2019 at our institution. Immunohistochemical staining of surgical FFPE specimens was performed for FRα and HER2. FRα was evaluated using the H-score and the 4-tired scoring system (0 to 3+). Subsequently, FRα expression (≥5% of tumor cells with ≥1+ intensity) and FRα-high (score 2+ and 3+) were evaluated. HER2 was scored according to the modified ASCO/CAP criteria. The association between FRα-high and clinicopathological features, HER2 expression, and survival was assessed in UCS. ResultsA total of 120 patients with UCS and nine patients with OCS were included. In UCS, FRα expression was observed in all patients, whereas FRα-high status was present in 20% of patients. Among HER2-negative UCS, 34% exhibited FRα-high. No significant association was observed between clinicopathological characteristics and FRα status. During the follow-up period (median 34.5 mo), FRα-high was not strongly associated with progression, free survival, and overall survival. All the OCS tumor specimens showed FRα-high expression. ConclusionsFRα expression was observed in all the UCS and OCS specimens, including HER2-negative UCS patients. This widespread FRα expression suggests that FRα-targeted therapies may hold promise for the treatment for gynecologic carcinosarcoma. However, in uterine carcinosarcoma, no significant relationship was observed between FRα expression and clinicopathological features or prognosis.

Germline drivers of gynecologic carcinosarcomas

ObjectivesTo describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma. MethodsPatients with endometrial or ovarian carcinosarcomas who underwent clinical tumor-normal sequencing from 1/1/2015 to 6/1/2021 and consented to germline assessment of ≥76 cancer predisposition genes were included. In patients with gPVs, biallelic inactivation was identified through analysis of loss of heterozygosity and somatic pathogenic alterations. ResultsOf 216 patients identified, 167 (77%) were diagnosed with endometrial carcinosarcoma and 49 (23%) with ovarian carcinosarcoma. Overall, 33 gPVs were observed in 29 patients (13%); 20 gPVs (61%) had biallelic loss in tumors. The rate of high-penetrance gPVs overall was 7% (16 of 216); 88% of high-penetrance gPVs had biallelic loss. In the endometrial carcinosarcoma cohort, 22 gPVs were found in 19 (11%) of 167 patients; 12 gPVs (55%) had biallelic loss in tumors, including 8 (89%) of 9 in high-penetrance gPVs. Among the ovarian carcinosarcoma cohort, 11 gPVs were found in 10 (20%) of 49 patients; 8 gPVs (73%) had biallelic loss in tumors, and all evaluable high-penetrance gPVs (n = 6) had biallelic loss. All gPVs in homologous recombination (BRCA1, BRCA2, RAD51C) and Lynch syndrome (MSH2, MSH6) genes had biallelic loss in tumors (n = 15). ConclusionsgPVs in genes affecting homologous recombination- or Lynch-associated mismatch repair exhibited biallelic inactivation within tumors, suggesting likely drivers of gynecologic carcinosarcoma. Our data support germline testing for patients with gynecologic carcinosarcomas, given implications for treatment and risk-reduction in patients and at-risk family members.

Abstract 3437: Whole genome and transcriptome sequencing of a pan cancer cohort unearths novel therapeutic avenues

Abstract Whole genome sequencing (WGS) has emerged as a tool to characterize the entire genomic landscape of cancer and capture potential new targets and predictive biomarkers. Using state-of-the-art whole-genome and transcriptome sequencing (WGTS) analysis we interrogated a pan cancer cohort to nominate new treatment options. WGS was performed on 414 tumor/germline pairs from our pan cancer cohort of 355 patients, of which 103 had results of other commercial NGS assays. RNAseq data was available in 96 samples. We employed the Isabl GxT analytic platform and manually curated single base substitution (COSMIC v3) mutational signatures and structural variants (SVs). WGTS results were correlated with available clinico-pathologic data. High throughput drug screening that included PARP inhibitors and functional validation were performed in 61 matched patient-derived tumor organoids (PDTO). We found 5,129 SVs affecting at least one cancer gene in 88% of cases. High-confidence homologous recombination deficiency (HRD), determined by curation of mutational signatures and mutations/SVs affecting oncogenes and tumor suppressor genes, was detected in 8.3% of solid tumors (e.g., prostate, pancreas, ovarian, uterine, breast, gallbladder, and stomach carcinomas). HRD status included tumors with BRCA1/2 wildtype and SVs impacting BRCA1/2, RAD51, ATM and other HRD genes. CDK12-loss associated genomic instability was detected in 7 cases including 3 cases of prostate adenocarcinoma. 93 gene fusions involving cancer genes were detected including known and novel fusions of potential significance (e.g., SLC45A3::ALK in metastatic prostate adenocarcinoma, TMEM106A::BRCA1 in serious ovarian carcinoma, ESR1::EP300 in metastatic breast cancer). Some tumor cohorts demonstrated enrichment of drivers e.g., FGFR1 amplification in male breast cancer, rearrangements at the TERT locus in adrenocortical carcinoma, enrichment for repeat-mediated deletion attributed to mismatch repair (MMR) in gynecological carcinosarcoma, and SVs affecting FHIT in gastric adenocarcinoma. Drug screening of PDTO and functional testing with RAD51 immunofluorescence assay validated high-confidence HRD annotation. One example is a BRCA1/2 wildtype pancreatic adenocarcinoma with increased tandem duplications and SV (inversion) impacting BRCA2, and high-confidence HRD by our novel WGS classifier. Drug screening of the corresponding PDTO showed an enhanced response to Olaparib, in contrast to cases without HRD that did not. We have used state-of-the-art analysis of WGTS to improve the detection of targets and significant biomarkers in a pan cancer cohort, including HRD, CDK12-type genomic instability, pathogenic germline mutations and potential targetable novel fusions. A robust and clinically relevant ex vivo preclinical model allowed us to validate a WGS-based classifier that detects HRD even in cancers with wildtype BRCA1/2. Citation Format: Majd Al Assaad, Hui-Hsuan Kuo, Jones Nauseef, Max F. Levine, Gunes Gundem, Juan S. Medina-Martínez, Jyothi Manohar, Michael Sigouros, Ahmed Elsaeed, David Wilkes, Elli Papaemmanuil, Eloise Chapman, Scott T. Tagawa, Allyson Ocean, Cora N. Sternberg, Eleni Andreopoulou, Manish Shah, Andrea Sboner, Kevin Holcomb, David Nanus, Laura Martin, Olivier Elemento, Juan Miguel Mosquera. Whole genome and transcriptome sequencing of a pan cancer cohort unearths novel therapeutic avenues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3437.

Trends in Gynecologic Carcinosarcoma Based on Analysis of the Surveillance Epidemiology End Result (SEER) Database.

Carcinosarcomas (malignant mixed Mullerian tumors) of a female genital organ are rare tumors associated with a poor survival. The purpose of this study was to identify site-specific differences in the incidence and prognosis in carcinosarcomas originating in the uterus, cervix, or ovary. The data of patients with gynecologic carcinosarcomas were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2016. The characteristics of gynecologic carcinosarcomas were compared using Pearson X2 and Fisher's exact tests. Kaplan-Meier models were used for cause-specific survival (CSS) analysis. The cohort included 7086 females, including 5731 cases of uterine carcinosarcoma, 161 cervical carcinosarcomas, and 1193 ovarian carcinosarcomas. The age-adjusted incidence rates of uterine, cervical, and ovarian carcinosarcoma were 3.9, 0.1, and 0.6 per 1,000,000, respectively. In the distribution of carcinosarcoma incidence by race, compared with the uterus or cervix, those originating from the ovary were unequally distributed in Caucasians (84.4% versus 69.6%, 67.7%; p < 0.001). The incidence of uterine carcinosarcoma steadily increased over time, from 2.2 in 2000 to 5.5 in 2016 (per 1,000,000), while cervical or ovarian carcinosarcoma showed no significant difference in incidence. The five-year CSS rates based on the site of origin (uterus, cervix, and ovary) were 39.9%, 33.1%, and 25.8%, respectively. The incidence rates of gynecologic carcinosarcoma, especially uterine carcinosarcoma, are gradually increasing. Although uterine carcinosarcoma is associated with a higher incidence than the others, it has a better prognosis compared with ovarian and cervical carcinosarcoma. The survival rates were worst in ovarian carcinosarcoma.

Prognostic significance of heterologous component in carcinosarcoma of the gynecologic organs: a systematic review and meta-analysis.

The aim of this study is to determine the histologic presence of heterologous component as a prognostic factor in gynecologic carcinosarcoma through a systematic review and meta-analysis. PubMed, Web of Science, and Embase were searched for publications. Studies that evaluated survival effect of sarcomatous component based on histology in human ovarian or uterine carcinosarcoma were included. Two authors independently reviewed the references based on eligibility criteria and extracted the data including primary tumor site, survival outcome, type of survival outcome, and proportion of each sarcomatous differentiation. The quality of each eligible study was assessed with Newcastle-Ottawa scale. Meta-analysis was conducted using a random-effects model to estimate hazard ratio (HR) and 95% confidence intervals (CIs) of survival outcome for carcinosarcoma with or without heterologous component. Eight studies including 1,594 patients were identified. Overall proportion of carcinosarcoma with heterologous component was 43.3%. Presence of heterologous component was associated with worse overall survival (HR=1.81; 95% CI=1.15-2.85) but not with pooled recurrence-free survival and disease-free survival (HR=1.79; 95% CI=0.85-3.77). Removing multivariate analysis studies, early-stage studies, ovarian tumor study, or studies with large number of patient samples did not affect the significance between heterologous component and overall survival. Gynecologic carcinosarcoma is histologically a biphasic tumor which comprise of epithelial and mesenchymal components. Our study emphasizes pathologic evaluation of heterologous component as a prognostic factor in gynecologic carcinosarcoma when all stages were considered. PROSPERO Identifier: CRD42022298871.

Molecular Characterizations of Gynecologic Carcinosarcomas: A Focus on the Immune Microenvironment.

Simple SummaryGynecologic carcinosarcomas are rare and highly aggressive tumors. Despite treatment, response rates are low, and the survival outcomes of patients with carcinosarcoma are far worse than high-grade tumors of the same origin. Due to this, there is a need for new, tailored therapies. The role of immunotherapy has not been extensively studied in gynecologic carcinosarcomas, but emerging studies suggest that there is a potential role that should be explored further. The aim of this review is to outline the current knowledge about gynecologic carcinosarcomas, with a focus on their molecular profiles and the tumor immune microenvironment, and discuss possible directions for future research.Gynecologic carcinosarcomas, specifically of endometrial and ovarian origin, are aggressive and rare tumors. Treatment data are limited and are often extrapolated from other histologies and smaller retrospective studies. While the optimal therapy approach remains contentious, treatment is often multimodal and may include surgery, chemotherapy, radiation, or a combination of multiple strategies. However, despite aggressive treatment, these tumors fare worse than carcinomas of the same anatomic sites irrespective of their stage. Recent studies have described in-depth molecular characterizations of gynecologic carcinosarcomas. Although many molecular features mirror those seen in other uterine and ovarian epithelial tumors, the high prevalence of epithelial-mesenchymal transition is more unique. Recently, molecular descriptions have expanded to begin to characterize the tumor immune microenvironment. While the importance of the immune microenvironment has been well-established for other tumor types, it has been less systematically explored in gynecologic carcinosarcomas. Furthermore, the use of immunotherapy in patients with gynecologic carcinosarcomas has not been extensively evaluated. In this review, we summarize the available data surrounding gynecologic carcinosarcomas, with a focus on the immune microenvironment. We end with a discussion of potential immunotherapy uses and future directions for the field.

Sarcoma regimens for gynecologic carcinosarcoma: Is there a benefit? (186)

<b>Objectives:</b> To compare differences in overall survival (OS) in patients with carcinosarcomas of endometrial or ovarian origin who were ever treated with sarcoma chemotherapy regimens compared to those who only received traditional carcinoma regimens. <b>Methods:</b> We conducted a single-institution, retrospective cohort study of patients with a confirmed histologic diagnosis of uterine or ovarian carcinosarcoma diagnosed since the year 2000. Clinical, pathology, and outcomes data were collected. Patients were considered to have received a sarcoma-based regimen if any of their treatment courses included ifosfamide, combination gemcitabine/ docetaxel, or any other regimens listed on the NCCN guidelines for soft tissue sarcomas. Clinical and demographic characteristics were compared across groups using Chi-square, Fisher's exact, or Wilcoxon rank-sum tests. OS was evaluated using a log-rank test. <b>Results:</b> A total of 88 patients with carcinosarcoma of endometrial (77%) or ovarian (22%) origin were identified, 78 of whom had chemotherapy information available. Sixteen (23%) of the patients received chemotherapy that included a sarcoma regimen, 51 (65%) received only carcinoma regimens, and 13 (16%) did not receive any chemotherapy. We excluded ten patients for whom there was no chemotherapy information from the analysis. Among those who received any chemotherapy, there were no significant differences in age, BMI, race, use of radiation, number of lines of chemotherapy received, disease stage, or optimal cytoreduction rate between the two regimen groups. Patients were more likely to have an endometrial primary if they ever received a sarcoma regimen (Table 1). There was no difference in OS between the sarcoma regimen and non-sarcoma regimen groups (HR: 0.71, 95% CI: 0.30-1.64). Older age, stage IV disease, and suboptimal debulking status were associated with shorter OS in this group of patients (p<0.05). <b>Conclusions:</b> Patients who ever received a sarcoma-based regimen did not have longer OS. Since sarcoma regimens tend to have more toxicity, exclusive use of carcinoma regimens for patients with gynecologic carcinosarcomas may be beneficial.

Folate receptor alpha expression is widely observed in uterine and ovarian carcinosarcoma (209)

<b>Objectives:</b> Folate receptor alpha (FRα) expression has been observed in various cancers, including endometrial, ovarian, lung, and triple-negative breast cancers. FRα is an intriguing therapeutic target, and its expression and clinical significance in uterine and ovarian carcinosarcoma remain to be elucidated. <b>Methods:</b> This retrospective study included patients with gynecologic carcinosarcoma who underwent primary surgery at our institution between 1997 and 2019. Immunohistochemical staining of one representative section of the surgical formalin-fixed paraffin-embedded tissue specimens for FRα was performed using an anti-folate-binding protein/FBP antibody (1:200, ab67422; Abcam, Cambridge, UK). The H-score for FR expression was calculated as follows: 3X+2Y+Z, where X, Y, and Z were the proportions of tumor cells showing strong (3+), moderate (2+), and weak (1+) staining intensities, respectively. FRα-positive staining was defined as more than 5% tumor staining of any intensity and FRα-high as an H-score greater than 50. The association between FRα-high expression and clinical-pathologic features or survival was assessed. <b>Results:</b> Overall, 122 patients with uterine carcinosarcoma and seven patients with ovarian carcinosarcoma were included. In uterine carcinosarcoma, the median age was 62 years (range: 34-87). FIGO (2008) stage distribution was 49, 7, 39, and 26 patients in stage I, II, III, and IV, respectively. FRα expression was observed in all patients, and the median H-score was 50 (range: 10-170). FRα-high showed no significant correlation with age, FIGO stage, a predominant histologic subtype of carcinomatous component, or heterologous sarcomatous elements. During follow-up (median: 30.6 months, range: 0.7-216), 57 patients experienced disease recurrence or died, and 29 patients received palliative chemotherapy. FRα-high was not significantly associated with disease-free survival (HR: 1.16, 95% CI: 0.68-1.98, p=0.58) and overall survival (HR: 1.27, 95% CI: 0.74-2.20, p=0.38), respectively. There was no significant difference in the overall response rate to chemotherapy by FRα-high status. In ovarian carcinosarcoma, all tumor specimens showed FRα expression, and the median H-score was 45 (range: 10-70). The median age was 64 years (range: 55-88), and four patients had FIGO (2008) stage III or IV (57%). <b>Conclusions:</b> FRα expression was observed in all patients with uterine and ovarian carcinosarcoma, but the level of expression was lower than those previously reported in endometrial and ovarian cancers. In uterine carcinosarcoma, there was no significant relationship between FRα overexpression and clinical-pathologic features or prognosis. This widespread FRα expression may provide insights into the development of FRα-targeted therapies for gynecologic carcinosarcoma.

Programmed Death Ligand 1 (PD-L1) Expression and CD8 + Tumor-infiltrating Lymphocyte-based Tumor Immune Microenvironment Classification in Gynecologic Carcinosarcoma: Prognostic Impact and Implications for Therapy.

To investigate the prevalence and prognostic significance of programmed death ligand-1 (PD-L1) expression and CD8 + tumor-infiltrating lymphocytes (TILs) in gynecologic carcinosarcoma, 81 cases (68 uterine, 12 ovarian, and 1 fallopian tube) were immunostained with PD-L1 and CD8 using tissue microarrays (3 mm core diameter) from intratumoral areas with the highest TILs. Tumor proportion score (TPS) ≥1% and combined positive score (CPS) ≥1 were considered positive for PD-L1. CD8 + TILs were counted in each core, and CD8 + TIL density (CD8TILD) was calculated. Cases were classified as CD8 Neg (<1.4/mm 2 CD8TILD), CD8 Pos (≥1.4/mm 2 CD8TILD) and CD8 HIGH (≥14/mm 2 CD8TILD) and grouped into 4 tumor immune microenvironment (TIME) groups: (1) PD-L-1 Pos /CD8 Pos , (2) PD-L1 Neg /CD8 Neg , (3) PD-L1 Pos /CD8 Neg , and (4) PD-L1 Neg /CD8 Pos . PD-L1 expression by TPS and CPS was detected in 19.8% and 39.6% cases, respectively. Kaplan-Meier curves with log-rank analysis showed that higher density of CD8 + TILs were associated with longer overall survival (OS) ( P =0.05 for CD8 Pos and P =0.014 for CD8 HIGH ), and CD8 HIGH status was associated with longer OS irrespective of tumor stage ( P =0.045, hazard ratio: 0.11, 95% confidence interval: 0.014-0.951). Thirty-three percent of patients belonged to TIME group 1. PD-L1 expression and TIME groups were not associated with OS or progression-free survival. We found that high density of CD8 + TILs is an independent indicator of better OS. In 33% cases PD-L1 expression is associated with increased CD8 + TILs ("acquired immune evasion" pattern of PD-L1 expression), hence they may benefit from anti PD-1/PD-L1 therapy. PD-L1 expression alone and TIME groups do not affect survival in gynecologic carcinosarcoma.

Therapeutic Challenges in Patients with Gynecologic Carcinosarcomas: Analysis of a Multicenter National Cohort Study from the French Prospective TMRG Network.

Simple SummaryGynecologic carcinosarcomas are rare and aggressive diseases with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. Using the data from the French National Rare Malignant Gynecological Tumors (TMRG) network, we conducted a multicentric cohort study to explore several burned questions. The main objective was to assess the outcome of patients with carcinosarcomas recorded in the network and to investigate the efficacy of initial adjuvant treatment and recurrent therapeutic strategies in a real-life setting. Four hundred and twenty-five patients were analyzed including 313 uterine and 112 ovarian carcinosarcomas. Our data suggest positive impact of adjuvant chemotherapy on survival in all stages (including FIGO IA uterine carcinosarcomas) and the importance of platinum-based combination for the treatment of relapse. In addition we report median PFS for various therapeutic strategies in the relapse setting.Background: Gynecological carcinosarcomas are rare and aggressive diseases, with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. The objective of this study was to investigate the impact of initial adjuvant treatment and recurrent therapeutic strategies. Patients and methods: A multicentric cohort study within the French national prospective Rare Malignant Gynecological Tumors (TMRG) network was conducted. Data from all included carcinosarcomas diagnosed between 2011 and 2018 were retrospectively collected. Results: 425 cases of uterine and ovarian carcinosarcomas (n = 313 and n = 112, respectively) were collected and analyzed from 12 participating centers. At diagnosis, 140 patients (48%) had a FIGO stage III–IV uterine carcinosarcoma (UCS) and 88 patients (83%) had an advanced ovarian carcinosarcoma (OCS) (FIGO stage ≥ III). Two hundred sixty-seven patients (63%) received adjuvant chemotherapy, most preferably carboplatin-paclitaxel regimen (n = 227, 86%). After a median follow-up of 47.4 months, the median progression-free survival (mPFS) was 15.1 months (95% CI 12.3–20.6) and 14.8 months (95% CI 13.1–17.1) for OCS and UCS, respectively. The median overall survival for OCS and UCS was 37.1 months (95% CI 22.2–49.2) and 30.6 months (95% CI 24.1–40.9), respectively. With adjuvant chemotherapy followed by radiotherapy, mPFS was 41.0 months (95% CI 17.0–NR) and 18.9 months (95% CI 14.0–45.6) for UCS stages I–II and stages III–IV, respectively. In the early stage UCS subgroup (i.e., stage IA, n = 86, 30%), mPFS for patients treated with adjuvant chemotherapy (n = 24) was not reached (95% CI 22.2–NR), while mPFS for untreated patients (n = 62) was 19.9 months (95% IC 13.9–72.9) (HR 0.44 (0.20–0.95) p = 0.03). At the first relapse, median PFS for all patients was 4.2 months (95% CI 3.5–5.3). In the first relapse, mPFS was 6.7 months (95% CI 5.1–8.5) and 2.2 months (95% CI 1.9–2.9) with a combination of chemotherapy or monotherapy, respectively (p < 0.001). Conclusions: Interestingly, this vast prospective cohort of gynecological carcinosarcoma patients from the French national Rare Malignant Gynecological Tumors network (i) highlights the positive impact of adjuvant CT on survival in all localized stages (including FIGO IA uterine carcinosarcomas), (ii) confirms the importance of platinum-based combination as an option for relapse setting, and (iii) reports median PFS for various therapeutic strategies in the relapse setting.

Increased incidence with improved survival of gynecologic carcinosarcoma: A population-based study

ObjectiveTo evaluate trends in the incidence and survival of gynecologic carcinosarcoma over the last 35 years and to explore ethnic disparities. Study designUsing the Israeli National Cancer Registry database, all cases of gynecologic carcinosarcoma were included (1980–2014). Age at diagnosis, patient’s ethnicity and anatomical site were extracted. Age-standardized incidence rates (ASRs) were calculated for 3 time periods (1980–1994, 1995–2004 and 2005–2014). Relative survival was calculated using the Pohar-Perme method. ResultsOverall, 935 cases of gynecologic carcinosarcomas were diagnosed during 1980–2014. The most common gynecologic anatomical site was the uterus (83.4%). Most cases (66%) were diagnosed at ages 60–80, with median age of 69 years.There was a steady increase in ASRs from 5.6 to 8.2 per million women. Throughout 1980–1994 and 2005–2014, ASRs were significantly higher in the Jewish compared to the Arab population (5.8 vs. 3.1, p = 0.02 and 8.5 vs. 5.2, p = 0.002, respectively).Relative survival rates increased throughout the study period. No significant differences were noted in relative survival between the Jewish and Arab populations (p = 0.18). ConclusionThe incidence of gynecologic carcinosarcoma increased significantly from 1980 through 2014. Nevertheless, survival rates increased during this time, with no difference in survival between the Jewish and Arab populations.

Metronomic cyclophosphamide and bevacizumab for the treatment of recurrent gynecologic carcinosarcoma: A multi-institution, retrospective study.

5532 Background: The recent findings from the GOG 261 trial established carboplatin and paclitaxel as the standard first-line therapy for advanced gynecologic carcinosarcoma (GCS). Response rates to alternative regimens are limited, and the optimal chemotherapy for later line treatment of gynecologic carcinosarcoma has not yet been determined. The objective of this retrospective study is to report clinical response to treatment regimens for patients with GCS treated at 2 large academic referral comprehensive cancer centers. Methods: This multi-institution, retrospective analysis identified patients with recurrent GCS treated between January 1, 2015 and August 1, 2020 at the Massachusetts General Hospital and the University of Alabama O’Neal Comprehensive Cancer Center. All eligible patients received platinum/taxane as their first-line treatment regimen and were subsequently treated for recurrent disease. Subsequent treatment strategies were investigated. Objective responses were determined based on the clinical radiologist’s interpretation. Time on treatment (TOT) and treatment toxicity were identified for each subject. Given the small number of patients in this series, descriptive statistics were employed. Results: 29 patients met inclusion criteria. 15 patients had recurrent uterine carcinosarcoma, and 14 patients had recurrent ovarian carcinosarcoma. The most commonly used treatment regimens were: liposomal doxorubicin (PLD)/bevacizumab (ORR: 13%; Range TOT: 2-7 months), metronomic oral cyclophosphamide (MOC)/bevacizumab (ORR: 17%; Range TOT: 1-18 months), weekly paclitaxel/bevacizumab (ORR 60%; Range TOT: 3-18.5 months), liposomal doxorubicin (PLD) (ORR: 0%; Range TOT: 1-3 months), and weekly paclitaxel (ORR: 33%; Range TOT: 4.5-5.5). All regimens were generally well tolerated, and only 3 patients discontinued treatment due to toxicity concerns. Conclusions: In summary, in our cohort of gynecologic carcinosarcoma patients, the most active regimen (defined by mean TOT) was paclitaxel/bevacizumab, but prolonged TOT was also observed in the patients treated with MOC/bevacizumab. Given the rarity and aggressive nature of this tumor, further studies into optimal second line chemo (and beyond) are warranted; although, the combination of MOC/bevacizumab should be considered given the tolerability and the duration of treatment in this patient population.

Open-label, multicenter, phase 1b/2 study of rebastinib in combination with paclitaxel to assess safety and efficacy in patients with advanced or metastatic endometrial cancer.

5576 Background: Rebastinib is a first-in-class investigational, orally administered, potent and selective switch-control kinase inhibitor of tunica interna endothelial cell kinase (TIE2). This is a 2-part open-label, multicenter Phase 1b/2 study of rebastinib in combination with paclitaxel. Here we provide updated results (ASCO 2020) from the fully enrolled endometrial cancer (EC) cohort of the study. Methods: Part 2 of the study has five disease-specific cohorts (EC, platinum-resistant ovarian cancer, gynecological carcinosarcoma, TNBC and inflammatory breast cancer). Patients were treated at the RP2D and evaluated for efficacy (RECIST v1.1) and safety (CTCAE v5.0). Results: As of Jan 8, 2021, 38 EC patients were enrolled (median age of 66 years); 42% were of grade 2/3 endometroid histological subtype. All patients received at least 1 prior line of paclitaxel in combination with carboplatin and 79% of patients received ≥3 prior anti-cancer regimens. Sixteen of 38 patients were initially treated with a starting dose of rebastinib 100 mg BID, 11 of which dose reduced to 50 mg BID, and 22 patients were treated with a starting dose of rebastinib 50 mg BID, in combination with paclitaxel 80 mg/m2 IV weekly (days 1, 8, 15 of 28-day cycle). In 33 evaluable patients with median follow-up of 5.9 months, the ORR was 33% and clinical benefit rate at 8 and 16 weeks was 70% and 55%, respectively, including 11 PRs (8 confirmed) and 12 SDs. Treatment-emergent adverse events ( &gt; 20% of patients; mostly ≤ grade 2) included fatigue (n = 18), constipation, peripheral edema (each at n = 16), peripheral sensory neuropathy, nausea (each at n = 15), dyspnea (n = 13), alopecia, hypokalemia (each at n = 11), diarrhea, hypomagnesemia (each at n = 10), dry mouth, dysgeusia (each at n = 9), arthralgia, hypertension, dehydration, GERD and muscular weakness (each at n = 8). Serious adverse events (SAE) at least possibly related to rebastinib included muscular weakness (n = 2 at 100 mg BID, n = 1 at 50 mg BID), nausea (n = 2), acute myocardial infarction, atrial flutter, dehydration, non-infective encephalitis, peritonsillitis, and stress cardiomyopathy (each at n = 1) and were resolved after dose interruption. Conclusions: The updated results of rebastinib at 50 mg BID in combination with paclitaxel showed encouraging preliminary anti-tumor activity and an acceptable safety profile in heavily pretreated EC patients, and supports further development in patients with EC (NCT03601897). Clinical trial information: NCT03601897.

ROCSAN trial (GINECO-EN203b/ENGOT-EN8): A multicentric randomized phase II/III evaluating dostarlimab in combination with niraparib versus niraparib alone compared to chemotherapy in the treatment of endometrial/ovarian carcinosarcoma after at least one line of platinum based chemotherapy.

TPS5604 Background: Gynecological carcinosarcomas (CS) are rare and highly aggressive tumors with a 5-year overall survival (OS) &lt; 10%. After initial treatment majority of patients (pts) relapse and receive diverse chemotherapies (CT) producing modest benefits. The median PFS in relapse after platinum based CT is less than 4 months and median OS less than 1 year. New innovative strategies are urgently needed. Since CS showed high DNA damage response activity and potentially a high tumor mutation load resulting in neo-antigens, a synergy between PARPi and anti-PD1 is expected. Methods: ROCSAN is a multicentric, randomized, open-label, integrated Phase II/III study. In the Phase II, 63 pts with recurrent or progressing endometrial or ovarian CS after at least a first line of platinum-based CT will be randomized (2:2:1) to receive either niraparib in monotherapy, niraparib in combination with dostarlimab or standard CT (paclitaxel, doxorubicine, gemcitabine, topotecan). Stratification factors include the number of previous CT lines (1 vs 2-3), FIGO stage at diagnosis (I-II vs III-IV), CS localisation (ovarian vs endometrial), and performance status (0-1 vs 2). The primary objective of the Phase II is to select the best experimental strategy between niraparib and dostarlimab/niraparib combination based on Response Rate at 4 months (RR-4M by RECIST1.1). A single stage design with a 10% unacceptable RR-4M and a 30% targeted RR-4M was used to determine Phase II sample size, assuming a 10% one sided alpha for each comparison and more than 90% power. A pick-the-winner selection design could be used in case of promising efficacy in each experimental arm. At the interim analysis, an Independent Data Monitoring Committee will make recommendation for the selection of the optimal experimental arm. The Steering committee could then support to continue enrolment for the international Phase III which is calibrated to detect an improvement in median OS from 7 months (Standard CT) to 11.7 months (best experimental arm). Assuming a 5% alpha level and 80% power, 133 additional pts could be randomized (2:1). Secondary endpoints include safety, PFS, PFS2, TTST, ORR, duration of response, patient report outcomes (assessed via EORTC QLQ-C30 OV28, HADS, PRO-CTCAE). A translational program supported by European Community is associated to the clinical study to identify predictive biomarkers of response/resistance to study treatments, to correlate with immune environment, a special focus on genetic instability and the EMT process will be included. Trial is currently recruiting only in France for the phase II part, the first pt was randomized in July 2020. Clinical trial information: NCT 03651206.