Carcinosarcoma Patients Research Articles

Prognostic Nomogram for Predicting Survival, Clinicopathological Analysis, and Racial Disparities in Uterine Carcinosarcoma: A Retrospective Population-Based Study

Introduction: Uterine carcinosarcoma is an aggressive gynecologic malignancy that accounts for 5% of all gynecological malignancies. There is a disproportion in its incidence and mortality among different races. This study describes demographic and clinicopathological factors and racial disparities affecting the survival of patients with uterine carcinosarcoma. Methods: Data on uterine carcinosarcoma patients were obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2020. Results: Of the 11,338 patients identified, the median age at diagnosis was 68 years, and the five-year cause-specific survival (CSS) rate was 38.7%. for all races. Compared with Asian patients (39.5%, 95% CI, 36.0–43.4%), Hispanic patients (39.4%, 95% CI, 36.5–42.5%), and White patients (37.9%, 95% CI, 36.7–39.2%), Black patients accounted for 21% of the patients and had a significantly lower 5-year CSS (95% CI, 27.2–31.2%). The CSS rates were 84.4% (95% CI, 83.3–85.6%) for localized tumors, 68.5% (95% CI, 66.9–70.1%) for regional tumors, and 39.0% (95% CI, 36.9–41.2%) for distant tumors. Multimodal treatment involving chemotherapy, surgery, and radiation improved the overall one- and five-year survival rates by 88.2% (95% CI, 87.0–89.5%) and 52.8% (95% CI, 50.7–55.1%), respectively, across all disease stages. Multivariate analysis identified age >60 years, Black race, tumor size >4 cm, and distant metastases as independent risk factors for mortality (p < 0.0001). Conclusions: This large database study presents the most up-to-date epidemiological information regarding cases of uterine carcinosarcoma. The findings suggest that a combination of surgery, chemotherapy, and radiation may be most efficacious in treating this malignancy, especially in patients with distant disease.

Effect of histological subtype on the efficacy of perioperative chemotherapy in pulmonary sarcomatoid carcinoma: a retrospective study based on SEER population.

The efficacy of perioperative chemotherapy (PC) in pulmonary sarcomatoid carcinoma (PSC) is controversial. We conducted this study to investigate the effect of different histological subtypes on the efficacy of PC in PSC patients. Clinicopathological data of 811 PSC patients of different histological subtypes were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier method and log-rank test were used to evaluate the effects of PC on the overall survival (OS) and cancer-specific survival (CSS) in different subtypes of PSC patients. Propensity score matching (PSM) was used to reduce potential confounding effects. Subgroup analyses were conducted to further investigate the efficacy of PC in patients with different characteristics. A total of 210 (25.89%) enrolled PSC patients received PC. PC was not associated with OS or CSS benefit in pleomorphic carcinoma, giant cell carcinoma, or spindle cell carcinoma patients, neither before nor after matching. But survival benefit of PC was observed in carcinosarcoma patients both before (5-year OS: 48.79% vs. 38.75%, P=0.01) and after (5-year OS: 51.29% vs. 17.54%, P=0.003) matching. Subgroup analyses showed that in patients whose tumor larger than 4 cm, PC was still associated with improved survival in carcinosarcoma, but not in the other histological subtypes of PSC. The efficacy of PC varies between different subtypes of PSC. Survival benefit of PC was only observed in carcinosarcoma patients, but not in pleomorphic carcinoma, giant cell carcinoma, or spindle cell carcinoma patients. Histological subtype should be considered when treating PSC patients with PC.

Monitoring Treatment Response, Early Recurrence, and Survival in Uterine Serous Carcinoma and Carcinosarcoma Patients Using Personalized Circulating Tumor DNA Biomarkers.

Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology such as droplet digital polymerase chain reaction (ddPCR) may represent a novel platform for the identification of occult disease. We explored the use of personalized ctDNA markers for monitoring USC and CS patients. Tumor and plasma samples from USC/CS patients were collected at the time of surgery and/or during the treatment course for assessment of tumor-specific somatic structural variants (SSVs) by a clinical-grade next-generation sequencing (NGS) platform (i.e., Foundation Medicine) and a droplet digital PCR instrument (Raindance, ddPCR). The level of ctDNA was quantified by droplet digital PCR in plasma samples and correlated to clinical findings, including CA-125 serum and/or computed tomography (CT) scanning results. The genomic-profiling-based assay identified mutated "driver" target genes for ctDNA analysis in all USC/CS patients. In multiple patients, longitudinal ctDNA testing was able to detect the presence of cancer cells before the recurrent tumor was clinically detectable by either CA-125 or CT scanning. Persistent undetectable levels of ctDNA following initial treatment were associated with prolonged progression-free and overall survival. In a USC patient, CA-125 and TP53 mutations but not PIK3CA mutations become undetectable in the plasma at the time of recurrence, suggesting that more than one customized probe should be used for monitoring ctDNA. Longitudinal ctDNA testing using tumor-informed assays may identify the presence of residual tumors, predict responses to treatment, and identify early recurrences in USC/CS patients. Recognition of disease persistence and/or recurrence through ctDNA surveillance may allow earlier treatment of recurrent disease and has the potential to change clinical practice in the management of USC and CS patients. CtDNA validation studies in USC/CS patients prospectively enrolled in treatment trials are warranted.

Ovarian and uterine carcinosarcomas are sensitive in vitro and in vivo to elimusertib, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor

BackgroundCarcinosarcoma of the ovary (OCS) and uterus (UCS) are rare highly aggressive malignancies. Ataxia-telangiectasia-and-Rad3-related (ATR) kinase and homologous recombination play a pivotal role in DNA damage repair. Homologous recombination deficiency (HRD) has been demonstrated in >30% of OCS/UCS. We investigated the preclinical activity of elimusertib, a selective ATR kinase inhibitor, against carcinosarcoma (CS) cell lines and xenografts. MethodsSensitivity to elimusertib was evaluated in vitro against nine whole exome-sequenced (WES) primary CS cell lines and in vivo against HRD CS xenografts. Western blots were performed to determine baseline ATR and p-ATR protein expression in CS, and ATR pathway downstream effectors and apoptosis markers in CS HRD cell lines after Elimusertib treatment. ResultsOut of the 9 CS cell lines, 3 harbored HRD and 6 homologous recombination proficient (HRP) features. Most of CS (i.e., 7/9 = 85%) were found to be sensitive to Elimusertib in vitro. Among the 5 primary CS cell lines with a high-grade pure serous epithelial component, HRD cell lines were more sensitive to elimusertib than HRP tumors (mean IC50 ± SEM HRD CS = 61.3 nM ±15.2 vs HRP = 361.6 nM ±24.4 (p = 0.01)). Baseline ATR and p-ATR protein expression was higher in HRD CS cell lines. Elimusertib showed tumor growth inhibition in HRD CS xenografts (p < 0.0001) and increased overall animal survival (p < 0.0001). Western blot demonstrated dose-dependent inhibition of ATR, p-ATR and its downstream effector p-CHK1, and a dose-dependent increase in caspase-3 expression. ConclusionsElimusertib is preclinically active in vitro and in vivo against primary CS cell lines and xenografts, respectively. CS models harboring HRD or with pure/mixed endometrioid histology demonstrated higher sensitivity to ATR inhibition. Clinical trials with elimusertib in CS patients are warranted.

A novel hypoxia-related genes signature for prognosis and immunotherapeutic sensitivity in uterine carcinosarcoma patients

article: A novel hypoxia-related genes signature for prognosis and immunotherapeutic sensitivity in uterine carcinosarcoma patients - Gazzetta Medica Italiana - Archivio per le Scienze Mediche 2022 September;181(9):670-9 - Minerva Medica - Journals

Carcinosarcoma of the nasal cavity and paranasal sinuses: Review of the national cancer database.

Carcinosarcomas are rare, aggressive malignancies that can arise in the nasal cavity and paranasal sinuses. There are limited outcome data available. Accordingly, we sought to use the National Cancer Database (NCDB) to characterize patient demographics and outcomes. A retrospective analysis of the NCDB from 2004 to 2016 for patients with sinonasal carcinosarcoma was conducted. Thirty patients were included. The patients were predominantly male (n = 20), white (n = 23), and privately insured (n = 15), with an average age of 62.4 years. The nasal cavity was the most common subsite (n = 14), followed by the maxillary sinus (n = 8). Most patient were treated with surgery followed by radiation (n = 23), with the remaining undergoing surgery alone (n = 4), radiation alone (n = 2), or no treatment (n = 1). One-third (n = 10) received adjuvant chemotherapy. The 1- and 5-year overallsurvival (OS) in the cohort were 79.2% and 43.3%, respectively. Univariate log-rank testing showed OS varied based on intervention (P < 0.029), sex (P < 0.042), and age (P < 0.025), while on multivariate analysis none of these factors independently predicted OS. We describe the demographics and presenting features of a national cohort of sinonasal carcinosarcoma patients. Future research is needed to identify predictors of overall survival, and to assess the optimal roles for radiation and systemic chemotherapy.

Improved survival with combination chemotherapy and external beam radiation therapy in uterine carcinosarcoma

ObjectivesTo evaluate differences in survival and recurrence patterns in stage I–IV uterine carcinosarcoma patients treated with surgery followed by adjuvant chemotherapy alone, radiation alone, or a combination of both chemotherapy...

Homologous recombination deficiency (HRD) signature-3 in ovarian and uterine carcinosarcomas correlates with preclinical sensitivity to Olaparib, a Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor (043)

<b>Objectives:</b> Carcinosarcoma (CS) of the ovary and uterus are highly aggressive malignancies associated with poor survival. Poly (ADP-ribose)-polymerase (PARP) inhibitors are targeted agents impairing DNA repair via homologous-recombination-deficiency (HRD) mechanisms. We used whole-exome sequencing (WES) data from a large cohort of CS patients to investigate if ovarian carcinosarcoma (OCS) and uterine carcinosarcoma (UCS) possess the mutational signature of homologous recombination deficiency (HRD). The preclinical activity of olaparib in OCS and UCS cell lines and xenograft models were then evaluated. <b>Methods:</b> WES data from 73 CS samples (25 OCS and 48 UCS), including fresh frozen tissues and primary cell lines, were analyzed for HRD signatures as described by Alexandrov et al. (Nature;2020;578:94-101). Olaparib activity on cell cycle, apoptosis, and cytotoxicity was evaluated against ten fully WES primary CS cell lines. Olaparib antitumor activity was tested <i>in vivo</i> against HRD CS xenografts. <b>Results:</b> From a tot al of 73 CS patients, 60% (15 of 25) of OCS versus 17% (13 of 48) of UCS harbored an HRD-related signature (Signature-3), (p<0.002). Of the ten primary fully sequenced CS cell lines, four were HRD (3 OCS vs 1 UCS), and six were HR proficient (HRP) (5 UCS vs 1 OCS). HRD CS cell lines were significantly more sensitive to olaparib when compared to HRP cell lines [mean IC50 ± SEM: 2.94 μM ± 0.07 vs mean ± SEM: 23.3 μM ± 0.09, (p=0.02). In HRD cell lines, olaparib suppressed CS cell growth through cell cycle arrest in the G2/M phase and caused apoptosis (HRD vs HRP (<i>p</i> < 0.0001]). <i>In vivo</i>, olaparib significantly impaired HRD CS xenografts tumor growth (p= 0.001) and increased overall animal survival (p=0.002) (Figure). <b>Conclusions:</b> A large subset of OCS, and to a lower extent, UCS harbor an HRD-related signature. Primary HRD OCS and UCS cell lines are sensitive <i>in vitro</i> and <i>in vivo</i> to olaparib. Clinical studies with PARP inhibitors in CS patients with an HRD signature (Signature-3) are warranted.Fig. 1

Endometrial cancer molecular profiling in a Caribbean-Black patient population (404)

Objectives: To characterize the molecular profiles of endometrial cancer (EC) and correlate with clinical outcomes in a Caribbean- Black patient population. Methods: A multi-center retrospective analysis of Caribbean-Black patients with surgically staged EC from 2015-2021 was conducted. All patients underwent comprehensive surgical staging and/or tumor debulking and molecular tumor profiling performed on pathologic specimens via next-generation sequencing (NGS). Tumors were classified based on TCGA/ProMisE classification: MMR deficient (MMR-d/ MSI-H), p53 abnormal (p53abn), p53 wild type (p53wt), and POLE mutated (POLEmut). Differences in the frequencies of histologic subtypes, stage distribution, and adjuvant therapy were compared using Pearson’s Chi-square test. Progression-free survival (PFS) and overall survival (OS) rates were calculated between p53abn versus other mutational profiles (p53wt and MMR-d/MSI-H) using Kaplan- Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. Results: Of the 119 patients meeting inclusion criteria, the final analysis included 76 patients with complete follow-up data. Tumors were classified as MMR-d/MSI-H (n=11, 14.5%), p53abn (n=43, 56.6%), p53wt (n=21, 27.6%), and POLEmut (n=1, 1.3%). The median age at diagnosis was 64 years (range: 26-82). Histology included 44.0% endometrioid, 47.5% uterine serous (USC), 14.5% carcinosarcoma, and 8.5% clear cell adenocarcinomas. There was no significant difference in the stage distribution between different mutation profiles (p=0.725). USC tumors were associated with p53abn, and endometrioid tumors were associated with MMR-d/MSI-H (p<0.01). All carcinosarcoma patients were p53abn. Patients with p53abn tumors were significantly more likely to receive chemotherapy alone or in combination with radiotherapy versus all other cohorts (p<0.01). One patient with stage IA endometrioid tumor demonstrated POLEmut; this patient remains recurrence-free without adjuvant therapy and was excluded from survival analyses. When compared to all other mutational profiles, p53abn tumors trended towards poorer PFS (29 vs 22 months, respectively; p=0.209) and OS (not reached vs 43 months respectively; p=0.102). On MVA, USC histology and p53abn were significant independent predictors of survival (p=0.03 and p=0.05, respectively). Conclusions: Tumors with p53abn are found in more than half of Caribbean-Black EC patients, with an overrepresentation of aggressive type II histologies in this population compared to those previously reported in the general population. Although not reaching statistical significance, there is a trend towards worse survival outcomes in these p53abn tumors. Further studies are warranted to evaluate EC adjuvant therapy in the context of molecular profiles to improve outcomes for this high-risk patient population. Objectives: To characterize the molecular profiles of endometrial cancer (EC) and correlate with clinical outcomes in a Caribbean- Black patient population. Methods: A multi-center retrospective analysis of Caribbean-Black patients with surgically staged EC from 2015-2021 was conducted. All patients underwent comprehensive surgical staging and/or tumor debulking and molecular tumor profiling performed on pathologic specimens via next-generation sequencing (NGS). Tumors were classified based on TCGA/ProMisE classification: MMR deficient (MMR-d/ MSI-H), p53 abnormal (p53abn), p53 wild type (p53wt), and POLE mutated (POLEmut). Differences in the frequencies of histologic subtypes, stage distribution, and adjuvant therapy were compared using Pearson’s Chi-square test. Progression-free survival (PFS) and overall survival (OS) rates were calculated between p53abn versus other mutational profiles (p53wt and MMR-d/MSI-H) using Kaplan- Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. Results: Of the 119 patients meeting inclusion criteria, the final analysis included 76 patients with complete follow-up data. Tumors were classified as MMR-d/MSI-H (n=11, 14.5%), p53abn (n=43, 56.6%), p53wt (n=21, 27.6%), and POLEmut (n=1, 1.3%). The median age at diagnosis was 64 years (range: 26-82). Histology included 44.0% endometrioid, 47.5% uterine serous (USC), 14.5% carcinosarcoma, and 8.5% clear cell adenocarcinomas. There was no significant difference in the stage distribution between different mutation profiles (p=0.725). USC tumors were associated with p53abn, and endometrioid tumors were associated with MMR-d/MSI-H (p<0.01). All carcinosarcoma patients were p53abn. Patients with p53abn tumors were significantly more likely to receive chemotherapy alone or in combination with radiotherapy versus all other cohorts (p<0.01). One patient with stage IA endometrioid tumor demonstrated POLEmut; this patient remains recurrence-free without adjuvant therapy and was excluded from survival analyses. When compared to all other mutational profiles, p53abn tumors trended towards poorer PFS (29 vs 22 months, respectively; p=0.209) and OS (not reached vs 43 months respectively; p=0.102). On MVA, USC histology and p53abn were significant independent predictors of survival (p=0.03 and p=0.05, respectively). Conclusions: Tumors with p53abn are found in more than half of Caribbean-Black EC patients, with an overrepresentation of aggressive type II histologies in this population compared to those previously reported in the general population. Although not reaching statistical significance, there is a trend towards worse survival outcomes in these p53abn tumors. Further studies are warranted to evaluate EC adjuvant therapy in the context of molecular profiles to improve outcomes for this high-risk patient population.

Ovarian and uterine carcinosarcoma cell lines show preclinical sensitivity to BAY 1895344, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor (011)

<b>Objectives:</b> Carcinosarcoma (CS) of the ovary (OCS) and uterus (UCS) are highly aggressive malignancies, poorly responsive to currently available adjuvant treatment. Ataxia-telangiectasia and Rad3-related (ATR) kinase and homologous recombination play a pivotal role in DNA damage repair (DDR). Homologous recombination (HR) deficiency has been demonstrated in 60% of OCS and 17% of UCS. BAY 1895344 is a selective ATR kinase inhibitor that has proved strong monotherapy efficacy in models that carry DDR deficiencies, such as HRD. This study aimed to test <i>in vitro</i> and <i>in vivo</i> preclinical activity of BAY 1895344 in both HR deficient (HRD) and proficient (HRP) OCS and UCS cell lines and xenograft models. <b>Methods:</b> Sensitivity to BAY 1895344 was evaluated <i>in vitro</i> against nine fully whole-exome sequenced (WES) primary CS cell lines according to HR status. BAY 1895344 antitumor activity was tested <i>in vivo</i> against an HRD CS xenograft model. <b>Results:</b> Of the nine primary fully WES CS cell lines, three were HRD (2 OCS vs 1 UCS) and six HRP (5 UCS vs 1 OCS). <i>In vitro</i> sensitivity to BAY 1895344 was observed in seven out of nine CS cell lines (Figure A). While a trend was observed for higher sensitivity (i.e., lower IC50) in HRD tumors (mean IC50 ± SEM HRD: 64.44 nM ± 15.18 vs HRP: 147.2 nM ± 68.7); however, this difference was not statistically significant (p=0.4244) (Figure A). <i>In vivo</i>, BAY 1895344 showed significant tumor growth inhibition in HRD CS xenografts (p<0.0001) (Figure B) and increased overall animal survival (p<0.0001) (Figure C). No significant toxicity was observed when compared to vehicle controls. <b>Conclusions:</b> Most primary OCS and UCS cell lines with and without HRD signature (Signature-3) by WES are sensitive <i>in vitro</i> to BAY 1895344. Furthermore, <i>in vivo,</i> primary HRD OCS xenografts are responsive to the drug. While further research will be necessary to determine the mechanisms underlying ATR kinase inhibition sensitivity in HRP CS, clinical studies with BAY 1895344 in CS patients with an HRD signature are warranted.Fig. 1

Evaluation of chemotherapy and radiotherapy in the adjuvant management of uterine carcinosarcoma: a population-based analysis.

To evaluate the effects of adjuvant chemotherapy (CT) and radiotherapy (RT) on the survival of uterine carcinosarcoma (UCS) patients. We analyzed 3207 patients with uterine carcinosarcoma without distant metastasis after surgery from 2004 to 2015 by utilizing data from the Surveillance, Epidemiology, and End Results database. Generally, cancer-specific survival (CSS) and overall survival (OS) outcomes were analyzed by Kaplan-Meier and Cox proportional hazards regression models. Further subgroup survival analysis was performed for those receiving RT and chemoradiotherapy (CRT). In general, both univariate and multivariate analyses showed that age, race, marital status, stage, lymph node metastasis, lymphadenectomy (LND), RT, and chemotherapy (CT) were associated with improved CSS and OS (P < 0.05). Further subgroup analysis showed that CRT exhibited a survival advantage over RT or CT alone in different groups. Various RT modalities, including brachytherapy (BT), external radiotherapy (EBRT), and EBRT + BT, were correlated with improved survival for patients aged 60-69years with stage III-IV disease and lymph node metastasis. Patients with stage I-II disease aged > 70years seemed to gain survival benefits from brachytherapy (BT) alone. BT with or without external radiotherapy was associated with improved survival for those who did not undergo lymphadenectomy. For UCS without distant metastasis after surgery, CRT should be considered. Regarding RT, BT alone is efficient in improving survival, especially for patients with stage I-II disease aged > 70years old. EBRT alone does not show results in survival improvement for patients who did not undergo LND and those with lymph node metastasis. However, considering the limitation of SEER database, further studies with more large sample size and strict study design are needed to confirm it.

Sentinel lymph node biopsy alone compared to systematic lymphadenectomy in patients with uterine carcinosarcoma

ObjectiveTo assess survival among patients diagnosed with uterine carcinosarcoma (CS) who underwent sentinel lymph node (SLN) biopsy alone vs. systematic lymph node dissection (LND). MethodsWe identified newly diagnosed CS patients who underwent primary surgical management from January 1996–December 2019. The SLN cohort underwent SLN biopsy alone with bilateral SLNs identified. The systematic LND cohort did not undergo SLN biopsy. ResultsNinety-nine patients underwent SLN biopsy, and 100 patients underwent systematic LND. There was no difference by age, stage, body mass index, myoinvasion (<50%, ≥50%), lymphovascular space invasion, or positive washings. Eighty-five SLN (85.9%) and 15 LND (15%) underwent minimally invasive surgery (P < 0.001). The median total node count was four (range, 1–13) for SLN and 19 (range, 2–50) for LND (P < 0.001). Nodal metastasis occurred in 23 (23.2%) SLN and in 22 (22%) LND (P = 0.4). Postoperative therapy was administered to 85 (85.9%) SLN and 71 (71%) LND (P = 0.02). Median follow-up was 33 months (range, 1–205) for SLN and 55.3 months (range, 1–269) for LND (P = 0.001). The three-year progression-free survival (PFS) was 62.9% (SE 5.2%) for SLN and 52.3% (SE 5.3%) for LND (P = 0.13). The three-year overall survival (OS) was 72.1% (SE 5.1%) for SLN and 71.6% (SE 4.6%) for LND (P = 0.68). An isolated nodal recurrence occurred in two (2%) SLN and four (4%) LND (P = 0.26). ConclusionsThere is no difference in PFS or OS among CS patients who undergo SLN biopsy vs. systematic LND. SLN biopsy detects nodal metastasis without compromising oncologic outcomes.

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.

Prognosis of the patients suffered from uterine carcinosarcoma from rural and urban areas.

Uterine carcinosarcoma is a very aggressive neoplasm. Patients' median age at diagnosis ranges from 62 to 67 years. The aim of this study was to compare treatment results and prognostic factors for residents of urban and rural areas suffering from uterine carcinosarcoma. Clinical outcomes of 58 uterine carcinosarcoma patients treated in one institution were assessed: 25 residents of rural and 33 of urban areas. All the patients were treated by using surgery followed by chemotherapy (48 pts) or radiotherapy (10 pts). Standard chemotherapy regimen comprised of paclitaxel 175 mg/m2 and carboplatin on day one at area under curve (AUC) six every 21 days. Radiotherapy was performed by combined treatment - tele and brachytherapy. External beam pelvic radiation therapy (EBRT) once a day, five days a week with a daily fraction size of 1.8 Gy over five weeks at cumulative dose 50.4 Gy was the first part of adjuvant treatment. High-dose-rate (HDR) brachytherapy at dose 22.5 Gy was the second part of radiotherapy. A strong correlation between tumor diameter and the presence of lymph node metastasis was observed. Tumor size greater then 4.5 cm correlated with presence of node involvement and this parameter was statistically significant (p = 0.015). There was no significant correlation between other analyzed clinical factors and overall survival. In the period 2004-2010 43.5% (10/23) and 50% (14/28) of rural and urban residents, respectively, died due to carcinosarcoma progression. Uterine carcinosarcoma patients in rural and urban areas seem to have similar outcomes.

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.

Uterine Carcinosarcoma: A Plan for Treatment

Background: Uterine carcinosarcomas are very aggressive tumors in the womb that are associated with poor prognosis. They represent only less than 5% of uterine tumors and the incidence rate is less than 2 per 100,000 women per year. Objective: We reviewed diagnosis and treatment of women with uterine carcinosarcoma. To determine if lymphadenectomy, chemotherapy and radiotherapy are associated with decreased recurrence and increased survival. To prove that multimodality therapy including surgery, chemotherapy and radiotherapy are the ideal treatment for this malignancy. Patients and Methods: The rarity of the tumor made us depend on thirty cases done over 5 years mainly stage 1, 2 and 3 in University of Aswan between 2014 and 2018. We abstracted: histopathology results, survival outcomes from archived medical reports for the qualifying cases and patient demographics. Patient age at surgery and preoperative CA-125 for patient demographics. Histopathological results: cancer stage, depth of myometrial invasion, grade. Treatment data: Surgical details and use of postoperative adjuvant chemotherapy or radiotherapy or both. Results: Most uterine carcinosarcoma (UCS) patients are candidates for adjuvant chemotherapy combination therapy, but in-depth testing has not been widely used. The high rate of recurrence and poor overall survival indicate an ongoing need for clinical trials specifically. Hazard of death and recurrence decreased with chemotherapy multiagent and vaginal brachytherapy with five years of higher survival and disease free survival. Also lymphadenectomy decreased recurrence and rate of death associated with. Conclusion: Adjuvant chemotherapy with vaginal brachytherapy with lymphadenectomy were associated with increased survival and decreased recurrence of women with UCS.

Prognostic factors and survival outcomes of uterine sarcomas in a reference gynecologic oncology cancer center

Background/Aim: Uterine sarcomas are rare and aggressive tumors, and their clinical behavior is unpredictable. A clear-cut clinical course, proven treatment method or definitive prognostic factors affecting the survival of sarcoma patients are not reported in the literature. We aim to evaluate uterine sarcomas, determine clinicopathologic features, adjuvant therapies, and prognostic factors on survival while sharing our experience of these rare uterine tumors in light of the literature. Methods: This retrospective cohort study was conducted in Tepecik Training and Research Hospital, Izmir, Turkey between 2002-2020. Out of the total of 205 uterine sarcoma patients, 173 patients who underwent surgical procedures and were followed up in our hospital’s Gynecologic Oncology Clinic were included in the study. Data of patients were collected from the hospital database. Surgical interventions, clinicopathologic features, adjuvant therapies, and overall and disease-free survivals were evaluated. Patients were grouped as leiomyosarcoma (LMS), carcinosarcoma (CS), endometrial stromal sarcoma (ESS), adenosarcoma (AS), and undifferentiated sarcoma (US). Results: The mean age of the patients was 57.6 (11.2) years. According to the International Federation of Gynecology and Obstetrics (FIGO2009), 115 patients (66.5%) had stage 1, 17 patients (9.8%) had stage 2, 31 (17.9%) patients had stage 3, and 10 patients (5.8%) had stage 4 disease. One hundred and sixty-two patients (93.6%) received adjuvant therapy. Median follow-up period was 39 months (range 3-214). The 120-month OS for the entire group was 87.1%. Conclusion: Stage is a significant prognostic factor for survival in all sarcoma types and recurrence is a significant prognostic factor for survival for LMS and CS patients. Sarcoma type and adjuvant treatments have no impact on survival. ESS patients require extended surgical staging.

Clinical Nomograms for Predicting the Overall Survival and Cancer-specific Survival of patients with Ovarian Carcinosarcoma patients after Primary Surgery.

Background: At present, there is no clinical prediction model for ovarian carcinosarcoma (OCS) that is based on a large sample of real data. This study aimed to construct nomograms using data extracted from the Surveillance, Epidemiology, and End Results (SEER) database that can be used to predict the overall survival (OS) and cancer-specific survival (CSS) of patients with OCS and further guide the choice of clinical treatment.Methods: We selected 2753 cases of OCS from the SEER database from 1998 to 2016. Patients were randomly divided in a 7:3 ratio into a training cohort (n = 1929) and a validation cohort (n = 824). Cox analysis was used to select prognostic factors for OS and CSS, and nomograms were then established. The performance of nomogram models was assessed using the concordance index, the area under the receiver operating characteristic curve, calibration curves, and by decision curve analysis. Data from 21 OCS patients at Shengjing Hospital from 2001 to 2021 were collected for external verification. Kaplan-Meier curves were plotted to compare survival outcomes between subgroups.Results: Nomograms based on independent prognostic factors showed good predictive power and clinical practicality. Internal and external validation indicated that the nomograms performed better than staging and grading systems. Significant differences were observed in the survival curves of different risk subgroups.Conclusions: The developed nomograms will enable individualized evaluation of the OS and CSS, thus guiding the treatment of patients with OCS.

The PARP inhibitor niraparib demonstrates preclinical activity against HRD-deficient carcinosarcomas

Objective: Carcinosarcoma of the ovary and uterus represent rare, highly aggressive malignancies associated with poor survival outcomes. PARP inhibitors represent novel treatment options for cancers with underlying impaired DNA repair via homologous recombination mechanisms. We used whole exome sequencing (WES) data from a large cohort of carcinosarcoma patients to investigate whether ovarian (OCS) and uterine carcinosarcoma (UCS) possess the mutational signature of homologous recombination deficiency (HRD) and whether there may be a role for HRD-directed therapies.

Carcinosarcoma of the Uterus: A Study From the Surveillance Epidemiology and End Result (SEER) Database.

Background: Uterine cancer (UC) is one of the leading gynecologic neoplastic disorders in the United States (US), of which over 80% are endometrioid adenocarcinomas (EA). In contrast to EA, carcinosarcoma (CS) of the uterus is a sporadic and highly malignant tumor, phylogenetically containing both epithelial and mesenchymal histologic elements. This study sought to analyze demographic, pathological retrospectively, and survival characteristics of a large cohort of CS patients compared to EA patients to identify prognostic factors and treatment approaches that may improve the current clinical management of CS patients.Methods: Demographic and clinical data were abstracted from 88,530 patients diagnosed with uterine malignancy from the Surveillance, Epidemiology, and End Results (SEER) database for 38 years (1973-2010). Extracted variables were analyzed using the Chi-square test, paired t-test, and multivariate analysis, while Kaplan-Meier functions were used to compare survival between groups. Statistical analyses were performed with IBM Statistical Product and Service Solutions (SPSS©), version 20.2 (IBM Corp., Armonk, NY).Results: A total of 3,706 cases of CS comprised 38.2% of uterine sarcomas (n=9,702), and 4.1% of uterine cancers overall (n=88,530). EA made up 88.6% (n=78,481) of all uterine cancers. CS patients presented later in life (68.3±11.5 years) than EA (61.9±12.5 years). 65.2% of CS and 77.8% of EA occurred in Caucasians. The incidence (per million) of EA was higher in Caucasians compared to African-Americans (AA) (41% vs. 26.8%), while the incidence of CS was higher among AA than Caucasians (4% vs. 1.9%, p<0.001). 33.4% of CS was poorly differentiated at presentation, compared to 13.1% of EA. 27.8% of CS patients presented with a distant disease compared to only 4.7% of EA patients. 29.9% of AA patients with CS presented with metastatic disease, compared to 28.2% of Caucasian patients (p<0.001). Mean survival for CS patients (6.6±0.2 years) was significantly lower than that of EA patients (17.7±0.7 years, p<0.001), and AA CS patients had significantly lower survival than Caucasians CS patients (4.5±0.4 years vs. 7.1±0.3 years, p<0.001). CS patients treated with combined surgery and radiotherapy had the highest survival (9.4±0.5 years, p<0.001), while EA patients treated with surgery alone had the highest survival (20.4±1.2 years, p<0.001). Survival among AA CS patients treated with combination therapy was significantly inferior compared to Caucasians (6.5±0.6 years vs. 9.8±0.5 years, p<0.001). Multivariate analysis identified CS histology (odds ratio [OR] 1.9, CI=1.7-2.1), AA race (OR 1.3, CI=1.2-1.4), age over 40 (OR 3.4, CI=2.9-4.1), undifferentiated grade (OR 3.0, CI=2.6-3.4), and distant metastases (OR 6.2, CI=5.8-6.8) as independently associated with increased mortality (p<0.005). The use of radiotherapy in CS patients was independently associated with decreased mortality (OR 0.1, CI=0.02-0.6, p<0.005).Conclusions: Uterine CS is a highly malignant tumor with a significantly worse prognosis than EA. AA has a considerably higher CS incidence compared to EA. Moreover, AA CS had higher tumor grades, higher rates of metastatic disease, and experienced significantly lower overall survival compared to Caucasians despite receiving similar therapy. Primary radiotherapy or combination radiotherapy confers a survival advantage to AA uterine CS patients.