Serous Adenocarcinoma Research Articles

OPTIMISING THE TREATMENT OF PATIENTS WITH ADVANCED OVARIAN CANCER: AN ANALYSIS OF PRELIMINARY RESULTS

Summary. Aim: to evaluate surgical complications, side effects of chemotherapy, 1- and 3-year survival in patients with advanced ovarian cancer against the background of the introduction of optimized personalized treatment. Object and methods: for this purpose, a comparative analysis of the results of clinical examination and treatment of 74 patients with primary serous ovarian adenocarcinoma of stages III–IV (FIGO 2015) who were treated at the University Clinic of Odesa National Medical University was conducted. Patients were divided into 2 groups: Group IA — patients with primary ovarian cancer who were treated with primary cytoreductive surgery (PDS) + adjuvant chemotherapy (ACT) — 43 patients; IB group — patients with primary ovarian cancer who were treated with neoadjuvant chemotherapy (NACT) + interval cytoreductive surgery (ICS) + adjuvant chemotherapy — 16 patients. Results: the absence of statistical difference in the median overall survival in groups IA (PDS + ACT) and IB (NACT + ICS + ACT) was shown to be explained by the complete volume of cytoreduction performed. There was a change in 3-year survival from 56.3 to 70.7% (χ2 = 0.951; p = 0.329) and an increase in 5-year survival from 12.5 to 60.9% (φ = 0.0012; p < 0.05). In group IB, the percentage of postoperative complications in patients and the average length of hospital stay after cytoreductive surgery were lower than in group IA, but the difference was statistically insignificant. When comparing the frequency of side effects of paclitaxel/carboplatin chemotherapy treatment in groups IA and IB, the values of χ2 = 36.441; p = 0.0195 were obtained. Thus, it was proved that in the IB group, the toxic effects of chemotherapy of 3–4 degrees of severity were significantly more common. Conclusions: there was no statistical difference when comparing the median overall survival and progression-free survival in the study groups. It has also been shown that primary cytoreductive surgery with macroscopically visible residual masses, especially in suboptimal and suboptimal volume (CC 2-3), leads to a significant decrease in survival rates in patients with ovarian cancer.

Cytologic and immunohistochemical study on cell blocks of effusion fluids in patients with serous adenocarcinoma of the ovary

Cytologic and immunohistochemical study on cell blocks of effusion fluids in patients with serous adenocarcinoma of the ovary

ENDOMETRIALHYPERPLASIA AND ITS RELATIONSHIP WITH P16 STROMAL EXPRESSION OF ENDOMETRIAL POLYPS: REVIEW

Recently, p16 stromal expression has been reported in the examination of endometrial serous adenocarcinomas associated with endometrial polyps. Therefore, endometrial polyps are defined as preneoplastic formations in some textbooks. Due to these different expressions of stromal cells in endometrial polyps, we wanted to present the place of p16 expressions in stromal tissue in endometrial hyperplasia and endometrial polyps in the differential diagnosis in our review article.

STK4 protein expression pattern follows different trends in endometrioid and serous endometrial adenocarcinoma upon tumor progression

In a previous study, we showed that serine/threonine-protein kinase 4 (STK4) is involved in the control on proliferation and migration of endometrial cancer (EC) cells in vitro. In the present paper, we studied STK4 expression in EC tissues from a large cohort of patients to determine whether STK4 can serve as a marker for the aggressiveness and prognosis of EC. Tissue samples from patients with EC were examined for tumor type, grade, and stage. The STK4 protein expression in EC cells was assessed by immunohistochemistry and related to clinicopathological data of patients, such as progression and patient survival rate. The STK4 mRNA levels and its relation to the survival rate were analyzed also in publicly available databases. The STK4 gene expression was low at both, the mRNA and protein levels in EC, especially in serous tumors. Comparison of STK4 expression with the patient survival rate shows that the higher expression is associated with worse prognosis in serous EC, while no such dependence was found in endometrioid EC. Hence, the determination of the SKT4 expression pattern could be used as a putative prognostic marker for serous EC.

Does sarcopenia predict perioperative mortality in patients with advanced ovarian cancer?

The aim of this study was to assess prognostic value of frailty for the prediction of surgical complications and mortality in women with end-stage ovarian cancer subjected to curative oncological surgery and its value for long-term follow-up. A total of 75 advanced-stage consecutive ovarian cancer patients who underwent elective surgery were investigated. The demographic data and clinical information related to the oncologic treatment were collected in the electronic and physical case records and included the following: age, ethnic group, comorbidities, staging of cancer, surgical procedure details, lymphadenectomy, American Society of Anesthesiology (ASA) grade, anesthetic technique, operative blood loss, operative time, and residual disease. A radiologist, who was blinded to patient outcomes, performed quantitative assessment of psoas muscle areas using the available computed tomography scan images at the caudal end of the third lumbar vertebra. The mean age was 61.2 ± 18.2 years, and the percentage of patients over 65 years was 78%. Comorbidities (hypertension, diabetes, chronic obstructive pulmonary disease, renal insufficiency) were seen in 37 patients (49%). Histological types were adenocarcinoma in all patients (0) mostly serous adenocarcinoma (62%) and stage 3 (58%). According to psoas muscle measurement, 55 patients (73%) were nonsarcopenic and 20 patients (26%) were sarcopenic. Debulking procedures were performed on all patients. Also, bowel resection was applied in 40% of patients. Preoperative anesthetic examinations had shown that they were mostly ASA score 2 (44 patients). Moreover, 26 patients were ASA score 3. Generally, total operative time was between 121-240 minutes, and total blood loss was generally under 500 ml. Postoperative complications were seen in 26% of the patients. Non-surgical complications were observed in 14% of the patients, while non-surgical complications were observed in 12%. Length of the hospital stay >10 days was seen in 10 patients. Mortality was seen in 1 patient 30 days after operation. Nonsurgical complications (pneumonia, urinary tract infections, cardiac complications) were significantly higher in comparison to nonsarcopenic patients. However surgical complications were comparable between each group. Mortality after hospitalization and length of hospital stay were significantly higher in sarcopenic patients in comparison with the nonsarcopenic group. The use of the value of the psoas muscle region is considered to be a method to predict the in-hospital mortality when there is an available abdominal CT scan that has already been performed for ovarian cancer patients with a significant comparable clinical and laboratory background. According to the findings, patients had worse surgical outcomes and higher postoperative nonsurgical complication rate when sarcopenic patients were compared to nonsarcopenic patients. Moreover, postoperative mortality and length of hospital stay were significantly higher in sarcopenic patients in comparison to non-sarcopenic group.

Lymph Node Metastases and Local Cancer Spread in Serous Endometrial Cancer and Endometrial Adenocarcinoma – A Retrospective Study

Abstract Serous endometrial carcinoma is characterized by its highly aggressive nature and represents about 10% of all endometrial carcinomas. It causes about 80% of deaths among women suffering from endometrial cancer. The aim of our study was to determine the frequency, lymphatic and local spread of serous endometrial cancer compared with endometrial adenocarcinoma. Materials and methods: This was a retrospective study conducted in a period of 4 years (from 2015 to 2019). One hundred and twenty-three women aged between 39 and 84 years suffering from endometrial carcinoma in various stages according to FIGO from stage I to IV were included in the study. Diagnosis was established clinically and by imaging studies and was histologically proven in all women. We performed radical hysterectomy type B or C (2017 Update on the Querleu-Morrow Classification of Radical Hysterectomy) and pelvic lymph node dissection (PN) with or without paraaortic (PAR) lymph node dissection in all patients. Results: In 106 (86.2%) patients we found adenocarcinoma, in 9 (7.3%) of them – serous carcinoma, in 4 (3.3%) women – carcinosarcoma, in 4 (3.3%) women – clear cell carcinoma. The study compared the results only of 115 (100%) women with adenocarcinoma and serous carcinoma. In 17.8% of the patients with adenocarcinoma we found the presence of lymph node metastases, and in the group of patients with serous carcinoma we found lymph node metastases in 77.7% of them. There was a significant difference in the frequency of lymph node metastases according to the histological type EC (p < 0.00001). In 22.6% of patients with adenocarcinoma there was a local cancer spread, while such a spread was found in 66.7% of patients with serous cancer. After statistical processing of the results, we found a significant difference in the frequency of local tissue spread depending on the histological type of EC. Conclusion: Patients with serous endometrial cancer have significant more frequent lymphatic metastases and local spread than those with endometrial adenocarcinoma.

The diagnostic utility of trichorhinophalangeal syndrome type 1 immunohistochemistry for metastatic breast carcinoma in effusion cytology specimens.

Trichorhinophalangeal syndrome type 1 (TRPS1) is a novel immunohistochemical marker with excellent performance in distinguishing breast carcinoma from other cancers in surgical specimens. The aim of this study was to evaluate the diagnostic utility of TRPS1 compared with GATA3 for metastatic breast carcinoma in effusion cytology specimens. In total, 91 cell blocks of malignant effusion specimens, including 47 metastatic breast carcinomas (nine triple-negative breast carcinomas [TNBCs] and 38 non-TNBCs) and 44 nonmammary malignancies, were selected for TRPS1 and GATA3 immunohistochemistry. Modified H scores ≥ 200 were considered positive staining. The positive rate of TRPS1 was similar between TNBC and non-TNBC (77.8% vs 73.3%, p=.802), whereas the positive rate of GATA3 was lower in TNBC than in non-TNBC (66.7% vs 89.5%, p=.087). The positive rate of TRPS1 was significantly higher in breast carcinoma than in urothelial carcinoma (74.5% vs 0%, p<.001), whereas the positive rate of GATA3 showed no difference between these two (85.1% vs 85.7%, p=.956). Notably, diffuse and strong aberrant expression of TRPS1 was observed in one lung adenocarcinoma and one serous adenocarcinoma in this series. The overall sensitivity, specificity, positive predictive value, and negative predictive value of TRPS1 immunohistochemistry for breast carcinoma were 74.5%, 95.5%, 94.6%, and 77.8%, respectively. TRPS1 is a sensitive and specific marker for metastatic breast cancer in serous effusion cell-block specimens. It shows superior sensitivity and specificity compared with GATA3, especially in the TNBC setting and for excluding urothelial carcinoma.

Endometrial Serous Adenocarcinoma with Septate Uterus: A Rare Case Report

Abstract Introduction/Objective Congenital structural malformations of the uterus rarely coincide with uterine malignancies and can cause significant challenges to the detection of tumors originating from the uterine cavity. We report a case of delayed diagnosis of endometrial high-grade serous adenocarcinoma following an initial false-negative endometrial biopsy result. A septate uterus was discovered incidentally upon gross dissection, and it was recognized as the cause of the initial false-negative biopsy result. Exceptionally rare cases of uterine malformation combined with carcinoma have been reported in the literature and we are sharing this case to provide further awareness of such clinical scenario. Methods/Case Report A 67- year-old multigravida (G3P2103) female presented with postmenopausal bleeding. Initially, the patient underwent an endometrial biopsy revealing strips of benign glandular epithelium. Three months later endometrial biopsy showed high-grade serous carcinoma. A computed tomography scan (CT) of the abdomen and pelvis showed expanded and heterogeneously hypodense endometrium. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Gross examination of the specimen revealed a septate uterus with two cavities. Within the right cavity, there was an infiltrating polypoid mass and a superficial benign-appearing endometrial polyp was identified in the left cavity. After histologic examination of the right cavity mass, a diagnosis of endometrial high-grade serous adenocarcinoma was rendered. Results (if a Case Study enter NA) N/A Conclusion Congenital structural malformations of the uterus carry a higher risk of delayed or missed uterine cancer diagnosis. Septate uterus is associated with a higher chance of failed endometrial biopsy and can result in a false- negative outcome. The use of hysteroscopy, hysterosonography, and three-dimensional ultrasound could improve the diagnostic modality of malignant uterine tumors associated with structural malformations.

Survival Outcomes in the Patients of Ovarian Epithelial Carcinomas Treated with Fertility-Sparing Surgery: A Study from a Developing Country

Objective: To assess the outcomes of fertility-sparing surgery in patients with ovarian epithelial carcinoma treated at our centre.&#x0D; Study Design: Retrospective longitudinal study.&#x0D; Place and Duration of Study: Shaukat Khanum Memorial Cancer Hospital &amp; Research Center, Lahore Pakistan, from Jul 2001 to Aug 2015.&#x0D; Methodology: We studied 31 patients with ovarian epithelial carcinoma who underwent fertility-sparing surgery at Shaukat Khanum Memorial Hospital. The detail regarding patients and tumour characteristics, along with outcomes of the intervention, was obtained from secondary data kept in the electronic hospital information system.&#x0D; Results: A total of 132 patients with ovarian epithelial carcinoma were identified; 31 patients underwent fertility-sparing surgery (Stage-IA, n=19; Stage-IC, n=12). By histopathology, 14(45.0%) had mucinous cystadenocarcinoma, 7(22.6%) serous adenocarcinoma, 6(19.4%) endometroid, and 4(12.9%) with clear cell pathology. The mean duration of follow-up was 52.6±2.3 months (18-118 months) after fertility-sparing surgery. Five-year recurrence-free survival was 81.0%. (Three-year=89.0%), using the Kaplan-Meier graph. Three patients had successful pregnancies, with one having a twin pregnancy.&#x0D; Conclusion: Fertility-sparing surgery should be considered for children of early-stage epithelial ovarian carcinoma patients as it preserves fertility and endocrine function while avoiding recurrence.

GPP04 Presentation Time: 8:30 AM: What is Appropriate Target Delineation for MRI-Based Brachytherapy for Medically Inoperable Endometrial Cancer?

<h3>Purpose</h3> While the incidence of medically inoperable endometrial cancer (MIEC) is anticipated to rise within the growing elderly population, practice patterns demonstrate persistent underutilization of brachytherapy (BT). Contemporary Image-guided BT (IGBT) offers superior target dose escalation while sparing adjacent organs at risk. However, the volumetric target of IGBT techniques is not well established. We propose a high-risk CTV (HRCTV) concept and report associated rates of local control and toxicity. <h3>Materials and Methods</h3> A retrospective review identified all patients with MIEC receiving definitive external beam radiotherapy (EBRT) followed by MRI-based IGBT at a single institution. BT dose was prescribed to a HRCTV defined as gross tumor volume plus endometrial cavity with a planning goal of a summed equivalent dose at 2Gy/fraction (EQD2) D90 of 85Gy or greater. An additional intermediate-risk volume (IRCTV) was developed by global 5mm expansion upon this HRCTV, removing any volume entering into organs at risk (OAR). The myometrium and uninvolved uterine body was not defined as target volume. OARs including rectum, bladder, sigmoid and bowel were limited to EQD2 constraints directly adapted from cervical cancer. Late gastrointestinal (GI), genitourinary (GU), and vaginal toxicity events were graded using CTCAE, version 5.0. Clinical endpoints including local progression-free survival (LPFS), progression-free survival (PFS), and overall survival (OS) were estimated via the Kaplan Meier method. <h3>Results</h3> 32 patients received MRI-based HDR-BT for MIEC between 12/2015 and 8/2020, with a median follow up of 19.8 months (IQR 8.9 - 27.6 months). Patients were a median 71.5 years at diagnosis (range, 43 - 91 years), with a median ECOG 1 performance status (IQR 1 - 2). FIGO stages included 1A (56%), IB (16%), II (3%), III (22%), and IV (3%). Common histologies included endometrioid (56%), serous adenocarcinoma (22%), and carcinosarcoma (13%). All patients completed EBRT (45 Gy/25 fractions, 69%; 50.4 Gy/28 fractions, 16%; other, 16%) followed by MRI-guided HDR-BT (27.5 Gy/5 fractions, 66%; 28 Gy/4 fractions, 28%; other, 6%). Composite dosimetry included the following median EQD2 values: D90 HRCTV 91.3 Gy (IQR 88.2 - 96.4 Gy), D98 HRCTV 78.2 Gy (73.7 - 82.6 Gy), D90 IRCTV 73.4 Gy (69.9 - 76.0 Gy), D2cc Bladder 72.9 Gy (66.7 - 76.4 Gy), D2cc Rectum 57.0 Gy (52.1 - 66.0 Gy), D2cc Sigmoid 65.0 Gy (63.3 - 70.3 Gy), D2cc Bowel 60.2 Gy (53.2 - 66.0 Gy), and D2cc Vagina 82.9 Gy (79.9 - 90.6 Gy). 16% of patients received hormonal therapy, and 3% of patients received chemotherapy. Figure 1 provides LPFS, PFS, and OS. There were 14 (44%) total deaths, 3 local recurrences (9%), 3 nodal recurrences (9%), and 5 distant recurrences (16%). 2-year LPFS was 88.8%, and 2-year OS was 65.8%, with no locoregional or distant progression observed beyond 24 months post-BT. For the 3 patients with local progression, median D90 HRCTV was 99.2 Gy (range 77.9 - 103.5 Gy), D98 HRCTV 80.2 Gy (68.6 - 89.4 Gy), and D90 IRCTV 73.3 Gy (66.0 - 83.5 Gy). For patients with stage I/II disease (n=24), LPFS was 100% at 12 months and 94% (95% CI 81.9 - 100%) at 24 months. 23 (72%) patients experienced no RT-related toxicity. Two grade 3+ toxicities (6%) were observed: one grade 3 vomiting event prompting hospitalization and one grade 5 GI bleed presumed secondary to RT-induced proctitis in the setting of longstanding clopidogrel use. <h3>Conclusions</h3> Patients with MIEC receiving definitive EBRT followed by MRI-based IGBT demonstrated high rates of long-term local control with a favorable toxicity profile, when dose was prescribed to the MRI-defined GTV and endometrial cavity. These data compare favorably to historical controls despite a significant proportion of patients with locally advanced disease and/or aggressive histology.

Identification of serous ovarian tumors based on polarization imaging and correlation analysis with clinicopathological features

Ovarian cancer is one of the most aggressive and heterogeneous female tumors in the world, and serous ovarian cancer (SOC) is of particular concern for being the leading cause of ovarian cancer death. Due to its clinical and biological complexities, ovarian cancer is still considered one of the most difficult tumors to diagnose and manage. In this study, three datasets were assembled, including 30 cases of serous cystadenoma (SCA), 30 cases of serous borderline tumor (SBT), and 45 cases of serous adenocarcinoma (SAC). Mueller matrix microscopy is used to obtain the polarimetry basis parameters (PBPs) of each case, combined with a machine learning (ML) model to derive the polarimetry feature parameters (PFPs) for distinguishing serous ovarian tumor (SOT). The correlation between the mean values of PBPs and the clinicopathological features of serous ovarian cancer was analyzed. The accuracies of PFPs obtained from three types of SOT for identifying dichotomous groups (SCA versus SAC, SCA versus SBT, and SBT versus SAC) were 0.91, 0.92, and 0.8, respectively. The accuracy of PFP for identifying triadic groups (SCA versus SBT versus SAC) was 0.75. Correlation analysis between PBPs and the clinicopathological features of SOC was performed. There were correlations between some PBPs ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], rqcross, [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]) and clinicopathological features, including the International Federation of Gynecology and Obstetrics (FIGO) stage, pathological grading, preoperative ascites, malignant ascites, and peritoneal implantation. The research showed that PFPs extracted from polarization images have potential applications in quantitatively differentiating the SOTs. These polarimetry basis parameters related to the clinicopathological features of SOC can be used as prognostic factors.

Gene co-expression network analysis revealed novel biomarkers for ovarian cancer.

Ovarian cancer is the second most common gynecologic cancer and remains the leading cause of death of all gynecologic oncologic disease. Therefore, understanding the molecular mechanisms underlying the disease, and the identification of effective and predictive biomarkers are invaluable for the development of diagnostic and treatment strategies. In the present study, a differential co-expression network analysis was performed via meta-analysis of three transcriptome datasets of serous ovarian adenocarcinoma to identify novel candidate biomarker signatures, i.e. genes and miRNAs. We identified 439 common differentially expressed genes (DEGs), and reconstructed differential co-expression networks using common DEGs and considering two conditions, i.e. healthy ovarian surface epithelia samples and serous ovarian adenocarcinoma epithelia samples. The modular analyses of the constructed networks indicated a co-expressed gene module consisting of 17 genes. A total of 11 biomarker candidates were determined through receiver operating characteristic (ROC) curves of gene expression of module genes, and miRNAs targeting these genes were identified. As a result, six genes (CDT1, CNIH4, CRLS1, LIMCH1, POC1A, and SNX13), and two miRNAs (mir-147a, and mir-103a-3p) were suggested as novel candidate prognostic biomarkers for ovarian cancer. Further experimental and clinical validation of the proposed biomarkers could help future development of potential diagnostic and therapeutic innovations in ovarian cancer.

Gamma Knife radiosurgery for metastatic brain tumors from ovarian cancer: histopathological analysis of survival and local control. A Japanese multi-institutional cooperative and retrospective cohort study.

Brain metastasis is rare in ovarian cancer patients. The results of Gamma Knife radiosurgery (GKRS) for the treatment of patients with brain metastases from ovarian cancer were retrospectively analyzed to derive the efficacy and prognostic factors for survival and local tumor control. Further histopathological analysis was also performed. The authors retrospectively reviewed the medical records of 118 patients with 566 tumors who had undergone GKRS at the 10 GKRS institutions in Japan. After the initial GKRS, the median overall survival time was 18.1 months. Multivariate analysis showed that uncontrolled primary cancer (p = 0.003) and multiple intracranial metastases (p = 0.034) were significant unfavorable factors. Ten patients died of uncontrolled brain metastases at a median of 17.1 months. The 6-, 12-, and 24-month neurological death rates were 3.2%, 4.6%, and 11.9%, respectively. The 6-, 12-, and 24-month neurological deterioration rates were 7.2%, 13.5%, and 31.4%, respectively. The 6-, 12-, and 24-month distant brain control failure rates were 20.6%, 40.2%, and 42.3%, respectively. Median tumor volume was 1.6 cm3 and marginal dose was 20 Gy. The 6-, 12-, and 24-month local tumor control rates were 97.6%, 95.2%, and 88.0%, respectively. Peritumoral edema (p = 0.043), more than 7-cm3 volume (p = 0.021), and prescription dose less than 18 Gy (p = 0.014) were factors that were significantly correlated in local tumor control failure. Eight patients had symptomatic radiation injury. The 6-, 12-, and 24-month GKRS-related complication rates were 3.3%, 7.8%, and 12.2%, respectively. Primary ovarian cancer was histopathologically diagnosed for 313 tumors in 69 patients. Serous adenocarcinoma was found in 37 patients and other types in 32 patients. Median survival times were 32.3 months for the serous type and 17.4 months for other types after initial GKRS. Patients with serous-type tumors survived significantly longer than patients with other types (p = 0.039). The 6-, 12-, and 24-month local tumor control rates were 100%, 98.8%, and 98.8%, respectively. Serous-type tumors were a significantly good prognosis factor for local tumor control after GKRS (p = 0.005). This study established a relationship between the efficacy of GKRS treatment for brain metastases and the histological type of primary ovarian cancer. GKRS for ovarian cancer brain metastasis can provide satisfactory survival and local control, especially in cases of serous adenocarcinoma.

Role of reactive thrombocytosis after primary cytoreductive surgery in advanced ovarian cancer.

We investigated the incidence of reactive thrombocytosis after maximal cytoreductive surgery in advanced epithelial ovarian cancer (EOC) and its role in patient survival. We retrospectively reviewed the electronic medical records of patients who underwent primary cytoreductive surgery for advanced EOC from 1 January 2012 to 31 December 2017. We analyzed the serum platelet counts at various time points from before surgery, during the peri-operative period, and after each cycle of adjuvant chemotherapy. A total of 474 patients were eligible for the analysis. Among them, 401 patients (84.6%) had FIGO stage III disease status. The most common histology type was serous adenocarcinoma (405 patients, 85.4%). Seventy-nine patients (22.6%) received splenectomy, and optimal cytoreduction was achieved in 326 patients (68.8%). A week after surgery, thrombocytosis was observed in 165 patients (34.8%) in the entire cohort. Higher platelet counts were observed in patients with splenectomy compared with patients without splenectomy. In particular, thrombocytosis on the fifth cycle of adjuvant chemotherapy showed the most significant effects on overall survival in multivariate analysis. In a logistic regression model, splenectomy was significantly attributed to thrombocytosis on the fifth cycle of chemotherapy. Reactive thrombocytosis after primary cytoreductive surgery is associated with poor survival in advanced EOC, particularly when thrombocytosis is observed during adjuvant chemotherapy.

586P BRCA1, BRCA2 and RAD51C somatic RNAseq study in ovarian cancer: A description of physiological and pathogenic splicing patterns

Genomic molecular profiling is becoming a key step in the management of advanced ovarian cancer. Currently, the main indication for tumor analysis is on DNA (BRCA1/2 mutations and HRD status); there is no indication for RNA tumor analysis. The aims of this work were to describe physiological splicing profiles of BRCA1, BRCA2 and RAD51C in ovarian tissue and then search for pathogenic splicing of these genes in patients with high-grade serous papillary adenocarcinomas stage III of FIGO classification with good response to neoadjuvant cisplatin. RNAseq (Agilent SureSelect XT HS/capture-based target enrichment and NextSeq 550 Illumina Sequencer) was performed on RNA extracted from ovarian cell lines OVCAR4 and COV318 and five pre-cisplatin frozen ovarian tumors with wild-type BRCA1 and BRCA2 somatic DNA screening. We obtained the Genomic Instability Score with Myriad approach and performed RNAseq on post-cisplatin FFPE ovarian block. We also checked BRCA1 methylation status by digital PCR before their inclusion to describe physiological splicing patterns, in addition to OVCAR4 and COV318. A pathogenic skip of BRCA1 exon 3 was found in one tumor at a high level, comparing to the normal transcript. The loss of exon 3 caused a truncation of BRCA1 protein at codon 27; no variant was identified on DNA. This splicing event explained the high GIS at 66 and the good clinical response to cisplatin. Exon 3 skipping was tumoral as it was absent on the post-cisplatin residual ovarian block. Another tumor was BRCA1 methylated. There were neither enrichment of alternative nor novel splicing event of BRCA1, BRCA2 and RAD51C, specific of ovarian tissue. Physiological splicing profiles were qualitatively and quantitatively close to those reported in lymphoblastoid cell lines. Unlike BRCA2 and RAD51C, five known reported transcripts of BRCA1 were missing in the ovarian tissue. We provided a complete description of physiological splicing profiles of BRCA1, BRCA2 and RAD51C in the ovarian tissue. We also showed that somatic RNAseq analysis in ovarian cancer may modify the therapeutic prognosis by allowing access to targeted therapies.

Systematic review and meta-analysis of neoadjuvant chemotherapy compared to primary debulking surgery in advanced endometrial cancer (538)

Systematic review and meta-analysis of neoadjuvant chemotherapy compared to primary debulking surgery in advanced endometrial cancer (538)

Clinical, pathological genetics and intratumoral immune milieu of serrated adenocarcinoma of the colon.

Serrated adenocarcinoma (SAC), a recognised WHO variant of colonic adenocarcinoma, is the purported end-product of serrated neoplasia. However, the diagnosis of SAC is infrequently rendered, and little is known about its prognosis, immune microenvironment and molecular alterations. We assessed 903 consecutive colon carcinomas and recognised tumours with ≥ 5% (n = 77) serrated and ≥ 50% serrated patterns (n = 13). We assessed precursor polyps and synchronous polyps. We recorded demographic/clinical parameters, histological features and mismatch repair (MMR) status. We performed immunohistochemistry and quantification on tissue microarray for HLA class I/II proteins, B2MG, CD8, CD163, LAG3, FoxP3, PD-L1 and BRAF V600E. We identified ≥ 5% epithelial serration prevalence in 8.5% of cases and ≥ 50% epithelial serration prevalence in 1.4% of cases. Precursor lesions were present in 21.4% of cases; these were mostly tubular adenomas with two traditional serrated adenomas identified. SAC with ≥ 5% serrations exhibited lower numbers of CD8-positive lymphocytes (P = 0.002) and lower B2MG expression (P = 0.048), although neither value was significant at ≥ 50% serration threshold. There was no difference in HLA class I/II, or PD-L1 expression on tumour cells and no difference in PD-L1, LAG3, FoxP3 and CD163 expression on immune cells. There was no association with MMR status, or BRAFV600E relative to conventional adenocarcinoma. There was improved disease-specific survival on univariate (but not multivariate) analysis between carcinomas with serrated pattern and non-mucinous conventional colonic carcinomas at ≥ 5% epithelial serrations (P = 0.04). SAC category shows a limited impact on survival, and this phenotype may harbour a unique immunological milieu.

P-301 Exome sequencing reveals novel candidate variants for endometriosis and endometrial serous adenocarcinoma in a single family having multiple affected members

Abstract Study question Could genetic evaluation of a family, having multiple affected members with endometriosis, contribute to identifying novel rare variants for the missing heritability of the disease? Summary answer Two novel genetic variants one in each of TNFRSF1B and GEN1 genes detected only in all affected family members, suggesting potential new biomarkers forendometriosis. What is known already Endometriosis is an estrogen-dependent, chronic inflammatory disease that affects 10% of women during the reproductive ages. Despite the estimated 50% heritability for the condition, only 26% was associated with common genetic variants through GWAS studies. The necessity of identifying rare variants for the missing heritability is implicated in the literature. In this respect, only one familial study has suggested novel candidate variants utilizing whole exome sequencing (WES). Study design, size, duration A single family having 4 women diagnosed with endometriosis out of 6 were recruited for genetic delineation utilizing whole exome sequencing (WES). The average follow-up period of the patients were five years. Participants/materials, setting, methods Total of 6 women from the same family. Four women with endometriosis were diagnosed. WES was performed on these 3 women with endometriosis utilizing the Twist Core Exome Target Capture and Enrichment Kit on the Illumina Nextseq 550 platform with 50X coverage. Bioinformatics analyses along with variant prioritization at MAF &amp;lt;1% for all normal populations were performed on Genomize SEQ platform. Candidate genes were subjected to confirmation by Sanger sequencing followed by familial segregation. Main results and the role of chance All endometriosis patients presented with dysmenorrhea. Additionally, one of them reported having dyschezia, one had chronic pelvic pain and the other patient complained having dyspareunia. The 3 patients who underwent WES analysis were also under treatment for endometriosis related infertility. 2 out of these 3 patients had a positive history for endometriosis surgery and presented with recurrent endometriomas. Novel heterozygous missense variants one in each of TNFRSF1B and GEN1 genes were determined in all affected members, while a novel heterozygous missense variant in CRABP1 was detected only in daughters descending from the mother with cancer history. All variants were predicted to be deleterious by in silico tools Limitations, reasons for caution Our findings are limited to the family of interest and needs to be replicated in larger cohorts. Designation of the novel findings as causative mutations, functional validations need to be performed. Wider implications of the findings The novel genetic variants detected will help in providing genetic counseling to the family. Our findings, when replicated in larger cohorts and validated functionally, will provide significant contribution to the elucidation of the molecular mechanisms of the pertinent conditions. Trial registration number not applicable

Olaparib maintenance therapy after frontline chemotherapy in patients with BRCA-mutated ovarian cancer: real-world results in expanded access program

Introduction. Olaparib is the only PARP inhibitor approved in Russia for the maintenance therapy for BRCA-positive ovarian cancer after frontline chemotherapy. We conducted a real-world analysis of olaparib efficacy and safety for this indication.Aim. To assess the efficacy of PARP inhibitors in real-world clinical practice.Materials and methods. Patients with stage III-IV BRCA-mutated ovarian cancer who received olaparib maintenance therapy in expanded access program in 03.2019-12.2020 timeframe. Briefly, key inclusion criteria were: serous or endometrioid highgrade ovarian cancer; pathogenic BRCA1/2 mutation; primary or interval debulking; complete or partial response to frontline platinum-based therapy. Olaparib was administered as tablets (300 mg BID) up to 2-years, disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint of the study was progression-free survival (PFS), overall survival (OS) and safety were key secondary endpoints. Statistical analysis was done with R and RStudio software.Results and discussion. 23 patients were enrolled. Median age was 49 years, all patients had high-grade serous adenocarcinoma histology. Complete debulking at primary or interval surgery was achieved in 30% of patients. With median follow-up time equal to 22 months, median PFS and OS were not reached. The 2-year PFS and OS were 65 and 84%, respectively. Grade 3-4 adverse events was detected in 7 (30.4%) patients.Conclusion. Our results supports high efficacy of olaparib in real clinical practice setting reported in the SOLO1 trial.

Abstract 6042: Developing patient-derived organoids and tumor xenograft model for ovarian cancer for preclinical therapeutic evaluation

Abstract Purpose: Patient-derived organoid (PDO) and patient derived xenografts (PDX) models has been shown strong potential as experimental and preclinical research model which preserve original tumor characteristics. Here we represent our protocols setup process for ovarian cancer organoid establishment and PDX after data review and cell line xenograft experiments. Methods: First, we reviewed the histologic subtype of ovarian cancer of biobank in national cancer center, Korea then tried to match common subtype ovarian cancer cell line by literature review for xenograft experiments. Patient specimens were collected from histologically confirmed cancer patients under informed consent (NCC2020-0219). We obtained fresh tumor tissue from standard primary surgery of ovarian cancer patient and tissue was dissociated. Then we plated cells in matrigel with modified growth factors media. Organoids were passaged with diameter larger than 50µm and genetic analysis were performed to compare with original tumor. For PDX condition establishment, xenograft models using OVCAR3 in athymic nude and NOG mouse strains were compared, then SKOV3, SNU840, SNU251, and ES2 cell line subcutaneous xenograft growth were observed in NOG mouse. Results: Frequency of subtype of ovarian cancers (n=733) in biobank represented as following: serous adenocarcinoma (70%, n=509), endometrioid tumors (11%), clear cell tumors (10%), mucinous tumors (4%) and others (5%). After adjustment of organoid culture condition, PDOs (10 patients and 11 samples) were successfully long term cultured over 5 passages and the subtypes were including high grade serous type (n=5, 50%), clear cell carcinoma (n=2), mucinous carcinoma (n=2) and low grade serous type (n=1). The median age was 65 (28-82) years and stage III-IV (n=6) were frequent. Among them, number of recurred patients was three. Currently, the genetic information of each organoid is ongoing with CNV analysis, and the sensitivity and comparative analysis of the drug will be performed. Xenografts of OVCAR3 represented higher tumor growth rate in NOG mice than in athymic nude mice (p=0.03) then comparison of growth between cell lines in NOG mice showed fast as following in order: ES2, SKOV3, OVCAR3, SNU840, and SNU251 Conclusions: PDO from ovarian cancer were established and it might provide tools for personalized drug screening. To improve success rate we are continuing adjustment of PDO culture condition and PDX. (This work was supported by National Research Foundation of Korea grant, founded by the Korea government (MSIT) [No.2020R1A2C2010566]) Citation Format: Jihee Kim, Ji Hyeong Seo, Yun-Hee Kim, YoHan Woo, Yeon Jee Lee, Yena Kim, Wonyoung Choi, Young Ju Kim, Chong Woo Yoo, Sang Yoon Park, Myong Cheol Lim, Sun-Young Kong. Developing patient-derived organoids and tumor xenograft model for ovarian cancer for preclinical therapeutic evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6042.