High-grade Serous Adenocarcinoma Research Articles

Amplification of Hippo Signaling Pathway Genes Is Governed and Implicated in the Serous Subtype-Specific Ovarian Carcino-Genesis.

Among women, ovarian cancer ranks as the fifth most common cause of cancer-related deaths. This study examined the impact of Hippo signaling pathway on ovarian carcinogenesis. Therefore, the signatures related to Hippo signaling pathway were derived from the molecular signatures database (MSigDB) and were used for further analysis. The Z score-based pathway activation scoring method was employed to investigate the expression patterns of these signatures in the mRNA expression profiles of ovarian cancer cohorts. Compared to other subtype tumors, the results of this study show that the Hippo signaling pathway signatures are dysregulated prominently in serous subtype-specific ovarian carcinogenesis. A receiver operating characteristic (ROC) curve-based results of the Hippo gene set, yes-associated protein 1 (YAP1), and mammalian sterile 20-like kinases 1 (MST1) genes can predict the serous subtype tumors by higher specificity and sensitivity with significant areas under the curve values also further reconfirmed these signaling dysregulations. Moreover, these gene sets were studied further for mutation analysis in the profile of high-grade serous ovarian adenocarcinoma in the cBioPortal database. The OncoPrint results reveal that these Hippo signaling pathway genes are amplified highly during the grade three and stage third or fourth of serous type ovarian tumors. In addition, the results of the Dependency Map (DepMap) plot also clearly show that these genes are amplified significantly across the ovarian cancer cell lines. Finally, overall survival (OS) curve plot investigations also revealed that these gene expressions show poor survival patterns linked to highly expressed conditions in serous subtypes of ovarian cancer patients with significant p-values (p < 0.05). Thus, the current finding would help to develop the targeted therapies treatment for serous subtype ovarian carcinogenesis.

Abstract PR-006: A novel bispecific NK cell engager targeting FSHR and Siglec-7 displays potent anti-tumor immunity against ovarian cancer

Abstract Ovarian cancer (OC) is the deadliest gynecologic malignancy, with the highest mortality among cancers of the female reproductive system. Because of the close interaction between the OC cells and tumor microenvironment (TME), development of approaches which not only target tumor cells but also can maintain their anti-tumor function in this TME is of high importance. Uniquely, Follicle stimulating hormone receptor (FSHR) represents such an important target with specificity for OC and ovarian granulosa cells. We have recently developed monoclonal antibodies (mAbs) that specifically recognize human FSHR on the surface of multiple OC. We characterized them, selected potent anti-FSHR mAb: D2AP11 for detailed investigation and immune engineering in the form of a bispecific T cell engager (D2AP11-TCE) (Bordoloi et al., JCI Insight, 2022). Since most OCs are extremely aggressive and have restricted treatment choices, engaging additional immune effector components may further help. We have developed mAbs against PAN NK marker; Siglec 7 in humanized mice. We identified several Siglec-7 mAbs through high throughput screening and down-selected the pertinent clones. By using a highly potent anti-Siglec-7 clone DB7.2, we have developed a novel NK cell engager (NKCE): DB7.2xD2AP11 NKCE, by linking two antibody binding fragments (scFVs) arranged to bind FSHR, the OC antigen and hman Siglec-7, the NK marker. The NKCE was efficiently expressed in vitro and showed potent binding to both FSHR overexpressing K562 cells as well as Siglec-7 overexpressed HEK293T cells. This novel NKCE resulted in robust and specific killing of multiple OC targets in vitro in the presence of human PBMCs or NK cells, from multiple donors. The OC targets evaluated for killing by the NKCE include high grade serous adenocarcinoma, ovarian clear cell adenocarcinoma and ovarian cystadenocarcinoma lines which carry different mutations; BRCA1&amp;2, AKT, TP53, PIK3CA, BRAF etc. and exhibit resistance against a wide array of cancer drug targets; PARP, HSP90, HDAC, MTORC, DNA alkylating agents, EGFR, PI3K, and WEE1, among others. DB7.2xD2AP11 NKCE displayed killing with EC50-142.87 pM and 236.6 pM against target OVISE-FSHR and OVCAR3 cells respectively, indicating its potency. Further, DNA encoded DB7.2xD2AP11 NKCE significantly attenuated the tumor burden in OVCAR3-FSHR and OVISE challenged humanized mice model. Additionally, this novel NKCE significantly enhanced the median survival of OVCAR3-FSHR challenged mice, suggesting in vivo potency. These data support further research on this novel NKCE as crucial tools for treating OC as well as targeted therapies for other malignancies. Of note, it is the first study of the development of Siglec-7 or any Siglec family member as a bispecific immune engager for targeted immunotherapy. Citation Format: Devivasha Bordoloi, Abhijeet J. Kulkarni, Opeyemi S. Adeniji, Pratik S. Bhojnagarwala, Shushu Zhao, Candice Ionescu, Mohamed bdel-Mohsen, David B. Weiner. A novel bispecific NK cell engager targeting FSHR and Siglec-7 displays potent anti-tumor immunity against ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr PR-006.

Platinum desensitization therapy and its impact on the prognosis of ovary high-grade serous adenocarcinoma: a real world-data.

To examine the value of five-step platinum desensitization therapy in epithelial ovarian cancer. A retrospective study was conducted on the high-grade serous adenocarcinoma of the ovary (HGSAO) patients who developed a platinum allergy during treatment and received desensitization therapy between January, 2016 and December, 2020. The logistic-regression was adopted to analyze the relationship between platinum desensitization therapy and prognosis in HGSAO patients. 92 HGSAO patients were included in the study. Among these, 35 patients (38.0%) experienced mild allergic reactions, 51 (55.4%) experienced moderate allergic reactions, and 6 (6.5%) experienced severe allergic reactions. The desensitization therapy was successful in 86 patients (93.5%). Six patients had desensitization failure, of which five experienced severe allergic reactions during desensitization. The logistic-regression analysis revealed no significant correlation between platinum desensitization therapy and progression-free survival (PFS) or overall survival (OS) of patients (P < 0.05). However, the subgroup analysis demonstrated that the success or failure of platinum desensitization therapy significantly impacted the OS of patients who were platinum-sensitive recurrence. The patients who had successful desensitization therapy had a superior OS. Five-step platinum desensitization therapy has potential application value in patients who were platinum-sensitive recurrence after first-line treatment but may bear the risk of severe allergic reactions.

Prognosis prediction of high grade serous adenocarcinoma based on multi-modal convolution neural network

Prognosis prediction of high grade serous adenocarcinoma based on multi-modal convolution neural network

A phase 1/2 open-label, multicenter, dose escalation and expansion study of AVB-001, an intraperitoneally administered, cell-generated, human IL-2 immunotherapy in patients with platinum-resistant, high-grade, serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube.

TPS5616 Background: The potential of cytokines as cancer therapeutics has been limited by short half-life and severe adverse effects associated with high systemic exposure when delivered intravenously. Many strategies are being explored to overcome these limitations. A locoregional delivery approach to achieve high sustained local concentrations in the tumor microenvironment with minimal systemic exposure could widen the therapeutic window. Early experience with free recombinant human IL2 (rhIL-2) given intraperitoneally (IP) showed meaningful clinical activity in relapsed ovarian cancer. Still, the cumbersome delivery procedure requiring indwelling catheters and need for high volume IP infusions leading to frequent complications and poor patient compliance limited the utility of this approach. To overcome these shortcomings, we developed a clinically translatable localized delivery LOCOcyte platform composed of polymer encapsulated allogeneic epithelial cells engineered to produce immune effector molecules for local delivery with temporal regulation. The first product, AVB-001, produces native hIL-2, for the treatment of ovarian cancer and other peritoneal malignancies. IP AVB-001 inhibited tumor growth and improved survival in an in vivo ID8 ovarian cancer murine model. Sustained IL-2 production with well tolerated high IP concentrations were achieved, with &gt;100x differential concentration vs. systemic blood levels in both mice and non-human primates. Strong local and systemic immune activating effects, optimized T cell profile and immune memory were observed without concomitant increase of T regs. The first in human study of AVB-001 in patients with advanced ovarian cancer (NCT05538624) is described here. Methods: Part 1 dose escalation exploring 4 ascending dose levels (capsules target production of 0.6, 1.2, 2.4, and 3.6 ug hIL2/kg/d) with a Bayesian Optimal Interval 3+3 design, in patients with recurrent high grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube. A minimum of 12 and up to 24 patients will be enrolled to receive one dose of AVB-001 administered IP. The primary objective is to evaluate safety (Incidence and severity of adverse events per NCI CTCAE v5.0), tolerability, and feasibility of delivering AVB-001 IP, and establish the RP2D. Secondary objectives include assessment of antitumor activity (RECIST v1.1, iRECIST), pharmacokinetics, and pharmacodynamic correlates of immune activation. Part 2 will enroll 20 patients at the RP2D with efficacy as the primary objective. This multicenter study will be conducted at 5 sites, currently two sites are open. The first patient was dosed in December 2022. Recruitment in dose level 1 cohort continues. Clinical trial information: NCT05538624 .

Safety and survival in adult women with platinum sensitive relapsed BRCA mutant ovarian cancer: A study of patients in Olaparib Turkey Early Access Program—LynTurk study.

e17509 Background: SOLO-2 trial results have proven the efficacy of Olaparib in BRCA-mutant platinum-sensitive relapsed ovarian cancer patients. LynTurk as an open label, multi-center study, designed to show the real world safety and efficacy results of Turkey Olaparib managed access program. Methods: Patients with BRCA mutated relapsed ovarian cancer who are in complete or partial response following platinum based chemotherapy were eligible for Olaparib maintenance in Turkish managed access program. The primary aim was safety. Progression free survival, overall survival were the secondary endpoints. Results: Between December 2014 and March 2021, 48 patients were accepted for program. Due to immaturity of data, in this report, a total of 26 patient results were analyzed. BRCA2 mutation was present in 5 patients, one patient have both BRCA1 and BRCA2 mutations; 20 cases were found to be BRCA1 mutated. The median age of patients was 51 (29-61) years. All patients have high grade serous adenocarcinoma of ovary or primary peritoneal carcinoma. The most common site of involvement are lymph nodes and peritoneal surfaces; in 11% of cases there are liver parenchyma metastasis. All of the patients received at least two lines of platinum-based chemotherapy; median 3 lines (2-4) of treatment were applied before Olaparib maintenance. Previous bevacizumab treatment was allowed in this program, 53.8% of cases were received at least 3 cycles, maintenance bevacizumab was given to 12 patients. Median treatment duration with Olaparib was 26,2 months (3-80m). In 30.7% of cases no adverse events were noted, at least one level dose reduction was needed for 50% of patients due to toxicity. Hematological adverse events were the mostly encountered followed by dyspepsia and fatigue. Anemia was the reason for permanent drug discontinuation in 2 patients (0.7%). No febrile neutropenia was reported. During the follow-up, no secondary malignancy and pneumonitis was noted. Median progression free survival from the end of last chemotherapy was 19.3 months. One-year PFS rate was 88.4% and 2-y PFS rate was 53.8%. One-year OS rate from the end of chemotherapy was 92.3% and 2-year was 61.5%. Conclusions: The real world data from Turkey managed access program has showed that Olaparib has a safety profile in paralel with clinical trials (SOLO). No new safety signals were reported. Although a heterogenous population including heavily pretreated patients, maintenance Olaparib was found effective. This report will be updated as the data of all intent to treat population will gather and will get mature.

Somatic Variants in DNA Damage Response Genes in Ovarian Cancer Patients Using Whole-exome Sequencing.

Several clinical trials have investigated homologous recombination deficiency and BRCA1/2 status to select ovarian cancer patients for treatment with poly(ADP-ribose) polymerase-inhibitors (PARPi), but less attention has been given to other DNA-damage response (DDR) pathways. Therefore, we investigated somatic single/multiple nucleotide variants and small insertions/deletions in exonic and splice-site regions of 356 DDR genes to examine whether genes other than BRCA1/2 are altered. Whole-exome sequencing data from eight high-grade serous adenocarcinoma (HGSC) and four clear cell carcinoma (oCCC) patients were analyzed. Forty-two variants (pathogenic, likely pathogenic or variants of uncertain significance) in 28 genes from DDR pathways were identified. Seven out of nine TP53 variants were previously described in The Cancer Genome Atlas Ovarian Cancer; other variants were found in 23 out of 28 unique genes, whereas no variants were reported in FAAP24, GTF2H4, POLE4, RPA3, and XRCC4. As the identified variants were not only limited to well-known TP53, BRCA1/2, and HR-associated genes, our study might contribute to the better understanding of which DDR pathways potentially influence disease progression. Moreover, they may display a potential role as biomarkers to predict platinum-based chemotherapy or PARPi treatment response or disease progression, as differences in disrupted DDR pathways were observed between patients with long and short overall survival in HGSC and oCCC groups.

Abstract CT122: A phase 1/2 open-label, multicenter, dose escalation and expansion study of AVB-001, an intraperitoneally administered, cell-generated, human IL-2 immunotherapy in patients with platinum-resistant, high-grade, serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube

Abstract Background: The potential of cytokines as cancer therapeutics has been limited by short half-life and severe adverse effects associated with high systemic exposure when delivered intravenously. Many strategies are being explored to overcome these limitations. A locoregional delivery approach to achieve high sustained local concentrations in the tumor microenvironment with minimal systemic exposure could widen the therapeutic window. Early experience with free recombinant human IL2 (rhIL-2) given intraperitoneally (IP) showed meaningful clinical activity in relapsed ovarian cancer. Still, the cumbersome delivery procedure requiring indwelling catheters and need for high volume IP infusions leading to frequent complications and poor patient compliance limited the utility of this approach. To overcome these shortcomings, we developed a clinically translatable localized delivery LOCOcyteTM platform composed of polymer encapsulated allogeneic epithelial cells engineered to produce immune effector molecules for local delivery with temporal regulation. The first product, AVB-001, produces native hIL-2, for the treatment of ovarian cancer and other peritoneal malignancies. IP AVB-001 inhibited tumor growth and improved survival in an in vivo ID8 ovarian cancer murine model. Sustained IL-2 production with well tolerated high IP concentrations were achieved, with &amp;gt;100x differential concentration vs. systemic blood levels in both mice and non-human primates. Strong local and systemic immune activating effects, optimized T cell profile and immune memory were observed without concomitant increase of T regs. The first in human study of AVB-001 in patients with advanced ovarian cancer (NCT05538624) is described here. Methods: Part 1 dose escalation exploring 4 ascending dose levels (capsules target production of 0.6, 1.2, 2.4, and 3.6 ug hIL2/kg/d) with a Bayesian Optimal Interval 3+3 design, in patients with recurrent high grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube. A minimum of 12 and up to 24 patients will be enrolled to receive one dose of AVB-001 administered IP. The primary objective is to evaluate safety (Incidence and severity of adverse events per NCI CTCAE v5.0), tolerability, and feasibility of delivering AVB-001 IP, and establish the RP2D. Secondary objectives include assessment of antitumor activity (RECIST v1.1, iRECIST), pharmacokinetics, and pharmacodynamic correlates of immune activation. Part 2 will enroll 20 patients at the RP2D with efficacy as the primary objective. This multicenter study will be conducted at 5 sites, currently one site is open. The first patient was dosed in December 2022. Recruitment in dose level 1 cohort continues. Citation Format: Shannon N. Westin, Travis Sims, Karen Andreas, Eric Soliman, Manish Jain, Claudio A. Dansky Ullmann, Amir A. Jazaeri. A phase 1/2 open-label, multicenter, dose escalation and expansion study of AVB-001, an intraperitoneally administered, cell-generated, human IL-2 immunotherapy in patients with platinum-resistant, high-grade, serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT122.

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.

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.

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.

OSI-906 restores the sensitivity of ovarian clear cell carcinoma to cisplatin by targeting the IGF1R/AKT pathway.

Among the various histologic subtypes of ovarian cancers (OCs), ovarian clear cell carcinoma (OCCC) represents a great challenge due to its disease aggressiveness and resistance to chemotherapy. IGF1 is overexpressed in epithelial ovarian cancer (EOC), and IGF1 pathway activation is related to the chemoresistance of various cancers. In this study, we found that the expression level of IGF1 was higher in OCCC than in the most common type of OC, high-grade serous adenocarcinoma (HGSC). Then, we investigated the role of IGF1 pathway activation in the progression of OCCC, observing that activation of the IGF1 pathway using IGF1 promoted the proliferation and migration of ES2 cells, while inactivation of the IGF1 pathway using the selective IGF1R inhibitor OSI-906 reversed the alteration mediated by IGF1. Based on the role of the IGF1 pathway in cancer chemoresistance, we proposed that OSI-906 may restore the sensitivity of OCCC to cisplatin. We first validated that IGF1 increased the IC50 value of cisplatin in ES2 cells, while OSI-906 decreased it. Then we confirmed that IGF1 decreased the apoptosis rate of ES2 cells induced by cisplatin, while OSI-906 increased it. Finally, we conducted animal experiments to investigate whether OSI-906 helps cisplatin control the growth of OCCC. As expected, OSI-906 increased the effect of cisplatin in attenuating the growth of OCCC in vivo. Therefore, we conclude that using OSI-906 may be an effective method to restore the sensitivity of OCCC to cisplatin by targeting the IGF1R/AKT pathway.

StarD13 negatively regulates invadopodia formation and invasion in high-grade serous (HGS) ovarian adenocarcinoma cells by inhibiting Cdc42

Metastasis remains the main challenge to overcome for treating ovarian cancers. In this study, we investigate the potential role of the Cdc42 GAP StarD13 in the modulation of cell motility, invasion in ovarian cancer cells. StarD13 depletion does not affect the 2D motility of ovarian cancer cells. More importantly, StarD13 inhibits matrix degradation, invadopodia formation and cell invasion through the inhibition of Cdc42. StarD13 does not localize to mature TKS4-labeled invadopodia that possess matrix degradation ability, while a Cdc42 FRET biosensor, detects Cdc42 activation in these invadopodia. In fact, StarD13 localization and Cdc42 activation appear mutually exclusive in invadopodial structures. Finally, for the first time we uncover a potential role of Cdc42 in the direct recruitment of TKS4 to invadopodia. This study emphasizes the specific role of StarD13 as a narrow spatial regulator of Cdc42, inhibiting invasion, suggesting the suitability of StarD13 for targeted therapy.

Frequency of Mismatch Repair Deficiency/High Microsatellite Instability and Its Role as a Predictive Biomarker of Response to Immune Checkpoint Inhibitors in Gynecologic Cancers.

PurposeThis study was to investigate the frequency of mismatch repair deficiency/high microsatellite instability (MMRd/MSI-H) in gynecologic malignancies and the efficacy of immune checkpoint inhibitors (ICIs) in patients with recurrent gynecologic cancers according to MMR/MSI status.Materials and MethodsWe conducted a multi-center retrospective review on the patients who were diagnosed with gynecologic cancers between 2015 and 2020. Their clinicopathologic information, results of immunohistochemistry staining for MLH1/MSH2/MSH6/PMS2 and MSI analysis, tumor response to treatment with ICIs were investigated.ResultsAmong 1,093 patients included in the analysis, MMRd/MSI-H was most frequent in endometrial/uterine cancers (34.8%, 164/471), followed by ovarian, tubal, and peritoneal cancers (12.8%, 54/422) and cervical cancer (11.3%, 21/186). When assessed by histology without regard for cancer types, the frequency of MMRd/MSI-H was 11.0% (38/345) in high-grade serous adenocarcinoma, 38.6% (117/303) in endometrioid adenocarcinoma, and 30.2% (16/53) in carcinosarcoma. A total of 114 patients were treated with ICIs at least once. The objective response rate (ORR) was 21.6% (8/37) in cervical cancer, 4.7% (2/43) in ovarian cancer, and 25.8% (8/31) in endometrial/uterine cancers. Univariate regression analysis identified MMRd/MSI-H as the only significant factor associated with the ORR (28.9% [11/38] vs. 11.8% [9/76]; odds ratio, 3.033; 95% confidence interval, 1.129 to 8.144; p=0.028).ConclusionThe frequency of MMRd/MSI-H is moderate to high in gynecologic cancers in the Korean population. MMRd/MSI-H could be effective predictive biomarkers in gynecologic cancers of any type.

A monoclonal antibody against annexin A2 targets stem and progenitor cell fractions in tumors

The involvement of cancer stem cells (CSCs) in driving tumor dormancy and drug resistance is well established. Most therapeutic regimens however are ineffective in targeting these regenerative populations. We report the development and evaluation of a monoclonal antibody, mAb150, which targets the metastasis associated antigen, Annexin A2 (AnxA2) through recognition of a N-terminal epitope. Treatment with mAb150 potentiated re-entry of CSCs into the cell cycle that perturbed tumor dormancy and facilitated targeting of CSCs as was validated by in vitro and in vivo assays. Epigenetic potentiation further improved mAb150 efficacy in achieving total tumor regression by targeting regenerative populations to achieve tumor regression, specifically in high-grade serous ovarian adenocarcinoma.

Detection of BRCA1/2 Mutation and Analysis of Clinicopathological Characteristics in 141 Cases of Ovarian Cancer.

Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) are known biomarkers for hereditary ovarian cancer (OC). However, a comprehensive association study between BRCA1/2 mutation spectrum and clinicopathological characteristics in Chinese ovarian cancer patients has not been performed yet to our best knowledge. To fill in this gap, we collected BRCA1/2 sequencing data and clinical information of 141 OC patients from Fujian Cancer Hospital between April 2018 and March 2020. The clinical information includes the age of onset, FIGO staging, pathological types, serum 125 detection level, lymph node metastasis, distant metastasis, the expression of Ki67, and disease history of the patient and his/her family. We then studied their associations by software SciPy 1.0. As a result, we detected pathogenic and potentially pathogenic BRCA1/2 mutations in 27 out of 141 patients (19.15%). Among the 27 patients with mutations, the major type of mutation was frameshift, which was observed in 12 patients (44.4%). Most of the mutation sites were distributed on exons 10 and 11, accounting for 48.1% (13/27) and 22.2% (6/27), respectively. In terms of histological classification, high-grade serous adenocarcinoma accounted for 79.43% of the 141 samples. The BRCA1/2 mutation group was all high-grade serous adenocarcinoma, accounting for 24.1% (27/112) of this group. The incidence of pathogenic mutation in BRCA1 and BRCA2 was 15.7% (19/112) and 7.27% (8/112), respectively. Univariate analysis showed that there was no significant difference between patients with BRCA1/2 mutation and others in age-of-onset, FIGO stage, pathological types, serum CA125 level, lymph node metastasis, the expression of Ki67, and personal and family disease history. However, there are significant differences between patients with BRCA1/2 mutation and others in distant metastasis rate (P < 0.002). In addition, the BRCA1/2 mutation rate in 141 ovarian cancer patients was similar to those reported in other studies in China. Nearly one-quarter of high-grade serous carcinomas had BRCA1/2 mutations. In conclusion, our study indicated that patients with BRCA1/2 mutations were more likely to undergo distant metastasis, and BRCA1/2 mutation detection should be performed for patients with high-grade serous adenocarcinoma to guide the selection of clinical treatment options.

Ultrasound-Guided Omental Biopsy: Diagnostic Yield and Association With CT Features Based on a Single-Institution 18-Year Series.

BACKGROUND. The greater omentum can serve as a useful target for percutaneous biopsy; in clinical practice, CT is commonly used for biopsy guidance. OBJECTIVE. The purpose of this study was to evaluate the diagnostic yield of percutaneous ultrasound (US)-guided omental biopsy and to explore the association of the diagnostic yield with prebiopsy diagnostic CT findings. METHODS. This retrospective study included 163 patients (120 women and 43 men; mean age, 65 ± 12 [SD] years; mean body mass index [BMI], 28.9 ± 7.9) who underwent US-guided omental biopsy between 2002 and 2020 at a single institution at which US served as the first-line modality for omental biopsy guidance. Biopsies were performed by abdominal radiologists without dedicated interventional radiology fellowship training. Postbiopsy clinical follow-up and imaging follow-up were reviewed to establish the ultimate diagnosis for each patient. Omental biopsies were characterized as diagnostic or nondiagnostic relative to the ultimate diagnosis. Associations were explored between diagnostic yield and findings on prebiopsy CT and biopsy US. RESULTS. US-guided omental biopsy was performed using an 18-gauge core needle biopsy technique in 156 patients and fine-needle aspiration in seven patients. The mean number of biopsy passes was 2.5 ± 1.0, and mean omental thickness near the biopsy site on CT was 2.6 ± 1.2 cm. On prebiopsy diagnostic CT, omental disease appeared infiltrative in 127 (78%) patients versus mass-forming in 36 (22%) and appeared hypoechoic in 105 (64%) patients versus iso- to hyperechoic in 58 (36%). The ultimate diagnosis was malignant tumor in 154 (95%) patients (most commonly, gynecologic tumors in 82 patients [high-grade serous adenocarcinoma in 56] and gastrointestinal tumors in 45 patients) and a benign finding in nine (6%) patients. The omental biopsy was diagnostic relative to the ultimate diagnosis in 155 (95%) patients. A diagnostic versus nondiagnostic biopsy was not associated (p > .05) with age, BMI, number of biopsy passes, or omental target thickness or attenuation. A total of 94% (120/127) of US-guided omental biopsies of infiltrative cases and 97% (35/36) of biopsies of mass-forming cases were diagnostic (p = .50). A total of 96% (102/106) of US-guided omental biopsies of hypoechoic cases and 93% (53/57) of biopsies of iso- to hyperechoic cases were diagnostic (p = .36). No complications occurred. CONCLUSION. US-guided biopsy of omental disease suspected on CT is safe and effective for tissue diagnosis. Although omental disease commonly appears on US as diffuse infiltrative thickening without a discrete target, sampling based on prebiopsy CT landmarks is diagnostic in most cases. CLINICAL IMPACT. US should be considered the first-line modality for omental biopsy guidance when feasible.

Anti-M\xfcllerian hormone (AMH) autocrine signaling promotes survival and proliferation of ovarian cancer cells

In ovarian carcinoma, anti-Müllerian hormone (AMH) type II receptor (AMHRII) and the AMH/AMHRII signaling pathway are potential therapeutic targets. Here, AMH dose-dependent effect on signaling and proliferation was analyzed in four ovarian cancer cell lines, including sex cord stromal/granulosa cell tumors and high grade serous adenocarcinomas (COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN). As previously shown, incubation with exogenous AMH at concentrations above the physiological range (12.5–25 nM) decreased cell viability. Conversely, physiological concentrations of endogenous AMH improved cancer cell viability. Partial AMH depletion by siRNAs was sufficient to reduce cell viability in all four cell lines, by 20% (OVCAR8 cells) to 40% (COV434-AMHRII cells). In the presence of AMH concentrations within the physiological range (5 to 15 pM), the newly developed anti-AMH B10 antibody decreased by 25% (OVCAR8) to 50% (KGN) cell viability at concentrations ranging between 3 and 333 nM. At 70 nM, B10 reduced clonogenic survival by 57.5%, 57.1%, 64.7% and 37.5% in COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN cells, respectively. In the four cell lines, B10 reduced AKT phosphorylation, and increased PARP and caspase 3 cleavage. These results were confirmed in ovarian cancer cells isolated from patients’ ascites, demonstrating the translational potential of these results. Furthermore, B10 reduced COV434-MISRII tumor growth in vivo and significantly enhanced the median survival time compared with vehicle (69 vs 60 days; p = 0.0173). Our data provide evidence for a novel pro-survival autocrine role of AMH in the context of ovarian cancer, which was targeted therapeutically using an anti-AMH antibody to successfully repress tumor growth.

Minimally Invasive Molecular Diagnosis Of High-Grade And Low-Grade Serous Adenocarcinoma Of The Ovary

Minimally Invasive Molecular Diagnosis Of High-Grade And Low-Grade Serous Adenocarcinoma Of The Ovary

Features of the Copy Number Variation of Certain Genes in Tumor Cells in Patients with Serous Ovarian Adenocarcinoma.

We analyzed the peculiarities of the copy number variation of genes that regulate apoptosis, DNA repair, cell proliferation, metabolism, and estrogen reception in tumor and normal cells of high-grade and low-grade serous adenocarcinoma of the ovaries. Using real-time qPCR method, the relative copy number of 34 genes (BAX, BCL2, TP53, MDM2, CASP9, CASP3, CASP7, CASP8, PRKCI, SOX2, OCT4, PIK3, PTEN, C-MYC, SOX18, AKT1, NOTCH1, BRCA1, BRCA2, EXO1, SCNN1A, KRAS, EGFR, BRAF, CYP1A1, CYP1A2, CYP1B1, CYP19A, ESR1, ESR2, GPER, STS, SULT1A, and SULT1E1) was determined in normal and tumor cells of the ovaries extracted by contactless capture laser microsection from FFPE-blocks of 200 patients. The most typical molecular markers of ovarian serous adenocarcinoma cells were identified: copy number of PIK3CA, BCL2, BAX, CASP3, and CASP8 genes. Based on the differences in the gene copy number variation, two molecular subtypes of serous adenocarcinoma were identified, corresponding to two histological subtypes: high-grade (MDM2, SOX2, ESR1, CYP1B1, SULT1E1, TP53, BRCA2) and low-grade (PIK3CA, PTEN, BCL2, BAX, and CASP3). Each of these subtypes was also characterized by molecular heterogeneity and can be subdivided into several subgroups: 3 subgroups for high-grade and 4 subgroups for low-grade serous adenocarcinoma. These findings extend our understanding of the molecular mechanisms of carcinogenesis in the ovarian tissue, confirm molecular difference between the two histological subtypes of serous adenocarcinoma probably underlying their different clinical course.