High-grade Serous Cancer Research Articles

Reprogramming of ovarian granulosa cells by YAP1 leads to development of high-grade cancer with mesenchymal lineage and serous features

Understanding the cell-of-origin of ovarian high grade serous cancer (HGSC) is the prerequisite for efficient prevention and early diagnosis of this most lethal gynecological cancer. Recently, a mesenchymal type of ovarian HGSC with the poorest prognosis among ovarian cancers was identified by both TCGA and AOCS studies. The cell-of-origin of this subtype of ovarian cancer is unknown. While pursuing studies to understand the role of the Hippo pathway in ovarian granulosa cell physiology and pathology, we unexpectedly found that the Yes-associated protein 1 (YAP1), the major effector of the Hippo signaling pathway, induced dedifferentiation and reprogramming of the ovarian granulosa cells, a unique type of ovarian follicular cells with mesenchymal lineage and high plasticity, leading to the development of high grade ovarian cancer with serous features. Our research results unveil a potential cell-of-origin for a subtype of HGSC with mesenchymal features.

Prophylactic salpingectomy for the prevention of ovarian cancer: Who should we target?

Ovarian cancer is the most fatal gynecologic malignancy (50% 5-year survival) due to a typically advanced stage at diagnosis and a high rate of recurrence. Chemoprevention options are limited, and few interventions have been shown to reduce cancer risk or mortality. Emerging data support the model that fallopian tubes are the site of origin for a proportion of high-grade serous cancers. This implies that a subset of cancers may be prevented by removing the fallopian tubes while leaving the ovaries intact. Accordingly, there has been shift in clinical practice for average risk women; some now recommend removal of both the fallopian tubes only instead of tubal ligation for sterilization or at the time of benign gynecologic surgery. This has been termed opportunistic salpingectomy and represents a means of decreasing the burden of ovarian cancer by preventing cancers that arise in the fallopian tubes. There have been no detailed, prospective reports that have estimated ovarian cancer risk reduction with opportunistic salpingectomy, neither among women at baseline population risk nor among women at a high risk of developing the disease. The situation is complicated for women with a BRCA mutation-bilateral salpingo-oophorectomy is a proven means of risk reduction and salpingectomy alone is not the standard of care. Based on the existing data, salpingectomy alone should only be reserved for women with a lifetime risk of ovarian cancer of less than 5%.

The miR-34 family and its clinical significance in ovarian cancer.

The tumor suppressor miR-34 family is transcriptionally induced by p53. Clinical significance of the various miR-34 family members has not been studied in ovarian cancer. In 228 ovarian cancers and in 19 non-neoplastic fallopian tube samples we analysed miR-34 a/b/c expression in relation to clinicopathological characteristics and clinical outcome. We found significantly lower levels of miR-34 a/b/c in ovarian cancers as compared to control-tissues (P=0.002, P<0.001, P<0.001, respectively). Expression of miR-34 b/c revealed an inverse correlation with BRCA1/2 mRNA-expression (BRCA1: miR34 b/c P=0.002 each; BRCA2: miR-34 b/c P<0.001 each), the same was true for miR-34a and BRCA2 mRNA-expression (P<0.001). The miR-34 family expression was found to be significantly lower in type 2 in comparison to type 1 cancers (P<0.001) and in TP53-mutated compared with TP53-wild-type ovarian cancers (P<0.001, P=0.002, P=0.004, respectively). When low grade serous ovarian cancers were compared with high grade serous cancers the respective miR-34 a/b/c expression was 2.6-, 40.8- and 32.3-fold higher. The expression of each of the miR-34 family members was revealed to be of independent prognostic relevance regarding progression free survival (PFS); miR-34a: HR 0.6, P=0.033; miR-34b: HR 0.2, P=0.001 and miR-34c: HR 0.3, P=0.002, respectively). For overall survival (OS) independency of the prognostic value was confined to miR-34b (HR 0.4, P=0.016) and miR-34c (HR 0.6, P=0.049). The independency of the prognostic value of our identified thresholds was confirmed for PFS for miR-34c in a publicly available dataset (NCBI Gene Expression Omnibus GSE73582). Our findings suggest that downregulation of miR-34 family is a crucial part in ovarian cancer development. Low miR-34 levels are linked to a worse overall survival and progression free survival and may indicate a more aggressive disease.

Oral Squamous Cell Carcinoma as a Complication of Treatment for Recurrent High-Grade Serous Cancer.

Advances in cancer treatment have increased survival for many patients, prompting a need for greater recognition of the long-term complications of treatment. Chemotherapy agents have the potential to induce carcinogenesis and can increase the risk of secondary malignancy. Pegylated liposomal doxorubicin (PLD) used for maintenance treatment of recurrent high-grade serous cancers has been associated with the development of oral cavity squamous cell carcinoma (SCC). Retrospective review. Cases of oral cavity SCC in patients with recurrent high-grade serous cancer treated with PLD between 1997 and 2017 at a single institution were reviewed. Eight of 16 patients treated with PLD developed oral cavity SCC. The duration of PLD use ranged from 1.3 to 15 years (mean = 5.8 years) and cumulative dose ranged from 405 to 3,000 mg/m2 (mean = 1,542 mg/m2 ). Seven patients tested positive for BRCA mutations (four BRCA 1+, three BRCA 2+). No patients had a history of alcohol or tobacco use. All had early-stage oral cavity disease; five were T1N0, two were T2N0, and one had carcinoma in situ. All patients underwent surgery, and two received adjuvant radiation. Four developed locoregional recurrence requiring additional treatment. Of these, one patient died from complications of oral SCC, one developed recurrent ovarian cancer, and two had no evidence of disease of the oral cavity or ovarian cancer at the last follow-up. Long-term PLD therapy may be associated with the development of oral cavity SCC. A high index of suspicion and routine head and neck examination should be included in follow-up for exposed patients. 4 Laryngoscope, 130:2607-2610, 2020.

Prognostic utility of FDG PET/CT in advanced ovarian, fallopian and primary peritoneal high-grade serous cancer patients before and after neoadjuvant chemotherapy.

In patients with advanced ovarian, fallopian and primary peritoneal carcinoma, complete interval debulking surgery (IDS) is often performed after neoadjuvant chemotherapy (NAC) to achieve long progression-free survival (PFS) and overall survival (OS). We aimed to investigate the utility of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET/CT in patients with these malignancies who underwent complete IDS. Between 2009 and 2017, twenty-two patients underwent FDG PET/CT scans before and after NAC. The highest SUVmax/peak (standardized uptake value), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) for whole lesions were defined as target SUVmax/peak, tMTV and tTLG, respectively. We also calculated these reduction rates during NAC. These parameters were compared between the groups with platinum-free interval (PFI) > 12months (n = 10) and those with PFI ≤ 12months (n = 12). The PFS and OS were evaluated using these quantitative parameters, and in terms of the presence of visually detectable residual lesions after NAC. The target SUVmax/peak before NAC, the reduction rates in the target SUVmax, tMTV and tTLG were significantly higher in the group with PFI > 12months than the shorter PFI group (p < 0.05). Especially in PFS, the higher reduction rates in the target SUVmax/peak, tMTV, and tTLG had an excellent prognostic stratification (p < 0.05) and the FDG visually negative group after NAC had a significantly better prognosis than the other group (p < 0.01). The reduction rate of FDG PET-based quantitative values and visual analysis after NAC demonstrated prognostic potential, especially in PFS.

Diagnostic utility of immunohistochemical expression of HE4 in Epithelial Ovarian Neoplasm

Background: Mortality in case of ovarian malignancy is high due to late diagnosis. Early and accurate diagnosis can improve the case specific management. HE4 (human epididymis protein 4) which is proved to be overexpressed in the ovarian cancer cells, is considered a new biomarker for ovarian cancer diagnosis. Aims and objectives: The study was undertaken to evaluate the immunohistochemical expression of HE4 in various epithelial ovarian neoplasm. Material and Methods: It was a cross sectional, prospective, single institution based study, conducted in the department of Pathology in collaboration with the department of Gynecology and Obstetrics, from December 2016 to January 2019 in our institution. A total 71 cases were selected for this study. Results: Serous tumour was the most common epithelial tumour followed by mucinous tumour. Highest percentage of expression of HE4 was seen in high grade serous cancer and malignant endometrioid tumour. Benign serous and mucinous tumour shows negative expression mostly. We found statistically significant correlation between HE4 expression and different types of epithelial ovarian tumours (p=0.000). Conclusions: HE4 was highly expressed in malignant ovarian tumour especially serous and endometrioid carcinoma and can be used as an important biomarker for malignant ovarian neoplasm. Expression in high grade ovarian serous cancer supports its prognostic value also.

Abstract DP-012: STUDYING THE SIGNALING PATHWAYS OF DISTINCT SUBPOPULATIONS OF CELLS GENERATED UPON PTEN DELETION FROM FTE AND IDENTIFICATION OF MARKERS OF EARLY TUMORIGENESIS

Abstract SIGNIFICANCE: High Grade Serous Cancer (HGSOC) Requires Novel Biomarkers for early detection. Survival rates for HGSOC patients have not substantially improved, over the past decades, mainly because the disease is only detected at the metastatic stage. The findings of early pre-malignant lesions in the fallopian tube, but not in the ovary, suggested that HGSOCs may originate from the fallopian tube epithelium (FTE) and metastasize to the ovary. Studying the mechanisms of HGSOC genesis from the correct cell of origin is critical to the early detection of the disease. Our main goal is to determine how genetic and molecular alterations contribute to the early events of HGSOC genesis from FTE. Recent transgenic animal models of FTE-derived HGSOC have pointed out the critical role of loss of PTEN (phosphatase and tensin homolog) from FTE in generating HGSOC when in combination with p53 mutation and alteration of BRCA1/2, but not by itself. Our lab was the first to show that deletion of PTEN alone in FTE is sufficient to lead to tumor formation and peritoneal dissemination suggesting that the importance of PTEN in the early events of the tumorigenic cascade may have been underestimated. Loss of PTEN from FTE is sufficient to drive ovarian cancer, however, the key signaling driving tumorigenesis when PTEN expression is low remain poorly defined and yet pivotal to new treatment options given its common occurrence. Studying the progression of HGSOC genesis from FTE is essential to refining the strategy for targeted therapies and to discovering novel biomarkers for early detection of the disease. PURPOSE: to identify signaling pathways and drug response of different subpopulations of tumorigenic cells generated upon PTEN deletion. RESULTS: Loss of PTEN in the FTE upregulates markers of cancer stem cells (CSC) such as WNT4, LGR5, ALDH1, c-Kit, CD44, and Dll4. We also discovered that the CSC markers are confined in a specific subpopulation of cells with increased diameter that we call CSCHigh as compared to a smaller population that we call CSCLow. In fact, when these two populations are separated by flow cytometry based sorting, the CSCHigh retains all the CSC markers. In addition, using a limiting dilution assay, we found that the CSCHigh subpopulation forms tumor at a faster rate in vivo. In addition, CSCHigh forms bigger spheroids and are more resistant to chemotherapeutic agents, suggesting that more targeted therapy may be developed for these stem-like, tumorigenic subpopulations. We also show that loss of PAX2 is mediating the CSCHigh phenotype suggesting that therapies to re-express PAX2 may prevent development of HGSOC. CONCLUSIONS: Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis. Citation Format: Angela Russo, Austin A. Czarnecki, Matthew Dean, Dan Lantvit, Jian-Jun Wei Joanna E. Burdette. STUDYING THE SIGNALING PATHWAYS OF DISTINCT SUBPOPULATIONS OF CELLS GENERATED UPON PTEN DELETION FROM FTE AND IDENTIFICATION OF MARKERS OF EARLY TUMORIGENESIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-012.

Abstract AP21: A NOVEL TARGET FOR OVERCOMING ADAPTIVE RESISTANCE TO ANTI-ANGIOGENIC THERAPY IN OVARIAN CANCER

Abstract Anti-angiogenic therapy such as anti-VEGF antibody (AVA) has been being increasingly applied in patients with ovarian cancer, while vast majority developed adaptive resistance, highlighting the need for new therapies. We have screened a cohort of patients with high-grade serous cancer (HGSC) using cDNA-genomic array and immunohistochemistry. Our results indicated that p130cas [Crk-associated substrate], a central node in FAK/Src-mediated angiogenesis, was significantly upregulated in tumor-associated vascular endothelium, and the clinical analysis showed that HGSC patients with increased vascular p130cas have significantly shorter disease-progression survival than those with lower vascular p130cas levels. Our cell-based studies showed that AVA treatment in endothelial cells led to internalization of a 100-kD fragment of VEGFR2, which was released by caspase-10 cleavage from membrane-tethered VGFR2. This 100-kD form of VEGFR2 bound with TNKS1BP1 (a tankyrase-1-binding protein involved in p53-mediated cell cycle arrest) and internalized into LC3-tagged autophagosomes or translocated into nucleus to initiate cell death. Furthermore, the gene ablation of p130cas with CRISPR/CAS9 in endothelial cells that were originally resistant to AVA therapy re-sensitized them to AVA treatment. Our in vivo studies on targeting vascular p130cas with host-specific siRNA showed a robust inhibition of tumor growth and progression in orthotopic HGSC tumors through initiating autophagy-associated cell death in tumor-associated endothelial cells. To functionally characterize role of vascular p130cas in angiogenesis, we established the p130casflox/flox-Tie2Cre genomic-engineered mice (GEM) model. Using the ID8 syngeneic model, we found that depletion of vascular p130cas diminished resistance to AVA therapy and compromised angiogenesis by inducing elevated VEGFR2/TNKS1BP1 in autophagosomes and nucleus of tumor-associated endothelial cells, which were followed by cell death. To further explore the therapeutic potential of blocking tumor-associated vascular p130cas as a novel anti-angiogenic strategy, we have constituted a cell-permeable, peptide-nanoparticle complex using a p130cas antagonist encapsulated with biodegradable, long-circulating, core-crosslinked polymeric micelles (CCPM). This CCPM-p130cas antagonist contains a mutated Src-binding domain and is linked with Arg-Gly-Asp (RGD) peptide, which specifically targets angiogenic endothelial cells. We also performed the cell-based studies to show that this CCPM-p130cas antagonist is able to bind to the FAK and Src complex with high affinity and effectively block FAK/Src mediated angiogenic property in endothelial cells. Ongoing studies are focused on investigating the therapeutic efficacy and mechanism of actions for RGD-CCPM-p130cas antagonist as a novel anti-angiogenic therapy to overcome adaptive resistance occurred in patients with HGSC. In summary, our studies provided new knowledge regarding the pivotal role of vascular p130cas in tumor-associated endothelial vasculature, and the critical pre-clinical evidences for applying the RGD-CCPM-p130cas antagonist as a novel therapeutic for treatment of ovarian cancer. Citation Format: Yunfei Wen, Alpa M Nick, G Lopez-Berestein, Gary E Gallick, Robert L Coleman Robert , Mien-Chie Hung, and Anil K Sood. A NOVEL TARGET FOR OVERCOMING ADAPTIVE RESISTANCE TO ANTI-ANGIOGENIC THERAPY IN OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP21.

313P - Immunotherapy application for advanced cancers: One institution experiences since 2016 to 2019

BackgroundImmunotherapy has brought clinical benefits in several kinds of advanced cancers, including melanoma, renal cell carcinoma, non-small cell lung cancer, gastric cancer, HNSCC, esophageal cancer, hepatocellular carcinoma, and urinary tract cancers. Reliable biomarkers, best sequencing, and novel combinations for cancer immunotherapy warrant further investigation. Our group will present immunotherapy experiences for advanced cancers since 2016 to 2019 to show possible clinical impacts, choices of several combinations, toxicity profiles, favorable cancer types, and potential biomarkers exploratio. MethodsSince Jan 2016 to Feb 2019, we reviewed the details of immunotherapy(anti-PD1or anti-PDL1 or anti-CTLA4 monoclonal antibody) application from cancer patients in Yin-lin Branch of National Taiwan University Hospital. ResultsTotal 153 refractory cancer patients were collected due to previous or current use of immunotherapy. 69 patients received pembrolizumab(33 with triweekly 2 mg/kg & 36 with triweekly 200 mg); 74 received nivolumab(from 20 mg totally to 3 mg/kg biweekly); 2 ever received pembrolizumab and then nivolumab with ipilimumab; 1 ever received pembrolizumab and then pembrolizumab with ipilimumab; 5 received atezolizumab(2 NSCLC, 1 SCLC, 2 urinary tract cancers); 2 durvalumab (NSCLC). The cancer types were listed as following: 32 NSCLC(11 SCC, 19 adenocarcinoma, 1 adenosquamous, 1 pleomorphic); 2 SCLCs; 30 HNSCC(1 HPV, 29 non-HPV); 5 NPC; 15 esophageal cancers; 6 gastric cancers(1 with MSI-H); 2 high grade serous ovary cancer; 1 skin basal cell carcinoma; 1 thymic cancer; 36 HCC; 3 intra-hepatic cholangiocarcinoma; 2 malignant peripheral nerve sheath tumors; 8 urinary tract cancers; 1 RCC; 2 liver neuroendocrine tumors; 1 adrenal carcinoma; 1 breast cancer; 1 mesothelioma; 2 melanoma; 1 primary CNS lymphoma; 1 Papilla of Vater cancer(HER2 amplification and high TMB). The overall clinical benefits were 85%(130/153) and objective response rates were 43%(66/153).Table313PTableCancer typesORRCommentsUrinary tract cancers7/8(87.5%)With Avastin and chemotherapyEsophageal cancer9/15(60%)Afatinib with anti-PD1NSCLC19/32(59%)KN189/IMpower150 in Adeno; CM227 in SCCHNSCC14/30(47%)Afatinib with anti-PD1(easy autoimmune cholestasis and interstitial pneumonitis with pembrolizumab)HCC9/36(25%)With metronomic therapy, Avastin, or chemotherapySCLC1/2(50%)+/-AvastinNPC2/5(40%)Biomarkers neededGC1/6(17%)Responder in MSI-HPapilla of Vater cancer1 stable diseaseHER2 amplification and high TMBSkin cancer1/1High TMBCholangiocarcinoma0/3Combinations searchingRCC1/1With anti-angiogenesis TxPCNSL1/1Rituximab with nivolumab ConclusionsIn one institutional experiences, immunotherapy combinations for refractory advanced cancers have brought encouraging responses and clinical benefits, esp. in urinary tract cancer, esophageal cancers, NSCLC, HNSCC, HCC(the top 5 cancer types endemic in Yun-lin), NPC, skin cancers, primary CNS lymphoma, and cancers with MSI-H or high TMB. Individual combinations, biomarkers, sequencing, and toxicities may be explored in different kinds of advanced cancers to reach favorable outcomes. Legal entity responsible for the studyIRB in National Taiwan University Hospital. FundingHas not received any funding. DisclosureThe author has declared no conflicts of interest.

Meeting report from the 2018 12th Biennial Ovarian Cancer Research Symposium detection and prevention of ovarian cancer

The objective of this review is to summarize recent research advances in the detection and prevention of ovarian cancer and discuss the experts’ opinions of future directions. The 12th Biennial...

Abstract 4174: Familiality of ovarian cancer histotypes in the Utah Population Database

Abstract Introduction: Ovarian cancer is a heterogeneous disease; each histotype has distinct molecular origins, risk factors and outcomes. While it is well established that ovarian cancer has a familial risk component, the familiality of ovarian cancer histotypes has not been well described. The Utah Population Database (UPDB) captures over 10 million individuals, including more than 5 million with a minimum of three generations of genealogy data. By linking records from the UPDB to the Utah Cancer Registry (UCR) and other statewide data sources, we sought to describe the familiality of ovarian cancer histotypes. Methods: Our study includes all ovarian cancer cases in the UPDB and leverages clinical data reported to UCR for the case histotypes. Cases were matched to controls on age, birth cohort and at least three generations of UPDB data versus not. We quantified familiality by comparing the odds of ovarian cancer occurrence among family members of cases to the odds of ovarian cancer among family members of matched controls. We calculated odds ratios for first-degree relatives, second-degree relatives, and first cousins. Results: As of September 2018, the UPDB included 3,989 ovarian cancer cases. We observed an increased risk of epithelial ovarian cancer among first-degree relatives (OR=1.62, 95%CI=1.36-1.93), second-degree relatives (OR=1.53, 95%CI=1.34-1.74), and first cousins (OR=1.38, 95%CI=1.26-1.53) of ovarian cancer cases. When we analyzed epithelial ovarian cancers by histotype, familiality was most evident for high-grade serous, mucinous, and unclassified cancers. For example, we observed a 1.62-fold increased odds (95%CI=1.14-2.29) of high-grade serous ovarian cancer among the first-degree relatives of high-grade serous cases, and a 5.59-fold increased odds (95%CI=2.09-14.92) of mucinous ovarian cancer among first-degree relatives of mucinous ovarian cancer cases. Familiality patterns were less clear among endometrioid and clear cell cases. Conclusions: The UPDB has the potential to contribute greatly to family-based studies of the genetics of ovarian cancer histotypes. Despite the possible variations in quality of histotype data across generations, preliminary results suggest some histotypes may be particularly familial and good candidates for gene mapping studies. Work is ongoing to refine the histotype assignments for cases by performing pathology review using the 2014 World Health Organization guidelines. Analyses are also in progress to stratify analyses by BRCA mutation status, and to consider the potential for shared familiality across ovarian cancer histotypes and with cancers at other sites. Citation Format: Mollie E. Barnard, Nicola J. Camp, Jennifer A. Doherty. Familiality of ovarian cancer histotypes in the Utah Population Database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4174.

T cell trafficking within the peritoneal tumor environment and ovarian cancer progression.

5573 Background: Ovarian cancer is associated with high mortality due to detection at late stages with widespread peritoneal metastases at diagnosis in a majority of patients. Ovarian cancer recurrences are primarily found in the peritoneal cavity, and peritoneal disease is the primary cause of morbidity and mortality in this disease. This pattern of tumor engraftment and recurrence indicates that the peritoneal tumor environment is distinct from other niches. Our data indicate that selective peritoneal dissemination is immunologically mediated, based on functional differences in peritoneal and systemic T cells during ovarian cancer progression. This is consistent with data in other solid tumors demonstrating that tumor immunity is driven by regional lymphocyte populations. However, less is known about the mechanisms that establish a permissive immune environment in the peritoneal cavity. We hypothesize that pathways regulating T cell recruitment and retention in the peritoneal cavity (PC) are co-opted by ovarian cancer cells to enable intraperitoneal cancer dissemination and recurrence. Methods: We have developed a novel model that uses direct in vivo labeling of peritoneal cells in an established immune-competent high grade serous murine cancer model. This functional approach enables us to identify T cell subsets retained in the PC with tumor engraftment and progression. Results: We identified high expression of CD49d (a4 integrin) as the most prevalent cell surface marker on T cells retained in the peritoneal cavity, consistent with prior published data in healthy mice and people. We demonstrated a functional role for CD49dhi in T cell retention by showing preferential binding to VCAM. A role for tumor cells mediating this interaction was observed based on enhanced binding affinity in vitro with tumor monolayers. The importance of this mechanism is supported by high VCAM expression in multiple murine and human ovarian cancer cell lines, and T cell localization to VCAM rich areas within ovarian cancer tumors in vivo. Conclusions: CD49d not only defines a lymphocyte subset with a significant role in tumor immunity but presents itself as an important potential therapeutic target to modulate T cell trafficking.

Performance of the MasSpec Pen for Rapid Diagnosis of Ovarian Cancer.

Accurate tissue diagnosis during ovarian cancer surgery is critical to maximize cancer excision and define treatment options. Yet, current methods for intraoperative tissue evaluation can be time intensive and subjective. We have developed a handheld and biocompatible device coupled to a mass spectrometer, the MasSpec Pen, which uses a discrete water droplet for molecular extraction and rapid tissue diagnosis. Here we evaluated the performance of this technology for ovarian cancer diagnosis across different sample sets, tissue types, and mass spectrometry systems. MasSpec Pen analyses were performed on 192 ovarian, fallopian tube, and peritoneum tissue samples. Samples were evaluated by expert pathologists to confirm diagnosis. Performance using an Orbitrap and a linear ion trap mass spectrometer was tested. Statistical models were generated using machine learning and evaluated using validation and test sets. High performance for high-grade serous carcinoma (n = 131; clinical sensitivity, 96.7%; specificity, 95.7%) and overall cancer (n = 138; clinical sensitivity, 94.0%; specificity, 94.4%) diagnoses was achieved using Orbitrap data. Variations in the mass spectra from normal tissue, low-grade, and high-grade serous ovarian cancers were observed. Discrimination between cancer and fallopian tube or peritoneum tissues was also achieved with accuracies of 92.6% and 87.9%, respectively, and 100% clinical specificity for both. Using ion trap data, excellent results for high-grade serous cancer vs normal ovarian differentiation (n = 40; clinical sensitivity, 100%; specificity, 100%) were obtained. The MasSpec Pen, together with machine learning, provides robust molecular models for ovarian serous cancer prediction and thus has potential for clinical use for rapid and accurate ovarian cancer diagnosis.

PARP Inhibitors and the Evolving Landscape of Ovarian Cancer Management: A Review.

As a drug class, inhibitors of poly-(ADP-ribose) polymerase (PARP) have had their greatest impact on the treatment of women with epithelial ovarian cancers (EOC), in particular, those with the most common histological subtype, high-grade serous cancer, as it has high rates of homologous recombination (HR) deficiency. PARP inhibition exploits this cancer vulnerability by further disrupting DNA repair, thus leading to genomic catastrophe. Early clinical data demonstrated the effectiveness of PARP inhibition in women with recurrent EOC harbouring BRCA1/2 mutations and those with platinum-sensitive recurrences. Three PARP inhibitors (olaparib, niraparib, and rucaparib) are now approved for use in women with recurrent EOC. Based upon randomised controlled trials, PARP inhibitors are in use as "maintenance" therapy for those with platinum-sensitive and platinum-responsive recurrences (irrespective of BRCA1/2 mutation status). Among women with BRCA1/2 mutations (either germline or somatic), maintenance PARP inhibitor therapy for those with recurrence has led to a nearly fourfold prolongation of progression-free survival compared to placebo control. Those without BRCA1/2 mutations experience an approximately twofold increase in progression-free survival. The latest clinical data demonstrate that women with BRCA1/2 mutations who respond to first-line chemotherapy and go on to have maintenance olaparib experience a doubling of the rate of freedom from death at 3years when compared to placebo (60% vs 27%). PARP inhibitors are also approved as active therapy for women with germline or tumour BRCA1/2 mutations and recurrent EOC treated with three or more prior lines of therapy. Apart from the presence of a BRCA1/2 mutation (germline or somatic) and clinical factors such as platinum sensitivity and responsiveness, other predictive biomarkers are not in routine clinical use. Assays to identify genomic aberrations caused by HR deficiency, or mutations in genes involved in HR, have not been sufficiently sensitive to identify all patients who benefit from treatment. The mechanisms of PARP-inhibitor resistance include restoration of HR through reversion mutations in HR genes, capable of re-establishing the DNA open-reading frame and leading to resumed HR function. Other mechanisms that sustain sufficient DNA repair may also be important. This review focuses on the rationale for the use of PARP inhibitors in EOC. The data that have shaped clinical research are presented, and the trials that have changed management standards are reviewed and discussed. Highlighted are the past and ongoing efforts to further improve and explore the use of PARP inhibitors in EOC.

&lt;p&gt;&lt;em&gt;Chlamydia&amp;nbsp;trachomatis&lt;/em&gt; infection in primary fallopian tube and high-grade serous ovarian cancers: a pilot study&lt;/p&gt;

BackgroundThe aim of this study was to evaluate the association of Chlamydia trachomatis (CT) infection with primary tubal and high-grade serous ovarian cancers.MethodsThis is a cross-sectional, retrospective study conducted at Ain Shams University Maternity Hospital, Egypt, from February 2008 to October 2017. Sixty-seven paraffin archival blocks specimens were retrieved from cases who underwent staging laparotomy due to high-grade serous ovarian cancer (30 cases), primary tubal serous cancer (25 cases), and control specimens of (12) tubal specimens from cases of benign gynecological conditions. All samples were examined for CT DNA using semiquantitative qRT-PCR.ResultsCT DNA was detected in 84% of high-grade tubal serous cancer, 16.7% of high-grade serous ovarian cancer, and 13.3% in controls (P<0.0005). Mean CT DNA relative quantity was significantly high (256) in tubal carcinoma, in comparison to that in high-grade serous ovarian cancer and controls (13.5 and 0.28, respectively; P<0.0005).ConclusionTo the best of our knowledge, this is the first report on relation of CT to the tubal serous cancer, so the responsibility of CT tubal infection in the pathogenesis of primary tubal cancer needs to be considered.

Survival of Ovarian Cancer Patients Is Independent of the Presence of DC and T Cell Subsets in Ascites.

Ascites is a prominent feature of ovarian cancer and could serve as liquid biopsy to assess the immune status of patients. Tumor-infiltrating T lymphocytes are correlated with improved survival in ovarian cancer. To investigate whether immune cells in ascites are associated with patient outcome, we analyzed the amount of dendritic cell (DC) and T cell subsets in ascites from ovarian cancer patients diagnosed with high-grade serous cancer (HGSC). Ascites was collected from 62 HGSC patients prior to chemotherapy. Clinicopathological, histological and follow-up data from patients were collected. Ascites-derived immune cells were isolated using density-gradient centrifugation. The presence of myeloid DCs (BDCA-1+, BDCA-3+, CD16+), pDCs (CD123+BDCA-2+), and T cells (CD4+, CD8+) was analyzed using flow cytometry. Complete cytoreduction, response to primary treatment and chemosensitivity were associated with improved patient outcome. In contrast, immune cells in ascites did not significantly correlate with patient survival. However, we observed a trend toward improved outcome for patients having low percentages of CD4+ T cells. Furthermore, we assessed the expression of co-stimulatory and co-inhibitory molecules on T cells and non-immune cells in 10 ascites samples. PD-1 was expressed by 30% of ascites-derived T cells and PD-L1 by 50% of non-immune cells. However, the percentage of DC and T cell subsets in ascites was not directly correlated to the survival of HGSC patients.

Hysterectomy and opportunistic salpingectomy (HOPPSA): study protocol for a register-based randomized controlled trial

Abstract Background There is a great need for a prospective randomized trial to evaluate the risks and benefits of opportunistic salpingectomy. Recently, genetic and morphologic studies have indicated that epithelial ovarian cancer predominantly develops in the Fallopian tubes. Consequently, there is reason to believe that salpingectomy would reduce the risk of ovarian cancer. Studies on reducing the risk of ovarian cancer have compared indicated salpingectomy with no salpingectomy, while studies on surgical safety as well as ovarian function after opportunistic salpingectomy have been small with a short follow-up. No study has reported menopausal symptoms. Methods/design In this national register-based randomized controlled trial, women &lt;55 years old, planned for a hysterectomy for a benign cause, will be randomized to concomitant salpingectomy or no salpingectomy. The follow-up will be conducted according to already established routines within the register using on-line questionnaires. Primary outcomes have been defined for three different time points: short-term complications up to 8 weeks postoperatively (n = 2800), intermediate-term changes in menopausal symptoms measured by the Menopause Rating Scale at baseline and after 1 year (n = 1670), and long-term epithelial ovarian cancer assessed through national registers after 30 years (n = 5052) (or n = 7001 for high-grade serous cancer). In a sub-study of 75 women, ovarian function will be evaluated through change in anti-Müllerian hormone measured before surgery and after 1 year. Discussion Hysterectomy for a benign cause is a common surgical procedure and several national societies recommend salpingectomy while performing a benign hysterectomy, despite a lack of scientific evidence for the safety of the procedure. Sweden has unique conditions for clinical trials because of its national quality registers and health registers with excellent quality and near complete coverage. If no additional risks are associated with concomitant salpingectomy, it can be recommended at the time of benign hysterectomy to reduce the risk of epithelial ovarian cancer. If not, the risks and benefits must be balanced. The results of this study will be important for informing women undergoing a benign hysterectomy. Trial registration ClinicalTrials.gov, NCT03045965. Registered on 8 February 2017.

Single-agent bevacizumab for the management of refractory malignant effusions in heavily pretreated patients with recurrent high-grade serous cancers of the ovary, fallopian tube or peritoneum: results from a single institution

Single-agent bevacizumab for the management of refractory malignant effusions in heavily pretreated patients with recurrent high-grade serous cancers of the ovary, fallopian tube or peritoneum: results from a single institution

Back to the Future? The Fallopian Tube, Precursor Escape and a Dualistic Model of High-Grade Serous Carcinogenesis.

Beginning with the discovery of the BRCA-associated ovarian cancer susceptibility genes and subsequent detailed examination of risk-reducing salpingo-oophorectomy (RRSO) specimens, a new paradigm of ovarian carcinogenesis has unfolded with attention to the distal fallopian tube. The primary focus has been an early cancer or neoplasm in the fallopian tube which is seen in virtually all incidentally discovered high-grade serous cancers in asymptomatic women. This high-frequency of tubal involvement in early serous neoplasm (usually in the form of serous tubal intraepithelial carcinoma—STIC) has galvanized attention to this organ as a primary source of this disease. However, an enduring mystery has been the relatively low frequency of STIC in the fallopian tubes of women with advanced malignancy. This paradox, a high frequency of tubal involvement early on and a low frequency of involvement later in the disease process, has spurred interest in other potential sources, such as the ovarian surface epithelium or cortical inclusions and the secondary Mullerian system. However, because essentially all high-grade serous carcinomas are linked by TP53 mutations, and because fallopian tubes frequently contain early serous proliferations (ESPs) with these mutations, attention has turned to the possibility that the nonmalignant but TP53 mutated tubal epithelium could be responsible for an eventual malignancy. Recent data have shown evidence of a lineage continuity between ESPs and concurrent serous carcinomas prompting the concept of “precursor escape”. This creates a second component of the paradigm by which cells from early precursors are shed from the tube and undergo subsequent malignant transformation, emerging suddenly as widespread intraperitoneal malignancy. This dualistic model thus provides a unique pathway by which the future outcome (wide spread high-grade serous carcinomas—HGSC) is ultimately explained by going back in time to an early serous proliferation. This paradigm also brings the peritoneal cavity into focus, raising new questions about the potential co-variables or exposures that might facilitate the occasional malignant transformation of an ESP in the peritoneal cavity or on the peritoneal surface.

Targeted metabolomic profiling of low and high grade serous epithelial ovarian cancer tissues: a pilot study.

Epithelial ovarian cancer (EOC) remains the leading cause of death from gynecologic malignancies and has an alarming global fatality rate. Besides the differences in underlying pathogenesis, distinguishing between high grade (HG) and low grade (LG) EOC is imperative for the prediction of disease progression and responsiveness to chemotherapy. The aim of this study was to investigate, the tissue metabolome associated with HG and LG serous epithelial ovarian cancer. A combination of one dimensional proton nuclear magnetic resonance (1D H NMR) spectroscopy and targeted mass spectrometry (MS) was employed to profile the tissue metabolome of HG, LG serous EOCs, and controls. Using partial least squares-discriminant analysis, we observed significant separation between all groups (p < 0.05) following cross validation. We identified which metabolites were significantly perturbed in each EOC grade as compared with controls and report the biochemical pathways which were perturbed due to the disease. Among these metabolic pathways, ascorbate and aldarate metabolism was identified, for the first time, as being significantly altered in both LG and HG serous cancers. Further, we have identified potential biomarkers of EOC and generated predictive algorithms with AUC (CI) = 0.940 and 0.929 for HG and LG, respectively. These previously unreported biochemical changes provide a framework for future metabolomic studies for the development of EOC biomarkers. Finally, pharmacologic targeting of the key metabolic pathways identified herein could lead to novel and effective treatments of EOC.