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Abstract

Ovarian cancer remains the most lethal gynecologic malignancy, owing to late detection, intrinsic and acquired chemoresistance and remarkable heterogeneity. Despite optimization of surgical and chemotherapy protocols and initiation of clinical trials incorporating targeted therapy, only modest gains have been achieved in prolonging survival in this cancer. This review provides an update of recent developments in our understanding of the etiology, origin, diagnosis, progression and treatment of this malignancy, with emphasis on clinically relevant genetic classification approaches. In the authors' opinion, focused effort directed at understanding the molecular make-up of recurrent and metastatic ovarian cancer, while keeping in mind the unique molecular character of each of its histological types, is central to our effort to improve patient outcome in this cancer.

Keywords

chemotherapy resistance microenvironment ovarian cancer prognosis progression

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RELEASE DATE: 22 October 2014; EXPIRATION DATE: 22 October 2015

LEARNING OBJECTIVES

Upon completion of this activity, participants will be able to:

Evaluate the causes and classifications of ovarian cancer

Distinguish the strongest prognostic markers for ovarian cancer

Assess different biomarkers in ovarian cancer

Analyze the application of microRNAs to cases of ovarian cancer

Financial & competing interests disclosure

Editor: Laura Dormer , Senior Manager – Commissioning & Journal Development, Future Science Group.

Disclosure: Laura Dormer has disclosed no relevant financial relationships.

CME author: Charles P Vega, MD, Clinical Professor of Family Medicine, University of California, Irvine.

Disclosure: Charles P Vega, MD, served as an advisor or consultant for: McNeil Pharmaceuticals.

Author & credentials: Ben Davidson, MD PhD, Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

Disclosure: Ben Davidson, MD, PhD, has disclosed no relevant financial relationships.

Claes G Tropé, MD, PhD, Department of Gynecologic Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

Disclosure: Claes G Tropé, MD, PhD, has disclosed no relevant financial relationships.

No writing assistance was utilized in the production of this manuscript.

Clinical presentation & treatment

Ovarian cancer is the most lethal gynecological cancer, ranking ninth in incidence, but fifth in lethality, among women in the USA [1]. This owes mainly to presentation with advanced-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage III–IV) due to late symptoms and the lack of effective screening for early disease, as well as increasing chemoresistance along with tumor progression. stage III tumors characteristically metastasize widely within the abdominal cavity, as evidenced by the presence of both solid nodules on the peritoneum and malignant ascites [2,3].

Ovarian cancer is treated by surgery, aimed at tumor debulking to no macroscopic disease, and chemotherapy with combination taxanes and platinum. While such treatment prolongs survival even in the presence of stage IV disease [4], the 5-year survival rate of patients with advanced-stage disease has remained at less than 30%.

The most common site defining FIGO stage IV disease is the pleural cavity [2].

Etiology

The etiology of ovarian cancer is not fully established. Nulliparity, early menarche and late menopause are associated with an increased risk of this cancer, whereas oral contraceptive use, pregnancy and lactation are associated with reduced risk [5]. However, the strongest risk factor is history of ovarian cancer in a first-degree relative. Hereditary ovarian cancer, believed to account for 20% of cases, belongs mainly to the hereditary breast and ovarian cancer syndrome, in which mutations occur in the DNA repair genes BRCA1 and BRCA2, or Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome), in which mutations occur in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. The lifetime risk of developing ovarian cancer is 40, 20 and 4–11% for patients with BRCA1 mutation, BRCA2 mutation or Lynch syndrome, respectively. Patients with BRCA mutations, particularly in BRCA2, have better outcome than those with wild-type BRCA [6].

Classification, diagnosis & origin

Malignant primary ovarian tumors fall into three main groups – epithelial, sex cord/stromal and germ cell tumors – with rare miscellaneous entities outside these groups. Epithelial tumors, that is, ovarian carcinomas (OCs), are by far the most common group, accounting for 90% of cancers. Besides differences in morphology and immunophenotype, recent studies have highlighted the fact that the molecular characteristics of nonepithelial tumors differ from those of OC, as evidenced by the detection of mutations in the FOXL2 and DICER1 genes in granulosa cell tumors and Sertoli-Leydig cell tumors, respectively [7,8]. The following sections of this review focus on OC.

It is widely recognized at present that the different histological subtypes of OC are five different diseases, each with its own morphological, immunohistochemical, molecular and clinical characteristics. These include low-grade serous carcinoma (LGSC), high-grade serous carcinoma (HGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC) and clear cell carcinoma (CCC) [9]. While mixed forms occur, ancillary analyses show that they are less frequent than previously thought. Malignant Brenner tumors, undifferentiated carcinomas and malignant mixed mesodermal tumors (carcinosarcomas) are additional entities.

LGSCs often harbor KRAS and BRAF mutations, whereas the majority of HGSCs have TP53 mutations and gross genomic aberrations manifested as aneuploidy. Mutations in the ARID1A, PIK3CA, PTEN and KRAS genes characterize CCC, whereas ECs, in common with their uterine counterparts, have mutations in ARID1A, CTNNB1 and PTEN, as well as microsatellite instability [9]. Molecular analyses are nevertheless not part of the diagnostic workup of OC at present, and the diagnosis is based on morphology and immunohistochemistry (IHC). Several recent studies have demonstrated that trained gynecologic pathologists are able to classify OC with high reproducibility based on morphology and a limited panel of immunomarkers [10 –12].

Different IHC panels have been used in the literature. The markers that the authors of this review find to be the most useful in classifying OC subtypes and in excluding metastasis to the ovary include PAX8, WT1, estrogen receptor (ER), HNF1β, p16, CDX2 and CEA. PAX8 is expressed by carcinomas of female genital origin, including OC [13]. The majority of serous carcinomas are WT1-positive, with variable ER expression, whereas EC express ER, but are WT1-negative [14,15]. CCCs stain for HNF1β [9] and are commonly negative for both ER and WT1 [14]. Primary MC with intestinal differentiation and metastatic gastrointestinal adenocarcinomas stain diffusely for CEA, CDX2 and CA19.9, whereas tumors of Müllerian type are negative or focally positive for these markers and tend to be positive for ER and CA 125 [16]. Colon carcinoma metastases to the ovary often, although not always, express CK20 and are only focally positive or negative for CK7, whereas the opposite is true for ovarian MC.

There origin of OC has been long debated. Recent data suggest that the origin of HGSC, the most common OC histotype, may be in the Fallopian tube, in particular the fimbriae. This may occur via the development of an in situ lesion in the fimbriae, termed tubal intraepithelial carcinoma (TIC) or by Fallopian tube epithelium implants on the ovarian surface [17]. The Fallopian tube may also be the origin of at least some peritoneal serous carcinomas (SCs), as evidenced by common TP53 mutations [18]. Whether the Fallopian tube is the origin of all HGSCs or merely the majority of these tumors remains to be established. The other histological types of OC appear to have other origins. LGSC develops from borderline tumors, whereas endometriosis is the likely precursor of EC and CCC. The origin of MC and transitional cell tumors is still uncertain.

Prognostic & predictive markers

The difficulty in OC research

The strongest prognostic markers in OC are disease stage at diagnosis and the volume of residual disease after primary surgery, the latter additionally impacting on chemotherapy response. Older age, histological type and high-volume ascites are additional prognostic factors [19]. Despite this fact, considerable effort has been made with the aim of better stratifying OC patients in terms of outcome. Recent years have consequently seen an exponential increase in the number of publications dealing with the clinical course of this cancer. A PubMed search performed on February 11 2014, using the terms ‘ovarian’ and ‘prognostic’ generated over 4600 hits (almost 3700 for ‘ovarian’ and ‘predictive’), whereas changing the latter term to ‘prognosis’ increases the number of references to almost 20,000. Although remarkably enough, not a single molecule, with the exception of PARP in BRCA-mutated OC, is currently universally accepted as a predictive marker or therapeutic target in this disease. With the possible exception of BRCA status, no prognostic biological markers exist either and, despite numerous reports on molecules that have prognostic value in OC independently of clinical parameters, no such biological marker is universally accepted as such at present.

While the yield of predictive or prognostic markers that enter the clinic falls very much short of the number of biomarkers proposed by different research groups in any given cancer type, there are several factors that make the situation still worse in OC.

First and foremost are the inclusion criteria. The majority of studies dealing with OC have investigated tumors of different histological type together, a practice that has changed, at least in part, in recent years, as a growing number of papers focus on one histological type. Even more problematic is the inclusion of carcinosarcomas or malignant nonepithelial tumors in some series. Studies in which non-serous tumors are grouped as ‘other’ are similarly difficult to evaluate.

Another crucial factor is our evolving ability to diagnose OC more accurately owing to the inclusion of the above-described IHC markers, in particular PAX8, WT1 and CDX2, in routine practice. Many tumors previously diagnosed as undifferentiated carcinomas or poorly differentiated EC have been reclassified as serous OC [20], whereas many mucinous tumors diagnosed as primary in the ovary have been shown to be metastases from the GI tract [21]. Studies in which tumor classification is not done by trained gynecologic pathologists and studies that include older specimens without proper review of the studied material are, therefore, likely to generate inaccurate data.

The clinical relevance of adequate histological typing is highlighted by a recent analysis of 575 optimally debulked OCs, in which histology was reviewed for all cases, and where tumor type was significantly related to survival [10].

Although not unique to OC, changing therapeutic approach is another confounding factor in this cancer. Surgery has become more aggressive, with the acceptable cut-off for residual disease falling from 2 to 1 cm to the current goal of no macroscopic disease, affecting survival. The addition of paclitaxel to platinum as standard chemotherapy regimen in the 1990s has similarly impacted on disease outcome. Consequently, the inclusion of tumors from patients diagnosed before 1990 presents potential bias. Analysis of specimens obtained post-chemotherapy along with chemo-naive ones is yet another potential source of error that is becoming increasingly relevant, as many OC patients are operated following neoadjuvant chemotherapy. Since chemotherapy changes considerably the genotype and phenotype of tumor cells and selects chemoresistant cell populations, post-chemotherapy tumor characteristics are likely to markedly differ from chemo-naive ones.

The following sections discuss some of the recent studies focusing on biomarkers associated with outcome in OC. Keeping the above-mentioned caveats in mind, the papers discussed are those that analyzed large tumor series, preferably of one histotype or several histotypes analyzed separately, with a minimal number of pre-1990 tumors or tumors classified histologically as ‘various’ or ‘unknown’.

Receptor tyrosine kinases & intracellular signaling proteins

Analysis of 183 HGSC specimens for protein expression of the fibroblast growth factor (FGF) receptor family member FGFR4 showed association between FGFR4 expression and poor overall survival (OS) in both univariate and multivariate analysis. FGFR4 silencing in vitro abrogated signaling via the MAPK, Wnt and NF-κB pathways, resulting in reduced proliferation and survival, increased apoptosis and reduced invasion [22]. Presence of the 388Arg FGFR4 allele was significantly associated with longer OS and progression-free survival (PFS) in both univariate and multivariate analysis, as well as platinum sensitivity, in patients with optimally debulked tumors, in analysis of predominantly serous OC [23].

Expression of the epidermal growth factor (EGF) family receptors EGFR, p-EGFR and HER-2/Neu in a series of 232 OCs of mixed histotype was unrelated to disease outcome, whereas expression of the PI3K negative regulator phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was significantly related to longer OS and PFS in both univariate and multivariate analysis [24]. HER-2 protein expression was similarly unrelated to survival in an analysis of 90 CCCs [25], nor was PTEN associated with prognosis in this tumor type [26]. Overexpression of PIK3CA, the catalytic subunit of PI3K, by IHC was associated with longer OS in CCC [26], whereas no relation to clinical outcome was observed in analysis of PIK3CA mutation status in another CCC series [27].

The receptor tyrosine kinase MET was reported to be overexpressed in CCC compared with other OC histotypes and its expression was associated with poor OS [28].

Expression of DKK1, negative regulator of the Wnt pathway, and of the MAPK member JNK-1 was studied in 178 OCs. Expression of both markers, separately or together, was associated with poor survival. DKK1 promoted formation of actin filaments and filopodia in vitro and tumor growth in nude mice [29].

DNA repair proteins & transcriptional regulators

Expression of the DNA repair protein PARP1 was associated with poor OS and PFS in a series of 174 HGSCs [30], a finding in agreement with the targeting of this protein as a potential therapeutic approach in OC [31]. In another study, expression of the E3 ubiquitin ligase EDD was associated with increased risk of recurrence or death irrespective of FIGO stage and debulking status, and siRNA-mediated EDD knockdown partially restored platinum sensitivity in the resistant line A2780-cp70 [32]. Two studies that have assessed BRCA1 protein expression by IHC in OC of mixed histotype reached opposite conclusions with respect to its relationship to clinical role [33,34]. The presence of ERCC1, another DNA repair protein, was observed in 27% of 408 OCs of different histotype. Expression by IHC was unrelated to clinical outcome or to the presence of polymorphisms in the ERCC1 gene [35].

Mutations in the TP53 gene are a hallmark of HGSC, and their almost universal presence in this tumor is expectedly associated with lack of predictive or prognostic relevance [36].

Loss of expression of ARID1A, an accessory subunit of the SWI-SNF chromatin remodeling complex, is often seen in CCC and its loss was associated with poor PFS and with chemoresistance in this tumor in one series [37], whereas no such relationship was found by another group [27]. Amplification of the ZNF217 gene at chromosome 20q13.2, detected by FISH, was significantly related to poor PFS and OS in CCC and ZNF217 silencing by siRNA resulted in growth inhibition and apoptosis in vitro [38].

Expression of steroid receptor coactivator-3 was significantly related to poor survival in an analysis of 471 OCs of mixed histotype [39]. PAX8 expression, while useful in the diagnostic setting, had no prognostic role in analysis of 148 SCs [40].

Immune response parameters

The role of immune response mediators in determining outcome in OC has been investigated in several studies, with the focus on tumor-infiltrating lymphocytes (TILs). Hwang et al. recently published a meta-analysis of 10 studies comprising a total of 1815 patients assessing this parameter. Two of the studies focused exclusively on SC, whereas the remaining eight studied OCs of different histotype. Significant association was observed between the presence of CD3-positive or CD8-positive TILs and longer survival [41]. In the paper by Clarke et al. listed among the 10 above-mentioned studies, the presence of CD8-positive, but not CD3-positive, TILs was a prognostic marker, and this finding was limited to SC, with no such role for TILs in EC or CCC [42].

In another study, the clinical role of multiple immune response-related proteins, including leukocyte CD1a, CD3, CD4, CD8, CD20, CD25, CD45RO, CD56, CD57, CD68, CD208, OX-40, TIA-1, granzyme B, FOXP3 and myeloperoxidase expression and tumor cell COX-2 and MHC class I and II expression, was assessed. The presence of cells positive for CD8, CD3, FoxP3, TIA-1, CD20 and MHC class I and class II was significantly associated with disease-specific survival (DSS) in HGSC from optimally debulked patients, whereas immune infiltrates were less evident and of lesser clinical relevance in other OC histotypes [43].

Other markers

Several other biomarkers have been studied for a potential role in survival in OC.

Analysis of the protein expression of YB-1, found to be related to cisplatin resistance in breast cancer cell lines, and RPS4X in 192 HGSCs showed significant association between reduced expression of the latter and poor PFS and OS, which was retained in multivariate analysis. RPS4X depletion in OC cells lines in vitro was associated with resistance to cisplatin [44].

Analysis of protein expression of AEG-1 by IHC in 131 stage III–IV SCs showed significant direct association with higher residual disease volume, platinum resistance and poor PFS and OS [45].

Protein expression of Emi1, an anaphase-promoting complex/cyclosome (APC/C) inhibitor inducing genetic instability and mitotic catastrophe, was found in 30% of 129 CCCs and was associated with poor OS. No such association was found for the galactoside-binding protein Galectin-3, p53 or the proliferation marker Ki-67 [46].

Expression of the mitotic spindle protein Aurora-A by IHC was associated with poor disease-free survival and OS in EC, with the opposite finding for BRCA [47].

Histotype-specific analyses of the expression of the RNA-binding protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3; IMP3) and the autophagy marker microtubule associated protein 1 light chain 3A (LC3A), identified a role for these markers in detecting patients with poor survival in CCC, but not in HGSC or EC [48,49].

The clinical role of ER and progesterone receptor (PR) was recently investigated in a series of 2933 OCs, including 1742 HGSCs, 110 LGSCs, 207 MCs, 484 ECs and 390 CCCs. PR expression was significantly related to longer DSS in EC and HGSC and ER expression was associated with longer DSS in EC. No prognostic role was found for ER and PR in the other OC subtypes [50].

Analyses of OCs of mixed histotype have identified an association between high TRAP1 and ERα expression [51], as well as lower proteasomal subunit MB1 expression [52] and improved outcome.

Molecular signatures related to OC outcome

The heterogeneity across the different OC histotypes, as well as morphological and molecular differences within each group, has led to efforts to classify OC into groups with different clinical course based on high-throughput analyses.

Analysis of 267 OCs, predominantly HGSCs, and 18 serous borderline tumors, identified six molecular subtypes, designated C1–6. C3 and C6 tumors, which were associated with the best prognosis, included predominantly serous borderline and low-grade early-stage ECs, respectively, and had low levels of genes related to proliferation, as well as overexpression of genes related to the MAPK pathway (C3 tumors) or the β-catenin signaling pathway (C6 tumors). Tumors in the C1, C2, C4 and C5 groups consisted of high-grade and advanced-stage SCs and ECs. C5 tumors had a mesenchymal expression profile, C1 tumors had a stromal signature with greater degree of desmoplasia and C2 and C4 tumors were associated with immune response activation. Prognosis was worse for patients with C1 tumors [53]. This classification was recently validated in an independent series of 240 OCs [54].

In the Cancer Genome Atlas project (TCGA), mRNA and microRNA (miRNA, miR) expression, promoter methylation and DNA copy number were analyzed in 489 HGSCs, of which 316 were additionally studied by DNA exome sequencing. TP53 mutations were commonly found, with much lower frequency of mutations in eight other genes investigated. Patients with BRCA1/2-mutated tumors had longer survival. Recurrent gains and losses were detected in eight and 22 extended chromosome regions, respectively. Promoter methylation of 168 genes was found. mRNA and miRNA profiling identified four and three OC subtypes, respectively, the former designated ‘immunoreactive’, ‘differentiated’, ‘proliferative’ and ‘mesenchymal‘. A 193-gene transcriptional signature was associated with survival. The NOTCH and FOXM1 signaling pathways were found to be characteristic of HGSC [55]. Analysis of 511 SCs using the TCGA database identified 23 genes involved in platinum-induced DNA damage repair that were significantly associated with chemoresponse and PFS [56]. A prognostic signature of 100 genes for HGSC, termed Classification of Ovarian Cancer (CLOVAR), was recently published [57].

Four other studies focusing predominantly or uniquely on SC have identified different gene signatures related to OC prognosis [58 –61]. Comparative genomic hybridization analysis of 50 CCCs identified molecular heterogeneity between tumors and identified areas of high-level gain or amplification at chromosomes 8, 17, 19 and 20, which were associated with poor outcome independent of clinicopathologic parameters [62].

Recent analysis of 1538 OCs, including newly-studied tumors and tumors from several public databases, classified OC into five biologically distinct subgroups, termed Epi-A, Epi-B, Mes, Stem-A and Stem-B. The Mes and Stem-A groups were enriched for HGSC, whereas Stem-B tumors included many non-serous OCs. Patients with tumors classified as Mes and Stem-A had significantly worse survival than those with Epi-A, Epi-B and Stem-B tumors [63].

Meta-analyses of 10,000 OCs analyzed for the presence of gene polymorphisms found no prognostic role for this analysis in OC [64].

miRNAs in OC

miRNAs are small (20–22 nucleotides) non-coding RNAs that post-transcriptionally regulate mRNA synthesis. miRNAs may have a tumor-promoting or inhibiting role depending on their target mRNAs. Mutations in cancer-associated miRNAs are rare in OC [65,66], and single nucleotide polymorphisms in miRNA biosynthesis genes and in the putative miRNA-binding sites are not related to increased risk of ovarian cancer [67]. miRNAs have nevertheless received growing attention in recent years with respect to their diagnostic, biological, predictive and prognostic role in OC.

miRNA targets in OC include BRCA1, tumor suppressors (PTEN), receptor tyrosine kinases (MET), molecules involved in cancer stem cell biology and hypoxia (SOX4, HIF1α) and modulators of epithelial-to-mesenchymal transition (HMGA2, Zeb1, Zeb2) [68 –72]. A role for miRNAs in modifying chemotherapy response (either negatively or positively) has been documented through regulation of various molecules, including, among others, BRCA1 [73], MET [74], PTEN [75], VEGFB and VEGFR2 [76], the RNA-binding protein IMP1 [77] and the multidrug resistance protein MDR1 [77].

A role for miRNAs in disease progression in OC has been demonstrated in several studies, in which altered miRNA profiles were seen in comparative analyses of primary OC and recurrent tumors [78,79], as well as comparison between primary OC and OC effusions [80].

The levels of multiple miRNAs have been reported to be related to disease outcome in OC, among which miR-29b [81], miR-100 [82], miR-187 [83], miR-200a [84], miR-200c [85], miR-203 [86], miR-221 [87], miR-222 [87], miR-410 [88] and let-7b [89] were independent prognosticators, the latter in meta-analysis.

The OC stroma

Cancer is increasingly perceived to be a pathologic process involving both tumor cells and their microenvironment, which consists of leukocytes, endothelial cells and stromal myofibroblasts. While all classes of host cells have an important role in the biological make-up and the clinical behavior of malignant tumors, cancer-associated fibroblasts (CAFs) have a particularly important role in this context owing to their ability to produce and secrete an array of tumor-promoting factors and to dynamically modify the composition of the extracellular matrix. These in turn enable tumor cells to invade the stroma and vessels and subsequently metastasize to distant organs. In view of this, attempts have been made to develop therapeutic strategies for targeting stromal myofibroblasts in cancer [90 –93].

Studies applying mRNA in situ hybridization have shown that the OC stroma, as its counterpart in other carcinomas, has extensive synthetic capacity, as evidenced by the production of a wide array of cancer-associated molecules, including proteases of different classes, extracellular matrix components, growth factors and angiogenic molecules. The OC stroma additionally expresses transcriptional regulators, molecules that modulate the immune response, cell cycle- and apoptosis-related proteins, hormones and myriad other proteins [122].

More recent studies have applied high-throughput technology to studies of OC fibroblasts, often in conjunction with microdissection, which ensures that genomic profiles are indeed localized to this cellular compartment.

Analysis of genome-wide copy number and loss of heterozygosity in OC and breast carcinoma CAFs using single nucleotide polymorphism arrays showed only rare loss of heterozygosity and copy number alterations [94].

Kataoka et al. isolated the stroma of 74 OCs of different histotype, obtained from patients diagnosed at FIGO stages IIC–IV. Microarray analysis of 24 specimens identified 52 candidate genes that were significantly related to PFS. Of these genes, EGR1 and FOSB were validated in the remaining 50 tumors and found to be independent prognostic markers of poor PFS [95].

Exosomes are secreted 30–100 nm lipoprotein vesicles containing proteins, mRNAs and miRNAs, which are present in most circulating body fluids and mediate autocrine and paracrine effects in different cellular systems, including cancer [96]. Proteins found in exosomes are involved in multiple biological pathways, including adhesion, signal transduction, membrane transport and fusion, immune response modulation and cytoskeletal organization (reviewed in [97]). Exosomes are overexpressed in the serum of OC patients compared with controls [97], and exosomes in the serum of OC patients were reported to contain the gap junction protein claudin-4 [98], which is considered a target for therapeutic intervention in this cancer [99], as well as various glycans – molecules whose expression is deregulated in different cancers [100]. Exosomes were also detected in OC ascites and were shown to mediate immune response suppression at this anatomic site [101]. Proteomic analysis of IGROV-1 and OVCAR-3 exosomes identified 2230 proteins related to multiple cellular pathways, of which approximately 50% were common to both lines [102]. SKOV-3 and OVCAR-3 cells were recently reported to have different content of Let-7 and miR-200 [103]. Exosomes from SKOV-3 and OVCAR-3 OC cells induced adipose tissue-derived stem cells to acquire myofibroblast characteristics, with resulting activation of the TGFβ pathway [104].

Inhibition of Gli1, part of the Hedgehog pathway, in the stroma of mice bearing OC xenografts using the cyclopamine derivative IPI-926 was tested in combination with chemotherapy. The clinical role of Gli1 was demonstrated in stroma from human OC, where higher levels of this transcript were associated with worse survival [105].

Downregulation of miR-31 and miR-214 and upregulation of miR-155 was recently found in CAF compared with normal or tumor-adjacent fibroblasts, and experimental manipulation of these miRNAs converted normal fibroblasts to CAF. Reprogrammed fibroblasts and patient-derived CAF were enriched for chemokines, particularly CCL5, and the latter was identified as a target of miR-214 [106].

Metastatic OC

The above-discussed studies have provided important data regarding the molecular make-up of primary OC and the clinical relevance of cancer-associated molecules at this anatomic site. However, large series and histotype-specific analyses of metastatic disease are critically missing in this cancer. This owes in part to the fact that many patients with recurrent disease are not operated on, but additionally reflects the unbalanced allocation of research effort and resources. As the majority of OC patients die of metastatic disease rather than from their primary tumor, it is critical to expand our understanding of disease progression in OC through focusing on disease recurrence and metastasis.

Larger studies, in which a minimum of 100 SC metastases or 200 metastatic OCs of mixed histotype have been included, are to date limited to analyses of malignant effusions. The prognostic factors identified by the authors' group at this anatomic site include the transcription factors NF-κB p65 [107] and HOXB8 [108] and the microtubule-associated protein class III β-tubulin [109], and the expression of the latter was additionally associated with primary chemoresistance. Analysis of 176 serous OC effusion supernatants by another group identified significant association between higher levels of soluble L1CAM and poor PFS [110]. A separate prognostic signature for prechemotherapy and post-chemotherapy SC effusions at the protein level was recently characterized by the authors [111].

Future perspective

In view of the lack of tangible improvement in the outcome of OC patients despite optimized surgery and chemotherapy protocols, efforts are being applied in two directions – prevention and early diagnosis of OC and investigation of the clinical role of targeted therapy agents, particularly as adjuvant to standard therapy.

In light of the tubal origin theory for OC development, bilateral salpingectomy, followed by delayed bilateral oophorectomy closer to menopause, is increasingly regarded as a widely accepted modality for reducing the risk of developing OC in high-risk populations, particularly carriers of BRCA mutations [112,113], and may be applied to women in low-risk populations in the future. The issue of OC screening with the aim of detecting early-stage disease is more contentious. The US Preventive Task Force Services recently reaffirmed its recommendation that women not belonging to populations at high-risk for developing OC should not be screened for this cancer [114], a view shared by other authors [115,116] and supported by a recent meta-analysis [117]. Detection of 11 OCs by screening a cohort of 1455 women was similarly not interpreted to justify large-scale screening in the DOvE study [118]. By contrast, Lu et al. recently reported that annual serum CA 125 measurement followed by transvaginal ultrasound resulted in excellent sensitivity and specificity for detecting gynecological tumors, including OC, in the ROCA study [119]. The debate on this issue is therefore likely to continue.

Targeted therapy approaches evaluated in clinical trials include inhibition of angiogenesis using VEGF inhibitors (bevacizumab, aflibercept), tyrosine kinase inhibitors of VEGFR and other angiogenic molecules (sorafenib, sunitinib, nintedanib, pazopanib, cediranib, others) or blocking the interaction between angiopoietins and their Tie receptor on endothelial cells (trebananib); PARP inhibition (olaparib); use of EGFR family inhibitors (erlotinib, gefitinib, lapatinib, canertinib); PDGFR inhibition (imatinib mesylate); SRC inhibition (dasatinib); folate receptor-α blocking; and inhibition of the IGF and PI3K/AKT/mTOR pathways [31,120,121]. Results have by-and-large been disappointing to date, with none of the above agents accepted as standard therapy even for subgroups of patients to date. There are various factors contributing to this outcome. Recurrent OCs are biologically aggressive, as evidenced by resistance against all types of chemotherapy. Cancer cells at this stage are able to activate alternative pathways when a given pathway is blocked, hampering all therapeutic attempts. Additionally, the markedly different genomic, transcriptomic and proteomic profiles of tumors of different histology argue against uniform treatment, as is current practice. Side effects resulting from targeting of molecules that are important for normal physiology are an additional factor that may limit therapeutic options.

While some of these limitations are hard to circumvent, it is to be expected that the combination of advanced molecular analyses, particularly next generation sequencing, combined with a focus on large multi-institutional histotype-specific studies, will generate more solid data as a basis to interventional studies in the future. Applying targeted therapy at an earlier stage, as adjunct to primary treatment rather than at later stages of the disease, may prove more effective in clearing residual tumor cell populations, particularly in optimally debulked patients. A focus on understanding the biological make-up of recurrent and/or chemoresistant disease may improve our ability to prolong the life of patients with metastatic OC.

Financial & competing interests disclosure

This work was supported by the Inger and John Fredriksen Foundation for Ovarian Cancer Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Ovarian carcinoma is a heterogeneous disease

The five main ovarian carcinoma (OC) histotypes are distinct diagnostic entities with unique genotypes and phenotypes.

Changing concepts regarding the origin of OC, particularly of the serous type, may affect early detection strategies, prophylactic measures and tumor staging.

Widely-accepted prognostic markers in OC are missing

Large studies that focus on each histotype separately are becoming more common and may improve consensus regarding the clinical role of biomarkers in OC.

Malignant ovarian tumors that are not carcinomas should not be included in studies of OC.

Genome-wide approaches aimed at defining clinically relevant signatures are underway, but different inclusion criteria and methodology affect results.

miRNAs are key regulators of OC biology

The rapid increase in studies focusing on miRNAs in OC reflects growing recognition of their role in regulating the expression of cancer-associated molecules, with relevance for chemotherapy response and patient survival.

Metastasis & tumor recurrence are underrepresented in OC research

There is an obvious need to invest more efforts in understanding the biology of metastases in OC, ideally in sequential patient-matched specimens.

Targeted therapy approaches at metastatic or recurrent disease need to base treatment on analyses of the extraovarian specimens.

In optimally debulked patients receiving standard chemotherapy, targeted therapy based on the genetic make-up of the tumor may prolong life, while cure requires early detection.

The tumor microenvironment has a critical role in OC progression

Better understanding of the contribution of host cells, particularly cancer-associated fibroblasts, to OC progression may lead to new therapeutic strategies.

Footnotes

Ovarian cancer: diagnostic,biological and prognostic aspects

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Ovarian Cancer: Diagnostic,Biological and Prognostic Aspects

Abstract

Keywords

RELEASE DATE: 22 October 2014; EXPIRATION DATE: 22 October 2015

Financial & competing interests disclosure

Clinical presentation & treatment

Etiology

Classification, diagnosis & origin

Prognostic & predictive markers

The difficulty in OC research

Receptor tyrosine kinases & intracellular signaling proteins

DNA repair proteins & transcriptional regulators

Immune response parameters

Other markers

Molecular signatures related to OC outcome

miRNAs in OC

The OC stroma

Metastatic OC

Future perspective

Financial & competing interests disclosure

Footnotes

Ovarian cancer: diagnostic,biological and prognostic aspects

References