Review - CME

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Ovarian cancer: diagnostic, biological and

prognostic aspects

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

Ben Davidson*,1,2
& Claes G Trop2,3
1
Department of Pathology, Oslo
University Hospital, Norwegian Radium
Hospital, N-0310 Oslo, Norway
2
University of Oslo, Faculty of Medicine,
Institute of Clinical Medicine,
N-0310 Oslo, Norway.
3
Department of Gynecologic Oncology,
Oslo University Hospital, Norwegian
Radium Hospital, N-0310 Oslo, Norway.
*Author for correspondence:
Tel.: +47 2293 4871
Fax: +47 2250 8554
bend@ medisin.uio.no

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LEARNING OBJECTIVES
Upon completion of this activity, participants will be able to:
Evaluate the causes and classifications of ovarian cancer
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10.2217/WHE.14.37 2014 Future Medicine Ltd

Womens Health (2014) 10(5), 519533

part of

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Review Davidson & Trop

CME

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 Trop, 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 Trop, 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] stageIIIIV) due to late symptoms and the
lack of effective screening for early disease, as well as
increasing chemoresistance along with tumor progression. stageIII 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 stageIV 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 stageIV
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 411%

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Womens Health (2014) 10(5)

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

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Review Davidson & Trop

CME

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 Trop, 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 Trop, 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] stageIIIIV) due to late symptoms and the
lack of effective screening for early disease, as well as
increasing chemoresistance along with tumor progression. stageIII 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 stageIV 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 stageIV
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 411%

520

Womens Health (2014) 10(5)

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

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CME
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 [1012] .
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), HNF1, 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 HNF1 [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 Mllerian 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

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Ovarian cancer: diagnostic, biological & prognostic aspects

Review

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 2to 1 cm to the current goal of no macroscopic

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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-B 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] .

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CME
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 invitro
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 invitro [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

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CME
(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
etal. 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 invitro was
associated with resistance to cisplatin [44] .
Analysis of protein expression of AEG-1 by IHC in
131 stage IIIIV 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 factor2
mRNA-binding protein 3 (IGF2BP3; IMP3) and the
autophagy marker microtubule associated protein1 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] .

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Ovarian cancer: diagnostic, biological & prognostic aspects

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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 ER 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 C16. C3 and C6 tumors,
which were associated with the best prognosis,
included predominantly serous borderline and lowgrade 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 -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

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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 [5861] . 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 newlystudied 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 (2022 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, HIF1) and modulators of epithelial-to-mesenchymal transition (HMGA2, Zeb1,
Zeb2) [6872] . 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] .

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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 makeup 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 [9093] .
Studies applying mRNA insitu 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 cancerassociated 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 IICIV. Microarray analysis of 24
specimens identified 52 candidate genes that were

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CME
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 30100 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 glycansmolecules 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 TGF
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

future science group

Ovarian cancer: diagnostic, biological & prognostic aspects

Review

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-B p65 [107] and
HOXB8 [108] and the microtubule-associated protein class III -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

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525

Review Davidson & Trop

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- 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

CME
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.

526

Womens Health (2014) 10(5)

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Ovarian cancer: diagnostic, biological & prognostic aspects

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Rice GE. Ovarian cancer cell invasiveness is associated with

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Ovarian cancer: diagnostic, biological and prognostic aspects

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1. Which of the following statements regarding the cause and classification of ovarian cancer is most
accurate?
A Epithelial tumors account for 90% of ovarian cancers

B Early menopause is associated with a higher risk for ovarian cancer

C Most cases of ovarian cancer are hereditary
D The lifetime risk for ovarian cancer associated with the BRCA1 mutation is approximately 10%

2. Which of the following variables is considered the strongest prognostic marker in cases of ovarian
cancer?
A Volume of residual disease after surgery

B Fibroblast growth factor receptor 4 expression

C Poly(adenosine-diphosphate ribose) polymerase-1 expression
D Astrocyte elevated gene-1 expression
3. Which of the following statements regarding different biomarkers in ovarian cases is most accurate?

532

A HER-2 expression is negatively associated with survival time

B Mutations in the TP53 gene are particularly useful in evaluating prognosis
C Biomarkers have failed to predict resistance to chemotherapy
D The presence of CD3-positive lymphocytes in the tumor is associated with improved survival time

Womens Health (2014) 10(5)

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Ovarian cancer: diagnostic, biological & prognostic aspects

Review

4. Which of the following statements regarding microRNAs (miRNAs) in ovarian cancer is most accurate?

A Nearly all ovarian cancers contain cancer-associated miRNAs

B Single nucleotide polymorphisms in miRNA biosynthesis have been established to promote ovarian cancer
C miRNAs appear to modify the response to chemotherapy
D miRNAs play no role in disease progression in ovarian cancer

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