Critical Reviews in Oncology/Hematology 89 (2014) 207216

Sensitivity and resistance to treatment in the primary management of

epithelial ovarian cancer
Pierre-Emmanuel Colombo a, , Michel Fabbro b , Charles Theillet c , Frdric Bibeau d ,
Philippe Rouanet a , Isabelle Ray-Coquard e
a

Department of Surgical Oncology, Montpellier Cancer Institute (ICM), 34298 Montpellier, France
Departement of Medical Oncology, Montpellier Cancer Institute (ICM), 34298 Montpellier, France
Identity and Tumoral Plasticity, (INSERM U896), Research Cancer Institute IRCM Montpellier Cancer Institute, 34298 Montpellier, France
d Department of pathology, Montpellier Cancer Institute (ICM), 34298 Montpellier, France
e Departement of Medical Oncology, Centre Lon Brard, 69008 Lyon, France
b

Accepted 30 August 2013

Contents
1.
2.

3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Inter-tumour heterogeneity of ovarian cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
2.1. Independent histological subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
2.2. Histological and biological division of EOC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
2.3. Clinical and biological characteristics of the histological/molecular types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
2.4. Clinical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
Sensitivity and resistance of high-grade serous ovarian cancer to platinum-based drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
3.1. Clinical classification of resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
3.2. Biological mechanisms of sensitivity and resistance to platinum-based chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
3.3. Particular case of hereditary cancers from BRCA1/2 mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
Sporadic cancers and hypothesis of mechanisms of resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
4.1. A subgroup of sporadic cancers with good prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
4.2. Mechanism of resistance of the HGSOC sporadic forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
4.3. Evolution of HGSOC resistance and concepts of intra-tumour heterogeneity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

Abstract
Ovarian carcinoma is the most lethal gynaecologic malignancy. Despite wide initial sensibility to chemotherapy especially to platinum-based
regimens, the vast majority of patients with advanced stages of the disease develop recurrences and subsequent resistance to treatments.
Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; OS, overall survival; RFS, relapse-free survival; VEGF, vascular endothelial
growth factor; EGFR, epidermal growth factor receptor; CCNE1, cyclin E1; ERCC1, excision repair cross-complementation group 1; HER2, human epidermal
growth factor receptor-2; STIC, serous tubal intraepithelial carcinoma; MAPK, mitogen-activated protein kinases; K-RAS, v-Ki-ras2 Kirsten rat sarcoma viral
oncogene homolog; B-RAF, v-raf murine sarcoma viral oncogene homolog B1; PTEN, phosphatase and tensin homolog; BRCA1/2, breast cancer gene 1 or 2;
ARID1A, AT-rich interactive domain 1A gene; ASCO, American Society of Clinical Oncology; CTR1, copper transporter 1; GST, gluthatione S-transferase;
NER, nucleotide excision repair; BER, base excision repair; PARP, poly ADP ribose polymerase; HR, homologous recombination; MRP2, multidrug resistance
protein 2; GIST, gastro-intestinal stromal tumour; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3 related; FANCD2, Fanconi anaemia,
complementation group D2.
Corresponding author at: Department of Surgical Oncology, Montpellier Cancer Institute (ICM), 208 Rue des Apothicaires, Parc Euromedecine,
34298 Cedex 5, Montpellier, France. Tel.: +33 46 761 3114; fax: +33 46 761 8501.
E-mail addresses: Pierre-Emmanuel.Colombo@icm.unicancer.fr, pe.colombo@free.fr (P.-E. Colombo).
1040-8428/$ see front matter 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.critrevonc.2013.08.017

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P.-E. Colombo et al. / Critical Reviews in Oncology/Hematology 89 (2014) 207216

Ovarian cancer is actually considered as a heterogeneous disease at the clinical, histological and molecular level. In this review, the mechanisms
of intrinsic sensitivity or resistance to treatment, especially to platinum-based chemotherapy are considered with particular reference to the
significance of tumour heterogeneity. The molecular features involved in acquired resistance are reviewed and the current hypotheses are
discussed. In particular, potential disruptions of the DNA reparation pathways are highlighted.
2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ovarian cancer; Heterogeneity; Molecular subtypes; Resistance; DNA repair pathways

1. Introduction
Ovarian cancer (OC) is the main cause of gynaecological
cancer death in developed countries. An insidious progression and the inability to perform effective screening [1]
explain the late diagnosis at an advanced stage in 75%
of cases, with tumour cell spread throughout the abdominal cavity in the form of peritoneal carcinomatosis (FIGO
stages IIIIV) [2]. Management of these tumours employs
a combination of cytoreductive surgery and platinum-based
chemotherapy [3]. Despite very high initial chemosensitivity and a frequent complete clinical response, the majority
of patients with advanced OC relapse after a mean period of
18 months and progressively develop resistance to the various chemotherapeutic options [2,3]. The prognosis of these
advanced stages thus remains grim, with the 5-year overall
survival (OS) no more than 2535% [2].
The systemic treatment of OC has changed little, if at all,
since demonstration in the 1990s of the superiority of the
cisplatin (or carboplatin) and paclitaxel combination, with a
mean OS of around 38 months [4]. Studies have demonstrated
that carboplatin could replace cisplatin with comparable efficacy, better tolerance and improved quality of life [5]. The
carboplatin/paclitaxel combination has become the standard
of care for first-line chemotherapy in EOC. Most attempts at
improving this standard protocol, whether as consolidation
chemotherapy by the addition of a third drug, or as maintenance chemotherapy after the six recommended cycles,
have not demonstrated significant improvement with regard
to survival and at the cost of poorer tolerance. To date,
only the addition of bevacizumab (angiogenesis inhibitor
targeting VEGF) to carboplatin/paclitaxel following a oneyear maintenance phase was associated with improvement of
relapse-free survival (RFS) in two randomised, prospective
trials [6,7]. Nevertheless, this increase in efficacy remains
modest, between 3 and 6 months, without significant impact
on OS for all patients. It seems to mainly benefit patients with
poor prognosis and macroscopic residual disease, as shown
by an increase in OS in the ICON7 study [6]. The role of the
antiangiogenic treatments (including bevacizumab and also
other antiagiogenic treatments as nintedanib, pazopanib or
trebananib) as maintenance therapy and results of on-going
trials in EOC have recently been exhaustively reviewed in
[8].
Many unresolved questions remain at this time regarding
the management of advanced OC, and some of them are the
source of recurrent clinical problems:

- At the initial stage, patient selection for an aggressive

first surgery, or conversely, for neoadjuvant chemotherapy
followed by interval debulking surgery, remains difficult.
The only randomised clinical trial available to date found
comparable OS and RFS between both of these strategies
[9].
- Additional chemotherapeutic or targeted treatment individualised to tumours biology are not available so far to
improve the results of first-line systemic treatment.
- Finally, when relapse occurs, second- or third-line treatments are often determined empirically from the platinum
drug-free interval between the end of the initial treatment
and the recurrence [3,10].
Some of the different above-stated clinical problems could
be resolved through better prediction of treatment response
at the initial stage and at relapse. Such progress would
then enable therapeutic management to be better individualised to the intrinsic characteristics of each tumour. In
this review, we elaborate upon the main known factors
and the current hypotheses in order to explain the clinical
and biological heterogeneity of EOC and to understand the
mechanisms that lead to the development of treatment resistance.

2. Inter-tumour heterogeneity of ovarian cancers

It has now been demonstrated that OCs are not a single
clinical entity but are, from a clinical, histological and molecular standpoint, a heterogeneous group of tumours. At the
initial stage, the prognosis for ovarian cancer is described
in relation to three main related parameters [2,11]: (1) the
patient herself, with age, general health state and the BRCA
status if known playing a significant role; (2) the treatment
results, with a major prognostic impact from the postoperative
residual disease and the response to initial chemotherapy; (3)
and finally the intrinsic characteristics of the tumour, in which
many potential prognostic factors, both histological (histological subtype, FIGO stage, grade of differentiation, etc.)
[12] and biological (hormone receptors, BRCA1/2 somatic
mutations, VEGF, EGFR, CCNE1, ERCC1, HER2, molecular signatures, etc.) [13], have been described. Nevertheless,
although tumour biology seems to be of prominent importance in this disease, there are no prognostic and/or predictive
biomarkers that have been translated to date into clinical
practice.

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2.1. Independent histological subtypes

Several different histological subtypes of OC can be identified [14]. Over 90% of malignant ovarian tumours are
epithelial cancers (EOC), which are then classified into 5
broad histological subtypes [15]:
- serous tumours, which represent the majority (80%) of
the epithelial forms, are distinguished according to their
tumour differentiation grade as being high- or low-grade
- endometrioid cancers, which represent 1015% of the
epithelial tumours,
- mucinous tumours, (10%)
- ovarian clear cell carcinomas (OCCC), that are less frequent (5%)
- mixed or carcinosarcomatous mllerian tumours which
represent less than 5% of the epithelial forms
- intermediate malignant, i.e. borderline tumours that are not
detailed in this review.
These various histological subtypes, although fundamentally different, are currently grouped together as a single
clinical entity and are managed identically. Nevertheless, it
seems that these different subtypes, with their fundamentally
distinct clinical and biological characteristics, have consequently very different clinical evolution during treatment
[14,16].
2.2. Histological and biological division of EOC
Much progress has been made in recent years in understanding the origin of EOC, with the identification of
precursor lesions for each subtype and the main molecular
anomalies involved in tumour transformation and progression
[12,14,1719]. This progress has resulted in the development
of a histological/molecular classification with the definition
of two main types [14,20]:
- Low grade (type I) cancers could originate from the
ovarian surface epithelium with formation of inclusion
cysts through invagination of the epithelium in the ovarian stroma and the development of mllerian metaplasia,
resulting in fallopian tube, endometrial and endocervical
type epithelium. These three types of metaplasia will result
in serous cancer, in the case of papillary transformation;
endometrioid tumours, in the case of glandular transformation; and finally mucinous cancers following mucinous
transformation.
- Conversely, high grade (type II) EOCs might originate,
not from the ovarian surface epithelium, but from embryogenic mllerian base ducts from structures like the cervix,
fallopian tubes and uterine body. Type II tumours originate
in fact from the transformation of epithelial cells on the fimbriae of the fallopian tubes. These theories are supported
by the frequent observation of serous tubal intraepithelial
carcinoma lesions (STIC) in surgical pieces taken from
prophylactic adnexectomies in asymptomatic patients with

209

BRCA gene mutation [18,21]. Furthermore, these STIC

lesions are frequently associated with peritoneal carcinomatosis of serous histology originating in the ovaries,
peritoneum or fallopian tubes.
2.3. Clinical and biological characteristics of the
histological/molecular types
This classification of EOCs into two type is extremely
interesting, since concordance is shown both histologically
(subtypes and grade of differentation), as well as between the
different molecular characteristics and the clinical course of
the corresponding tumours [12] (Table 1).
- Low grade (type I) cancers (2030% of EOC) including low-grade serous cancers, endometrioid and mucinous
cancers are characterised by slow growth and low-grade,
unilateral lesions, which are often associated with intermediate, i.e. borderline, malignant lesions. These tumours
occur at a younger age than do high-grade tumours (mean
age 43 years) and are more likely to be less chemosensitive, but with better OS at an equivalent stage [12].
Advanced mucinous tumours, which are often refractory
to chemotherapy, have a very poor prognosis [16]. From
a molecular perspective, type I tumours are genetically
stable, with exceptional P53 mutations. They frequently
present however activation of the MAPK-kinase pathway
with activating mutations of K-RAS (found in 30% of
serous carcinomas and 50% of mucinous carcinomas at
codons 12 and 13) or B-RAF (present in 30% of serous carcinomas) [17]. These mutations are mutually exclusive and
occur early in malignant transformation. They are therefore
present in benign precursor lesions (cystadenomas) [17].
Endometrioid carcinomas present frequent gene mutations
of beta-catenin (CTNNB1) (48% of cases) and an inactivating PTEN mutation in around 20% of cases [22].
- High grade cancers (type II) are more common (7080%
of EOC) and usually present at an advanced stage, with
bilateral tumours and peritoneal carcinomatosis. Type II
includes primarily high-grade serous cancers, by far the
majority, and carcinosarcomas with a rarer incidence. The
mean age at diagnosis is 65 years, with an exceptional
association with benign or borderline tumours. From a
biological perspective, their genetic expression profile is
very close to that of primary ovarian, tubular or peritoneal
tumours, which are included in the group of high-grade
pelvic serous carcinomas. Type II tumours present
high genomic instability, with frequent p53 mutations
in over 90% or even 100% of cases. Familial types of
cancer (90% from BRCA1 and 2 mutations) are nearly
always type II, occurring in the form of high-grade serous
tumours. In sporadic forms, the BRCA1 and 2 genes are
usually defective, either through acquired mutation in the
tumour (somatic mutation) in around 69% of cases, or
are more often inactivated by loss of heterozygosity or
hypermethylation of their promoter [20].

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- Ovarian clear-cell carcinomas (OCCC) belong to type

1 low-grade cancers according to Kurmans classification [15,19]. OCCCs tumours frequently derive from
endometriosis as a precursor lesion and regularly present
genetic aberration including PTEN or ARID1A inactivation [23]. However, there is currently some controversy
about this taxonomy as their clinical profile with poor
prognosis, low chemosensitivity and some high-grade
histological features recalls type II tumours. Somatic
mutations of the ARID1A gene are present in 46% of
OCCC cases [23] and loss of this tumour suppressor
gene has been linked to a poorer prognosis and higher
resistance to platinum-based chemotherapy [24]. Owing
to low chemosensitivity, patients with OCCC are not good
candidates for neoadjuvant chemotherapy. Hence, the
importance of achieving no macroscopic residual disease
at primary (debulking) surgery is at least as paramount
as with other histological subtypes. Other chemotherapy
regimens including irinotecan plus cisplatin and molecular
targeting agents as PIK3CA inhibitors are now being
explored for this histological subtype [25].
2.4. Clinical implications
An understanding of the histological-molecular heterogeneity of epithelial EOC will probably change our approach
to the therapeutic and diagnostic clinical management of
these tumours in the near future [12]. Determination of
the histological subtype through biopsy, possibly with
laparoscopy, at diagnosis seems increasingly important in
the choice of strategy and therapeutic sequencing. The
forms known to be chemoresistant, such as mucinous cancers and OCCC, probably require extensive initial surgery
and are not good indications for neoadjuvant chemotherapy. Alternative treatments are now being explored to treat
EOCs according to their histological sub-type. For instance,
chemotherapy regimens generally used in intestinal cancers with oxaliplatin are explored in mucinous tumours.
The GOGH-0241 randomised trial is currently comparing the carboplatin/paclitaxel association (with or without
bevacizumab) with the oxaliplatin/capecitabine combination
(with or without bevacizumab) in the first-line therapy of
mucinous EOC [26]. Furthermore, recent data suggest that
early stage OCCCs (stages IC and II) could benefit from adjuvant irradiation [27]. Several trials are presently underway on
targeted treatments aimed at the main molecular anomalies
involved in tumour progression, and the signalling pathways
of each subtype. They will probably lead to better individualisation of treatment for each tumour in the medium term.

3. Sensitivity and resistance of high-grade serous

ovarian cancer to platinum-based drugs
High-grade serous ovarian cancers (HGSOC) make up
6070% of EOCs and are the main cause of mortality related

to this cancer. HGSOC are characterised by remarkable

initial chemosensitivity to platinum-based therapies, with
response rates to first-line chemotherapies greater than 80%
and with less than 1015% of the so-called refractory
forms, i.e. failure and progression during the initial treatment
(intrinsic resistance). Nevertheless, 75% of HGSOC cases
relapse after treatment ends and develop progressive resistance to chemotherapy, particularly platinum-based regimens
(acquired resistance).
3.1. Clinical classication of resistance
Despite recent progress in the histological and biological division of EOC, there are no clinical biomarkers
or molecular signatures to date that are predictive of the
chemotherapeutic response. In cases of recurrence, prediction
of the response to second-line chemotherapy is still currently
based on a previous clinical classification according to the
free interval between the end of the initial treatment and
recurrence, known as the platinum-free interval [10,28]
(Fig. 1):
- Recurrent EOC within 6 months (around 2030% of
patients) has a very low probability of response to secondline platinum-based chemotherapy (<1020%) and is
considered platinum-resistant. The prognosis in this case
is poor, and patients generally receive monotherapy without platinum-based drugs (paclitaxel weekly, topotecan,
pegylated-liposomal doxorubicin (PLD) or gemcitabine,
etc.), with particular attention to maintaining an acceptable
quality of life [29].
- Platinum-refractory tumours, (i.e. progressive disease
during the initial therapeutic sequence) with intrinsic
resistance to platinum-based chemotherapy are relatively
uncommon and constitute less than 10% of HGSOC
cases. Platinum-refractory tumours are associated with
poor short-term survival and are generally managed like
platinum-resistant tumours with monotherapy without platinum salts.
- Patients with recurrence at one year or more after the
end of treatment are considered platinum-sensitive, with
a probability of response to a second-line platinum agent
greater than 60%. These patients are best treated with a new
platinum-based drug combined with paclitaxel, PLD or
gemcitabine [29]. In case of allergy to carboplatin, desensitisation may be considered, or cisplatin can still be used
or the treatment can be replaced by a combination of PLD
and trabectedin.
- Finally, patients with recurrence between 6 months and 1
year after the end of treatment have moderate sensitivity,
with a significant probability of response, around 3040%;
they are generally treated like platinum-sensitive patients
or receive the PLD-trabectedin combination.
The results of the AURELIA and OCEANS trials, revealed
at ASCO 2012, have shown significant efficacy on SSR
and the response rates through the addition of bevacizumab

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211

Clinical predicon of response to planum salts

Inial treatment
carboplan-paclitaxel

REFRACTORY
10 - 15%
Probability of
response to
planum salts

Recommended
systemic
treatment

0%

PLATINORESISTANT (30%)

<10%

Monotherapy without planum

-Weekly paclitaxel
-Topotecan
-Gemcitabine
-PLD

INTERMEDIATE
SENSITIVITY

30%

PLATINOSENSISITIVE

>60%

Planum based chemotherapy (combinaon)

-CARBO (cis)planpaclitaxel
- CARBO-PLD
-CARBOplan-gemcitabin
Without planum:Trabectedin-PLD

Fig. 1. Prediction of the response to chemotherapy in recurrent ovarian cancer based on clinical classification according to the platinum-free interval (interval
between the end of the initial treatment and the recurrence) (PLD: pegylated liposomal doxorubicin).

to the chemotherapy regimen in the platinum-resistant and

platinum-sensitive relapse subgroups, respectively [30,31].
3.2. Biological mechanisms of sensitivity and resistance
to platinum-based chemotherapy
It is now well established that DNA of cancerous cells
is the primary target of platinum-based chemotherapy. After
penetration into the cytoplasm by the intermediary of a membrane transporter (CTR1) and activation through intracellular
metabolism (glutathion and GST), the platinum drug diffuses to the nucleus, where it binds to the DNA molecules
and induces the formation of intrastrand and interstrand
crosslinks, or adducts. These lesions then result in breaks
of the single- or double-strand DNA and consequently activate different repair pathways: (1) single-strand lesions are
mainly treated through nucleotide excision repair (NER),
with the aim of eliminating the adducts, and secondarily by
the base excision repair (BER) system; and (2) double-strand
lesions are repaired by the non-homologous end joining pathway and by the homologous recombination (HR) system. HR
is a fundamental molecular mechanism that performs exact
restoration of the double strand from the homologous helix
[32]. Activation of these repair pathways causes the cellular
cycle to stop in the S and G2 phases, and, if repair proves
impossible, cellular death and apoptosis follow.
Over 17 spontaneous or acquired mechanisms of resistance to platinum-based chemotherapy have been described
in tumour cells [33,34]. These include reports of anomalies
in the distribution of platinum in the tumour cell (reduction in the penetration or increase of its elimination by
MRP2 resistance proteins) or in its cellular metabolism, and
are potentially involved in several types of solid cancers,

including EOC [34]. The literature is quite rich in explanatory

models of resistance to platinum-based chemotherapy using
cellular lines or preclinical models. For instance, resistance
mechanisms linked to epithelial to mesenchymal transition (EMT) with up-regulation of EMT-related transcription
factors like snail, slug, twist2 or zeb2 [35] or associated
with transcription reprogramming modifications [33] have
recently been described in different types of solid cancers,
including EOC. More recently, PARP1 hyper-expression
has been observed in cisplatin-resistant cell-lines derived
from different histological origins including EOC and nonsmall-cell lung carcinomas [36]. Nevertheless, the study of
preclinical models of EOC and the distinctiveness of these
tumours occurring in cases of BRCA1 and 2 hereditary mutations suggest that the anomalies in the DNA repair pathways
of tumour cells are predominant in this disease. It is particularly relevant for understanding the mechanisms of sensitivity
and resistance to platinum-based chemotherapy.
Among these repair anomalies, hyper-expression or polymorphism of ERCC1, a gene that is particularly involved
in nucleotide excision repair (NER), have been for example
associated with EOC prognosis and prediction of the response
to platinum-based treatment [37,38]. Nevertheless the predictive role of ERCC1 in EOC remains controversial at this time
in several studies [39]. Furthermore, recent data in non-smallcell lung cancer demonstrated large inconstancies in ERCC1
expression evaluation by immunohistochemical analysis, in
particular for its functional isoform [40].
The HR pathway is a molecular mechanism that repairs
DNA double-strand lesions induced by platinum [32]. It
involves multiple gene partnerships around the classic
BRCA1 and BRCA2 genes, which are mutated in hereditary forms and are routinely inactivated in sporadic cancer.

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high-grade serous ovarian cancer

P.-E. Colombo et al. / Critical Reviews in Oncology/Hematology 89 (2014) 207216

HR procient

Amplification CCNE1= 15%

49%

MMR germline mutation = 2 %

Other aberrations

BRCA aberrations = 30% (BRCA1 = 23%)

BRCA1 (9%) / BRCA2 (8%) germline mutation = 17%
BRCA1 or BRCA2 somatic mutation = 3%

HR decient

BRCA1 epigenetic inactivation (methylation) = 11%

EMSY amplification/mutation = 8%

51%
PTEN deletion or mutation = 7%

Other HR abberations:
ATM or ATR mutation : 2%
RAD51C methylation: 3%
FA core mutation : 5%

Fig. 2. Homologous recombination pathway aberrations in high-grade serous ovarian cancer from the Cancer Genome Atlas research network. BRCA1/2:
breast cancer gene 1 or 2; PTEN: phosphatase and tensin homolog; ATM: ataxia telangiectasia mutated; ATR: ataxia telangiectasia and Rad3 related; FAN:
Fanconi anaemia; MMR: mismatch repair genes network.

The complete molecular characterisation of 489 HGSOC by

The Cancer Genome Atlas (TCGA) network thus showed
that anomalies of this homologous recombination pathway
were present in over 50% of analysed cases (Fig. 2) [41].
These results justify the study of these signalling pathways
and genes involved in DNA repair by HR in HGSOC with the
aim of better understanding these mechanisms of resistance
to platinum-based chemotherapy.
3.3. Particular case of hereditary cancers from
BRCA1/2 mutations
It is estimated that 1315% of ovarian cancer cases are secondary to germline mutations of BRCA1 or BRCA2 [41]. It
has now been demonstrated that hereditary HGSOC cases that
occur from germline mutation of BRCA2 as well as BRCA1
are associated with a better prognosis and better OS and
RFS compared to sporadic cancers. In a series of 2666 EOC
cases, the 5-year overall survival of patients with BRCA1
(44%) or BRCA2 (52%) mutation was significantly higher
than that observed in patients without the mutation (36%),
with a relative risk of death of 0.73 and 0.49, respectively
(p < 0.001) [42]. This improved prognosis contrasts with
the greater frequency of extra-peritoneal metastatic involvement in hereditary cancers compared to sporadic EOC [43].
This better prognosis is primarily explained by increased
sensitivity to platinum-based chemotherapy of tumour cells
that have lost their BRCA1/2 function through defects in
the HR pathways [44]. As evidence, tumours that developed in this context present with a particular sensitivity
to PARP inhibitors, potentiating the action of the platinum
drugs through a synergistic effect called synthetic lethality.

Inhibition of PARP, the enzyme involved in base-excision

repair of single-strand lesions, leads to an accumulation of
unrepaired single-strand and double-strand lesions in the
absence of effective HR and results in genomic instability
and cell death [45].
Despite high initial chemosensitivity, hereditary HGSOC
with BRCA mutation develops recurrence after treatment. It
was recently shown that these recurrent cases respond better after second-line treatment compared to sporadic cancers
and remain sensitive for longer periods to reintroduction of
platinum-based therapy [43]. This secondary sensitivity is
seen even in cases of early relapse before 6 months, defying
the clinical classification of platinum resistance as outlined
above [43].
Despite this chemosensitivity, a significant portion of
HGSOC that occurred in the presence of a germline BRCA
mutation develops acquired chemotherapeutic and platinum
resistance. Experimental studies have shown that when
exposed to platinum-based drugs, mammary tumours that
developed in transgenic mice, with large deletions of both
BRCA1 alleles (K14Cre Brca1ox/ox p53ox/ox mice), never
developed acquired resistance to this drug [34]. Conversely,
these tumours are capable of developing resistance to other
chemotherapies that have different mechanisms of action.
This unsettling observation reinforces the theory of molecular aberrations of repair pathways as the main mechanism
for the development of resistance. Important studies have
thus demonstrated that cell-lines derived from tumours of
patients with BRCA1/2 mutation who were exposed to
platinum-containing drugs frequently developed resistance to
this molecule through the appearance of a second BRCA1/2
mutation [46]. These secondary mutations restore BRCA

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function by re-establishing the wild-type sequence or reading frame and consequently result in a functional BRCA
protein and HR. The mutated BRCA cell lines with secondary mutation of this gene are consequently resistant
to platinum-based drugs, as well as to PARP inhibitors
[46].
These fundamental observations, which gave rise to two
publications in the journal Nature in 2008 [46,47], were also
observed clinically in patients with BRCA1/2 mutations. One
recent study published researched the presence of secondary
BRCA1/2 mutations in 110 cases of hereditary EOC, which
were analysed at diagnosis or at recurrence [48]. True secondary BRCA1/2 mutations were found and were associated
with clinical resistance to cisplatin and PARP inhibitors [48].
These mutations were more frequently observed in cases
of recurrence (28% vs. 3%) and were only detectable in
cases that had received previous chemotherapeutic treatment,
particularly with the use of several lines. At diagnosis, secondary mutations were only found in the primary cancer when
there was a history of breast cancer previously treated with
chemotherapy. This last point supports the hypothesis of the
existence of mutated cell clones (double mutation) during
development of the ovarian tumour, which are selected under
the pressure of treatment.
It is therefore extremely interesting to observe for the first
time that solid cancers, EOC in this case, develop acquired
resistance to cytotoxic chemotherapy according to molecular
mechanisms that are similar to those involved in resistance to
targeted therapies. For example, resistance to imatinib, a tyrosine kinase inhibitor used in gastrointestinal stromal tumours
usually occurs through the development of secondary CKit or PDGFR- mutations [49]. Secondary mechanisms of
resistance to erlotinib have similarly been described in EGFR
mutated lung cancers [50].

4. Sporadic cancers and hypothesis of mechanisms of

resistance
4.1. A subgroup of sporadic cancers with good prognosis
A sub-group of HGSOC that occurred without germline
BRCA mutation were found to share similar biological and
clinical profiles with hereditary cancers. These forms with
better prognosis, grouped under the phenotype BRCAness,
are probably linked to a defect in the HR pathways. The
involved mechanisms can in some cases bring into play
somatic inactivation of BRCA1 or 2 by mutation or epigenetic inactivation, or in other cases through an anomaly
of one of their partner genes (EMSY, ATM or ATR, PTEN,
RAD51, FANCD2, etc.) [41]. Somatic mutations of BRCA1
or BRCA2 are present in 3% of sporadic HGSOC and recent
data suggest that BRCA1/2 status shows a divergent outcome
for BRCA1/2 mutated cases with higher overall survival than
with BRCA1/2 wild type cases [41]. Nevertheless, BRCA1
epigenetically silenced cases harbour poorer outcomes than

213

mutated cases. However, this observation is not yet totally

understood.
Anomalies of the repair pathways are nevertheless difficult to recognise at diagnosis without clinically available
markers or laboratory tests for evaluating the efficacy of
the HR pathway. Some authors have proposed a molecular
signature for evaluating 60 genes, with expression profiles
that would be significantly correlated to those of hereditary
tumours with BRCA mutations [51]. This signature would
identify sporadic forms with good prognosis and with a high
or durable response to platinum-based chemotherapy and
PARP inhibitors [51].
PARP inhibition may be a useful therapeutic strategy for
a wider range of HGSOC which show deficiencies in the HR
pathway in more than 50% of cases [41]. In a recent phase II
randomised trial, patients with platinum-sensitive recurrent
EOC exhibited favourable responses and survival to maintenance therapy with the PARP inhibitor olaparib compared to
placebo [52]. Nevertheless, this significant therapeutic effect
was limited among this favourable subgroup bearing a high
percentage of HR deficiencies and was restricted to DFS with
no OS benefit at interim analysis [52]. Furthermore, adverse
events were more commonly reported in the olaparib group.
Also, AstraZenecaTM decided to not develop phase III trials with olaparib for the maintenance treatment of sporadic
serous EOC and limited the phase III trials to platinumsensitive relapsed HGSOC patients harbouring germ-line
BRCA1/2 mutations.
4.2. Mechanism of resistance of the HGSOC sporadic
forms
The mechanisms of resistance involved in the progression of sporadic forms of HGSOC have not been entirely
clarified at this time and are probably particular to each
tumour. The above-stated data and study of the hereditary forms nevertheless suggest that sporadic HGSOC,
though initially sensitive to platinum-based drugs through
a defect in HR frequently observed in HGSOC or in another
mechanism of repair, develop recurrence and resistance
through genetic or epigenetic restoration of an effective HR.
The genomic instability present in these tumours probably
facilitates the random occurrence of these molecular aberrations.
In addition to HR pathway anomalies, other molecular
mechanisms of resistance have been considered in HGSOC.
For example, CCNE1 gene which intervenes in cell cycle
progression and proliferation, is amplified in close to 20%
of HGSOC cases [41]. This amplification was associated
with a poor prognosis and primary (intrinsic) resistance of
HGSOC [53] and not with acquired resistance. TCGA data
suggest however that CCNE1 would be less frequently amplified in cases of BRCA mutation (8% versus 26% in cases of
wild-type BRCA), which would involve a bias and reduce
the independent prognostic impact of this amplification on
HGSOC prognosis.

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4.3. Evolution of HGSOC resistance and concepts of

intra-tumour heterogeneity
Apart from the refractory forms (intrinsic resistance),
platinum-resistant cancers are characterised by initial sensitivity to the platinum-based therapy and by the rapid
development of recurrence that is resistant to chemotherapy. Several theories have been considered to explain the
development in a few months of acquired resistance in the
progression of sporadic HGSOC. Among them, the hypothesis of intra-tumour heterogeneity from the initial stage
seems particularly interesting, with the presence at diagnosis of a majority of sensitive clones and a minority of
resistant clones. These concepts of intra-tumour heterogeneity were recently demonstrated in different types of
solid tumours by high throughput sequencing techniques,
which found different mutation profiles and oligoclonality
between the primary tumour and metastasis. This heterogeneity is even found within the primary tumour through
staged analyses of multiple samples from the same tumour
[54].
As with those observed in haematological tumours, the
mechanisms of resistance of platinum-resistant tumours
might, under the pressure of chemotherapy, stem from the
Darwinian selection of a resistant clone, which was likely
pre-existent and present at diagnosis [55]. It is in fact mathematically more probable that such mutations, which are
responsible for restoration of the effective DNA repair pathways, occurred randomly before the clinical diagnosis, during
the years necessary for carcinogenesis and the development
of genetically unstable tumours. Such hypotheses of intratumour heterogeneity would confirm the former principles
of total and early surgery in the therapeutic sequence of
HGSOC. The equivalence of initial debulking surgery and
interval surgery after neoadjuvant chemotherapy has been
observed in a recent randomised trial [9]. Nevertheless, these
results remains controversial since large retrospective studies and meta-analyses observed a survival advantage for
EOC cancer patients receiving initial and complete removal
of macroscopic tumours prior to initiation of chemotherapy [56,57]. In addition, a negative survival effect of an
increasing number of chemotherapy cycles prior to interval
surgery has been suggested in a large meta-analyse of EOC
patients treated with neoadjuvant chemotherapy [58]. Nevertheless, this study is a compilation of retrospective data
and no randomised trials has yet confirmed the interest of
an early surgical debulking in the management of advanced
EOC. One biological potential hypothesis to reinforce the
concept of complete and early resection of all macroscopic
deposits in EOC (surprising for a solid tumour considered as
really chemosensitive disease) can be extrapolated from intratumour heterogeneity: surgery performed as early as possible
would thus enable tumour bulks and resistant sub-clones to
be maximally removed through complete macroscopic excision, with the resistant populations dispersed in the initial
lesions.

5. Conclusion
Much progress has been made in the last several years in
the understanding of molecular anomalies that are responsible for carcinogenesis (drivers) and tumour progression
of EOC, resulting in the development of a histologicalmolecular classification. These data are fundamental in the
short term for the identification of potential therapeutic targets for each tumour subtype, and in the future for better
treatment individualisation.
The response (sensitivity/resistance) to cytotoxic
chemotherapy remains the essential determinant of EOC
tumour biology and will determine the prognosis of
patients at an advanced stage. Tumours occurring in case
of constitutional mutation of BRCA1/2 are genuine models
in the study of these mechanisms of resistance. Molecular
anomalies of DNA repair pathways, particularly of HR, are
probably one of the keys to the mechanisms of resistance
of sporadic cancers. The biological and clinical study
of these molecular pathways therefore seems paramount
in the development of new treatments for this disease.
In fact, the only currently available criterion that would
orient the therapeutic strategy in case of relapse is based
on the free interval between the end of treatment and the
recurrence. Our group has now planned to carefully study
the dysfunctions of the DNA damage pathways in HGSOC
with the aim of identifying molecular markers that are predictive of resistance to platinum-based chemotherapy in this
disease.

Conict of interest statement

The authors do not have any conflict of interest.

Reviewers
Frdrique Penault-Llorca, MD, PhD, Head, Dpartement
de Pathologie, Centre Jean Perrin, 58, rue Montalembert, BP
392, F-63011 Clermont-Ferrand, Cedex 1, France.
Konstantin J. Dedes, MD, Consultant, Universitiy
Hospital of Zurich, Department of Gynecology, Frauenklinikstrasse, CH-8091 Zurich, Switzerland.

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Biographies
Pierre-Emmanuel Colombo, M.D., Ph.D., is a surgical
oncologist at Montpellier Cancer Institute. He is particularly involved in ovarian cancer treatment and translational
researches in ovarian preclinical models.
Isabelle Ray-Coquard is a medical oncologist at Centre
Lon Berard (Lyon, France). She is particularly involved
in gynaecological cancers and sarcoma. She is leading the
observatory for rare malignant tumours of the ovaries.