Sensitivity and resistance to treatment in the primary management of epithelial ovarian cancer

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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. 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.

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 III–IV) [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 25–35% [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 one-year 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:

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    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].

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    Additional chemotherapeutic or targeted treatment individualised to tumour's biology are not available so far to improve the results of first-line systemic treatment.

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    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.

Section snippets

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

Sensitivity and resistance of high-grade serous ovarian cancer to platinum-based drugs

High-grade serous ovarian cancers (HGSOC) make up 60–70% 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 10–15% 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

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,

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 histological-molecular 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

Conflict of interest statement

The authors do not have any conflict of interest.

Reviewers

Frédérique Penault-Llorca, MD, PhD, Head, Département 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.

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.

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    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 Léon Berard (Lyon, France). She is particularly involved in gynaecological cancers and sarcoma. She is leading the observatory for rare malignant tumours of the ovaries.

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