Sensitivity and resistance to treatment in the primary management of epithelial ovarian cancer
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:
- -
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 tumour's 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.
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.
References (58)
- et al.
Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2010) - et al.
Antiangiogenic agents as a maintenance strategy for advanced epithelial ovarian cancer
Crit Rev Oncol Hematol
(2013) - et al.
Mucinous advanced epithelial ovarian carcinoma: clinical presentation and sensitivity to platinum-paclitaxel-based chemotherapy, the GINECO experience
Ann Oncol
(2010) - et al.
Diverse tumorigenic pathways in ovarian serous carcinoma
Am J Pathol
(2002) Intercepting pelvic cancer in the distal fallopian tube: theories and realities
Mol Oncol
(2009)- et al.
Treatment of recurrent ovarian cancer relapsing 6–12 months post platinum-based chemotherapy
Crit Rev Oncol Hematol
(2007) - et al.
Optimal treatment for relapsing ovarian cancer
Ann Oncol
(2010) - et al.
Pre-treatment tumor expression of ERCC1 in women with advanced stage epithelial ovarian cancer is not predictive of clinical outcomes: a Gynecologic Oncology Group study
Gynecol Oncol
(2012) - et al.
Evolution of platinum resistance in high-grade serous ovarian cancer
Lancet Oncol
(2011) - et al.
Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study
Gynecol Oncol
(1998)
Aggressive surgical strategies in advanced ovarian cancer: a monocentric study of 203 stage IIIC and IV patients
Eur J Surg Oncol
Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis
Gynecol Oncol
Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial
JAMA
Cancer of the ovary
N Engl J Med
Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer
N Engl J Med
A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer
J Natl Cancer Inst
A phase 3 trial of bevacizumab in ovarian cancer
N Engl J Med
Incorporation of bevacizumab in the primary treatment of ovarian cancer
N Engl J Med
Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer
N Engl J Med
Clinical trials in recurrent ovarian cancer
Int J Gynecol Cancer
Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study
J Clin Oncol
New insights into the pathogenesis of serous ovarian cancer and its clinical impact
J Clin Oncol
Optimizing molecular-targeted therapies in ovarian cancer: the renewed surge of interest in ovarian cancer biomarkers and cell signaling pathways
J Oncol
Ovarian cancer
Annu Rev Pathol
Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features
Virchows Arch
The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory
Am J Surg Pathol
Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications
Int J Gynecol Pathol
Ovarian epithelial dysplasia and prophylactic oophorectomy for genetic risk
Int J Gynecol Cancer
Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary
Cancer Res
Cited by (0)
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.