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Advanced ovarian cancer: 20 years of ovarian cancer treatment

2016; Elsevier BV; Volume: 27; Linguagem: Inglês

10.1093/annonc/mdw081

1569-8041

Andrés Poveda, Ignacio Romero,

Cancer-related molecular mechanisms research

Treatment of epithelial ovarian cancer (EOC) has slowly changed from one that looked at EOC as if it were a single disease to one focusing at different disease entities, requiring a specialized team approach and management with morpho-molecular diagnosis, the application of improved imaging techniques and more individualized surgical and medical treatments. Despite improvement in diagnosis, surgery, and medical treatment—particularly in the last 5 years—ovarian cancer continues to be one of the leading causes of death from gynecological cancer in western countries. It is true that the 5-year overall survival improved substantially in the last 20 years (now over 50%). However, the overall survival rate is barely over 30%. The main reason for this is a late diagnosis; more than two thirds of cases are still diagnosed when they are in the advanced stage. The results of studies on the ovarian cancer genome [1.Cancer Genome Atlas Research Network Integrated genomic analyses of ovarian carcinoma.Nature. 2011; 474: 609-615Google Scholar] provided us with useful information, not only regarding diagnosis but also related to prognosis and treatment. Increased prevalence of genomic screening for deleterious mutations in BRCA1/2 and other genes will facilitate decisions regarding early interventions and prophylactic surgery. Noninvasive high-resolution functional imaging will improve detection and presurgical diagnosis of disease in not only women at high-risk, or with elevated tumor markers, but also new clinical findings leading to a better selection of patients for newer treatments. Currently, several studies are looking for the development as well as early detection of ovarian cancer. Surgery continues to be the key to cure for these patients. Survival and response to chemotherapy vary significantly, depending on whether the surgery is performed optimally or suboptimally. Furthermore, surgery must be performed by a gynecologic oncologist with a large surgical experience as this has a crucial influence on survival. This has led the 4th International Ovarian Cancer Consensus Conference to conclude that only surgeons with specialist training should perform it [2.Stuart G.C. Kitchener H. Bacon M. et al.2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference.Int J Gynecol Cancer. 2011; 21: 750-755Google Scholar]. The consensus also revisited definition of terms (such as ‘optimal surgery’) and highlighted the need of surgical specialization and expertise. Recent important issues for ovarian cancer management were also a better definition of morphology [3.Malpica A. Deavers M.T. Lu K. et al.Grading ovarian serous carcinoma using a two-tier system.Am J Surg Pathol. 2004; 28: 496-504Google Scholar] and a new understanding and respect for molecular biology and its association with morphology [4.Shih Ie M. Kurman R.J. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis.Am J Pathol. 2004; 164: 1511-1518Google Scholar]. Clinicians are becoming more and more aware of this both for diagnosis and more recently also of its implications for treatment and treatment outcomes. The 4th Ovarian Cancer Consensus Conference remarked ‘The most promising targets in clinical trials are angiogenesis (AA) and homologous recombination deficiency (HRD)’. Today, this is a reality: both strategies—AA inhibition and HRD—have been developed with successful results in the last 4 years. The publication of positive results with bevacizumab both in the front-line setting and in the platinum-sensitive and platinum-resistant recurrent disease setting was the proof of concept for AA therapy. Results from other antiangiogenic compounds published later confirmed the benefit in progression-free survival (PFS) and overall response of adding AA to standard chemotherapy. However, after more than 8000 patients included in AA trials, no integral biomarker has been identified for use with these agents. Recently, exploratory analyses of ICON-7 and GOG-218 trials identified candidate biomarkers, which however require validation. Regarding HRD, BRCA mutation is recognized today as a prognostic and predictive biomarker. Fifty percent of the ovarian high-grade serous carcinomas (HGSOC) have HRD. Germline BRCAm was reported in around 20% of patients with ovarian HGSOC, and about 50% had no reported family history of breast or ovarian cancer. Patients carrying germline mutations had improved rates of PFS and overall survival. In the recurrent setting, patients carrying mutations responded more frequently than mutation-negative patients to both platinum- and nonplatinum-based regimens, even in patients with early relapse after primary treatment [5.Alsop K. Fereday S. Meldrum C. et al.BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group.J Clin Oncol. 2012; 30: 2654-2663Google Scholar]. Ongoing studies with PARP inhibitors (PARPi) both in the front-line setting and in the recurrent disease setting hopefully will confirm the impressive results reported with maintenance therapy in recurrent disease patients BRCA mutations (PFS 11.2 versus 4.3 months, hazard ratio 0.18 [6.Ledermann J. Harter P. Gourley C. et al.Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.Lancet Oncol. 2014; 15: 852-861Google Scholar]. For the first time in ovarian cancer treatment, personalized medicine has arrived. There is a general consensus that germline testing should be offered to all women with non-mucinous EOC, irrespective of age or family history, with testing performed at diagnosis as it provides information about their likely response to therapy. Exploratory analysis of germline mutations in genes associated with homologous recombination in addition to BRCA needs further development. However, clinical factors including platinum-free interval (PFI) and measurable disease should remain as integral biomarkers in trials of recurrent disease. Future studies should investigate best practices for ‘platinum intermediate sensitive’ patients (PFI 6–12 months) as well as the importance of defining platinum sensitivity, given that activity of new agents not related to former definitions has been seen: Bevacizumab or PARPi are both active in platinum-sensitive and platinum-resistant ovarian cancer patients. Preliminary data of BRCAm as predictive biomarkers of response have been published for additional agents such as pegylated-liposomal doxorubicin [7.Kaye S.B. Lubinski J. Matulonis U. et al.Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer.J Clin Oncol. 2012; 30: 372-379Google Scholar] and trabectedin [8.Monk B.J. Ghatage P. Parekh T. et al.Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory analysis of the phase 3 OVA-301 study.Ann Oncol. 2015; 26: 914-920Google Scholar]. In the past, individually managed by different institutions or small local groups was the standard and clinical trials results took longer to be reported. This fact created a need for national groups (such as GEICO in Spain) or even beyond that a need for international collaboration (such as the Gynecologic Cancer InterGroup, which set up was formalized in 1997). The future needs teamwork. Genomic screening for prevention, identification of predictive markers of response, early functional imaging, the use of patients-reported outcome endpoints to avoid missed opportunities (e.g., what does PFS prolongation really means to patients), the application of immunotherapy as a renewed treatment option for patients with ovarian cancer, prospective collection of biological samples with clinically associated information, … this all needs teamwork. Working in cooperative groups achieves faster accrual, earlier application of results, and avoid repetition of studies. The authors have declared no conflicts of interest.