Natural History Of Patients With Brca Mutated High Grade Epithelial Ovarian Cancer Hgeoc Before The Era Of Parp Inhibitors Maintenance In 1st Line Treatment

Natural History of Patients with BRCA-mutated High Grade Epithelial Ovarian Cancer (HGEOC) Before the Era of PARP Inhibitors Maintenance in 1st Line Treatment

Background : Maintenance therapy with olaparib considerably improved progression-free survival (PFS) among women with newly-diagnosed, advanced BRCA-mutated high grade epithelial ovarian carcinoma (HGEOC)(1). Based on the large real-life ESME ovarian cancer cohort, we aimed to describe the patient's characteristics and survival outcomes of a selected cohort of BRCA-mutated patients before the era of PARP inhibitors maintenance in first line.Methods : ESME ovarian cancer is a national cohort including all patients with ovarian carcinoma managed in the 18 French Comprehensive Cancer Centres (NCT03275298). ESME Research program collected retrospective data from patient's medical records. BRCA1, BRCA2, or both mutated patients with de novo diagnosed advanced (FIGO stage III or IV) HGEOC were eligible. All data for surgical and medical management were reviewed by medical oncologist or gynecologist oncologist in each centers. PFS was defined as the time from beginning of first line until earliest documented disease progression or death.Results : Of the 4777 patients with ovarian cancer treated in 1st line by platinum-based chemotherapy between 2011 and 2016, 266 patients were included. Median age was 57.0 years (33-81). 187 patients (70.3%) harbored a BRCA1 mutation, and 75 (28.2%) a BRCA2 mutation. Majority of patients (66.9%) had FIGO stage III disease. Almost all patients (95.5%) underwent surgical resection, after neoadjuvant chemotherapy (50%), or upfront debulking surgery (50%). 147 patients (55.3%) received maintenance therapy, majority with bevacizumab alone (78.9%). Some patients, included in clinical trials, received PARP inhibitor alone or in combination with bevacizumab. After a median follow-up of 51.7 months, the median PFS was 28.6 months [95 CI: 26.2-32.4]. A better mPFS was observed for patients with FIGO stage III than stage IV (32.4 months and 25.4 months, respectively), or BRCA2 mutation than BRCA1 (33.3 months and 27.7 months, respectively). Estimated 5-year overall survival (OS) for the whole population was 69.2% [95 CI: 65.3-73.0].Conclusion : This large ESME ovarian cancer cohort described clinical features and real-life survival outcomes among patients with newly diagnosed advanced BRCA-mutated HGEOC treated in comprehensive cancer centres. Looking to the poor prognosis of these patients, before PARPi area, already 55% of patients received maintenance therapy with bevacizumab.

Sequential Therapeutic Targeting of Ovarian Cancer Harboring Dysfunctional BRCA1

"Ovarian cancer (OC) remains the leading cause of death from gynecological malignancies. This cancer is typically diagnosed in advanced stages and still represents a challenge due to poor overall survival. Among all subtypes of OC, High-Grade Serous Ovarian Cancer (HGSOC) is the most common subtype (70%) and is characterized by having genomic instability represented by 50% of defective homologous recombination DNA repair pathways (HRD) and in 23% are mutated for BRCA1 and BRCA2. Today, the majority of HGSOC show a significant, but transient response to debulking surgery followed by platinum-based chemotherapy, however most patients will relapse and eventually develop platinum-resistant disease with a poor overall survival. For HGSC, the only successful and currently approved targeted therapy is the inhibition of poly (ADP-ribose) polymerase (PARP). PARP inhibitors (PARPi) are mostly used in BRCA1-mutated and non-mutated recurrent ovarian cancer patients with a known vulnerability in the HRD pathway.Previously, our research group described a significant reduction in PARP1 protein levels in patients treated with standard carbo-platinum-paclitaxel chemotherapy that affected the efficacy of PARPi in clinical trials. Also we showed that by using PARPi as a first line of therapy followed by standard chemotherapy might improve patient response rates. To understand this finding, in the current study, we have studied PARPi as a first line of treatment followed by standard chemotherapy on different ovarian cancer cell-lines (having wild-type, mutated and methylated BRCA1). Interestingly, we observed that this treatment regimen sensitized ovarian cancer cells to lower doses of chemotherapy. Moreover we found that PARPi as a first line of treatment is more efficient in growth inhibition and induction of apoptosis in comparison with the administration of standard chemotherapy followed by PARPi. Altogether provide new evidence and the basis for future pre-clinical work involving PARPi to be used as first line of treatment in HGSOC patients carrying functional or dysfunctional BRCA1." --

Hereditary Breast and Ovarian Cancer: Current Concepts of Prevention and Treatment