Impact of BRCA Mutation Status on Tumor Dissemination Pattern, Surgical Outcome and Patient Survival in Primary and Recurrent High-Grade Serous Ovarian Cancer: A Multicenter Retrospective Study by the Ovarian Cancer Therapy-Innovative Models Prolong Survival (OCTIPS) Consortium.

BACKGROUND: This study seeks to evaluate the impact of breast cancer (BRCA) gene status on tumor dissemination pattern, surgical outcome and survival in a multicenter cohort of paired primary ovarian cancer (pOC) and recurrent ovarian cancer (rOC). PATIENTS AND METHODS: Medical records and follow-up data from 190 patients were gathered retrospectively. All patients had surgery at pOC and at least one further rOC surgery at four European high-volume centers. Patients were divided into one cohort with confirmed mutation for BRCA1 and/or BRCA2 (BRCAmut) and a second cohort with BRCA wild type or unknown (BRCAwt). Patterns of tumor presentation, surgical outcome and survival data were analyzed between the two groups. RESULTS: Patients with BRCAmut disease were on average 4 years younger and had significantly more tumor involvement upon diagnosis. Patients with BRCAmut disease showed higher debulking rates at all stages. Multivariate analysis showed that only patient age had significant predictive value for complete tumor resection in pOC. At rOC, however, only BRCAmut status significantly correlated with optimal debulking. Patients with BRCAmut disease showed significantly prolonged overall survival (OS) by 24.3 months. Progression-free survival (PFS) was prolonged in the BRCAmut group at all stages as well, reaching statistical significance during recurrence. CONCLUSIONS: Patients with BRCAmut disease showed a more aggressive course of disease with earlier onset and more extensive tumor dissemination at pOC. However, surgical outcome and OS were significantly better in patients with BRCAmut disease compared with patients with BRCAwt disease. We therefore propose to consider BRCAmut status in regard to patient selection for cytoreductive surgery, especially in rOC.

Survey on implementation of molecular testing in ovarian cancer and PARP inhibitor: a national North-Eastern German Society of Gynecologic Oncology/Young Academy of Gynecologic Oncology/Arbeitsgemeinschaft Gynäkologische Onkologie intergroup analysis.

BACKGROUND: Since the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors, BRCA testing has evolved as a standard management in epithelial ovarian cancer. OBJECTIVE: To analyze the implementation of molecular testing and PARP inhibitor therapy in Germany. METHODS: The questionnaire contained 40 questions covering real-life data on genetic testing and the use of PARP inhibitors. It was divided into three main parts: basic demographics of respondents, genetic counseling and testing, and treatment with PARP inhibitors. The questionnaire was distributed via mail between August 2020 and May 2021. RESULTS: A total of 315 physicians participated in the survey, of whom 54.9% were specialized in the field of gynecologic oncology. Two-thirds of respondents (67.4%) stated that they tested more than 80% of patients with primary epithelial ovarian cancer for BRCA mutation; however, only 42.5% of gynecologists who performed genetic counseling had an additional qualification in subject-specific genetic counseling, which is mandatory for predictive genetic testing in Germany. The main reasons for failure of BRCA testing were patient refusal (54.6%) and organizational or logistical issues (31.7%). Only 13.7% of respondents felt sufficiently equipped with supportive information material on patient counseling, whereas a high need for information material was indicated by 86.3% of the respondents. Molecular tumor profiling to infer homologous recombination (HR) deficiency status was provided by only 53.3% of institutions. PARP inhibitors were applied on a regular basis by 62.1% of respondents. The most important criteria for selection of appropriate PARP inhibitor therapy were the side effect profile (78.2%) and efficacy (71.2%). The majority of respondents (66.5%) preferred a combination of olaparib and bevacizumab over PARP inhibitors alone in the frontline setting. CONCLUSION: Adequate structure for BRCA/HR deficiency testing, and systematic education programs are needed to prevent delay in counseling and undertreatment of women with epithelial ovarian cancer. In Germany, a combination of olaparib and bevacizumab seems to be the preferred treatment in the first-line setting.

Secondary malignancies in long-term ovarian cancer survivors: results of the 'Carolin meets HANNA' study.

OBJECTIVE: To evaluate the rate of secondary malignancies in long-term survivors with ovarian cancer. METHODS: Long-term survivors with ovarian cancer (survival ≥8 years after initial diagnosis) with multiple malignancies were identified within the Tumorbank Ovarian Cancer and our study 'Carolin meets HANNA - Holistic Analyses of Long-term Survivors with Ovarian Cancer'. RESULTS: Of a total of 225 long-term survivors with ovarian cancer, 36 patients (16%) had at least one more cancer diagnosis before, concomitant with, or after, ovarian cancer. Median age was 52.5 years (range 37-79). A total of 60% were diagnosed with stage III/IV and most tumors were high-grade (88.6%), as well as of serous histology (63.9%). Median overall survival was 10 years (range 8-19). Secondary cancer after ovarian cancer was found in 17 long-term survivors (7.6%). Breast cancer was the most frequent secondary malignancy. Median duration between diagnosis of primary ovarian cancer and secondary cancer diagnosis was 78.5 months (range 12-220). BRCA was tested in 11 patients with seven patients being BRCA1 and one patient BRCA2 positive. Secondary cancers were detected by screening in 35.3% and self-detected in 29.4% of patients (breast self-examination). CONCLUSION: A secondary malignancy was diagnosed in 7.6% of long-term survivors. Routine follow-up and cancer screening should be performed in long-term ovarian cancer survivors.

Impact of clinical factors and surgical outcome on long-term survival in high-grade serous ovarian cancer: a multicenter analysis.

INTRODUCTION: Long-term survivors of ovarian cancer are a unique group of patients in whom prognostic factors for long-term survival have been poorly described. Such factors may provide information for a more personalized therapeutic approach. The objective of this study is to determine further characteristics of long-term survivors with high-grade serous ovarian cancer. METHODS: Long-term survivors were defined as patients living longer than 8 years after first diagnosis and were recruited within seven high volume centers across Europe from November 1988 to November 2008. The control group included patients with high-grade serous ovarian cancer with less than 5 years' survival identified from the systematic 'Tumorbank ovarian cancer' database. A subanalysis of Charité patients only was performed separately for in-depth analysis of tumor dissemination. Propensity score matching with nearest-neighbor caliper width was used to match long-term survivors and the control group regarding age, FIGO stage, and residual tumor. RESULTS: A total of 276 patients with high-grade serous ovarian cancer were included, divided into 131 long-term survivors and 145 control group patients. After propensity score matching and multivariable adjustment, platinum sensitivity (p=0.002) was an independent favorable prognostic factor whereas recurrence (p<0.001) and ascites (p=0.021) were independent detrimental predictors for long-term survival. Significantly more long-term survivors tested positive for mutation in the BRCA1 gene than the BRCA2 gene (p=0.016). Intraoperatively, these patients had less tumor involvement of the upper abdomen at initial surgery (p=0.024). Complexity of surgery and surgical techniques were similar in both cohorts. CONCLUSION: Platinum sensitivity constitutes a favorable factor for long-term survival whereas tumor involvement of the upper abdomen, ascites, and recurrence have a negative impact. Based on clinical estimation, long-term survival is associated with combinations of clinical, surgical, and molecular factors.

Olaparib in an ovarian cancer patient with end-stage renal disease and hemodialysis.

PURPOSE: For patients with severe renal impairment (CrCl ≤ 30 ml/min) or end-stage renal disease (ESRD), olaparib intake is not recommended as the pharmacokinetics and safety of olaparib have not been evaluated in this patient group. Therefore, this valuable patient group is generally excluded from poly(ADP-ribose) polymerase inhibitor (PARPi) therapy. Here we report the pharmacokinetics (PK), efficacy, safety and tolerability of olaparib capsules 200 mg BID in a patient with recurrent epithelial ovarian cancer (EOC) and ESRD requiring hemodialysis. METHODS: Blood and dialysate samples of the patient were collected on a dialysis and non-dialysis day. Olaparib total plasma concentrations were determined through high-performance liquid chromatography with tandem mass spectrometric detection. Actual scheduled sample times were used in the PK analysis to determine multiple dose PK parameters at steady state. RESULTS: Maximum concentration was achieved 1.5 h after drug administration on non- dialysis and after 1 h on dialysis day. The steady-state trough concentration and the maximal plasma concentration were similar on dialysis and non- dialysis day. On non-dialysis day, the AUCss was 30% higher (24.0 µg.h/mL vs. 16.9 µg.h/ml) than on dialysis day. The plasma clearance CLss/F was lower on non-dialysis day. Olaparib was not detectable in the dialysate samples. CONCLUSION: A total dose of olaparib 200 mg BID capsule formulation was well tolerated by our patient with ESRD and hemodialysis. Moreover, this maintenance therapy led to 16 months of progression free survival. Further trials on PARPi therapy in patients with hemodialysis are warranted.

Current Treatment Practices and Prognostic Factors in Early-Stage Ovarian Cancer-An Analysis of the NOGGO/JAGO.

BACKGROUND: Surgery is the backbone of early-stage ovarian cancer (OC) management. However, in practice, there is disagreement about the extent of surgical staging and whether additional adjuvant treatment should be provided. As omitting relevant diagnostic or therapeutic procedures might lead to undertreatment, we aimed to structurally investigate treatment practice in addition to prognostic factors in a multicentre series of patients (pts) diagnosed with early-stage OC. PATIENTS: Within this retrospective, multicentre study, medical records of 379 pts who had undergone surgery for suspected early-stage OC between January 2014 and March 2020 were analysed. RESULTS: Of the 379 patients, 292 had pT stage 1a-2a and had complete data on the extent of surgical staging. At least one surgical step was omitted in 100 pts (34.2%). Complete surgical staging (n = 192; (65.8%)) was more often performed in high-grade serous OC and was independent of the healthcare level of the hospital where the initial diagnosis was made. Missing to take peritoneal biopsies was associated with reduced relapse-free-survival in incompletely staged, pT1 cases (p = 0.03). About every second patient (46.7%) with a final stage lower than FIGO IIB and treated with adjuvant chemotherapy received combination chemotherapy. BRCA1 and BRCA2 testing was only performed in a subset of pts, and mutations were detected in 18% (14/79) and 9% (7/85) pts, respectively. CONCLUSIONS: This study helps to increase our understanding of early-stage OC treatment and prognosis. In addition to treating patients in compliance with current guidelines, the need for BRCA testing should also be considered for early-stage OC.

Side Effects from Cancer Therapies and Perspective of 1044 Long-Term Ovarian Cancer Survivors-Results of Expression VI-Carolin Meets HANNA-Holistic Analysis of Long-Term Survival with Ovarian Cancer: The International NOGGO, ENGOT, and GCIG Survey.

The aim of this survey was to increase the knowledge on the characteristics and health concerns of long-term survivors (LTS; survival > 5 years) after ovarian cancer in order to tailor follow-up care. This international survey was initiated by the NOGGO and was made available to members of ENGOT and GCIG. The survey is anonymous and consists of 68 questions regarding sociodemographic, medical (cancer) history, health concerns including distress, long-term side effects, and lifestyle. For this analysis, 1044 LTS from 14 countries were recruited. In total, 58% were diagnosed with FIGO stage III/IV ovarian cancer and 43.4% developed recurrent disease, while 26.0% were receiving cancer treatment at the time of filling in the survey. LTS who survived 5-10 years self-estimated their health status as being significantly worse than LTS who survived more than 10 years (p = 0.034), whereas distress also remained high 10 years after cancer diagnosis. Almost half of the cohort (46.1%) reported still having symptoms, which were mainly lymphedema (37.7%), fatigue (23.9%), pain (21.6%), polyneuropathy (16.9%), gastrointestinal problems (16.6%), and memory problems (15.5%). Almost all patients (94.2%) regularly received follow-up care. Specialized survivorship care with a focus on long-term side effects, lifestyle, and prevention should be offered beyond the typical five years of follow-up care.