Role of fertility-sparing surgery and further prognostic factors in borderline tumors of the ovary.

OBJECTIVE: Borderline tumors of the ovary are a rare group of ovarian neoplasms with distinctive histological features. Considering their favorable prognosis and occurrence at a younger age, fertility-sparing surgery may be considered. Several risk factors have been identified as contributing to a higher recurrence rate, while the impact of pathohistological features varies in the literature. This study aimed to analyze risk factors for recurrence in patients with borderline tumors of the ovary. METHODS: Analysis included patients treated with first diagnosis of a borderline tumor at our center between January 1997 and December 2022 to analyze disease-free survival and to identify the role of fertility-sparing surgery, defined as preservation of at least one ovary, pathohistological features, and other prognostic factors for relapse. All stages classified according to the International Federation of Gynecology and Obstetrics (FIGO) were included. RESULTS: Among 507 patients, 26 patients (5.2%) had a recurrence, with 21 (4.1%) showing borderline histology and 5 (1%) with invasive relapses. Recurrence rate was higher following fertility-sparing surgery (p<0.0001). Median follow-up period was 49.2 (range 42.0-57.6) months. Among 153 patients (30.2%) who had fertility-sparing surgery, 21 (13.7%) experienced a recurrence (including one invasive relapse). Fertility-sparing surgery (HR 20; 95% CI 6.9 to 60; p<0.001), FIGO stage I with bilateral presence of tumor (HR 6.4; 95% CI 1.3 to 31; p=0.020), FIGO stage II (HR 15; 95% CI 3.4 to 68; p<0.001), FIGO stages III-IV (HR 38; 95% CI 10 to 140; p<0.001) in comparison with FIGO stage I with unilateral tumor, microinvasion (HR 8.6; 95% CI 2.7 to 28; p<0.001), and micropapillary growth patterns (HR 4.4; 95% CI 1.8 to 10; p=0.001) were identified as independent risk factors for recurrence in multivariate analysis. None of these factors were associated with an increased risk of disease-related death. CONCLUSIONS: Our study showed that although a fertility-preserving approach is associated with increased recurrence rates of a borderline tumor, it does not affect overall survival and can therefore be regarded as oncologically safe for patients desiring to preserve fertility. Additionally, presence of micropapillary patterns and microinvasion were identified as prognostic risk factors.

Low anterior resection syndrome and its impact on quality of life of ovarian carcinoma patients: A prospective longitudinal study.

OBJECTIVES: Bowel dysfunction is frequently reported in patients with ovarian carcinoma (OC). Our aim was to evaluate the incidence of low anterior resection syndrome (LARS) like symptoms in patients with primary OC and its impact on quality of life (QoL). METHODS: A prospective longitudinal observational cohort study was performed, including patients with newly diagnosed OC treated by primary or interval surgery with residual tumor <1 cm, from 2018 until 2021. Patients with a stoma or recurrence of disease were excluded. Intestinal dysfunction was assessed using the validated LARS score questionnaire pre- and postoperatively. There are 3 subgroups based on the results: no, minor, or major LARS. The impact on QoL was evaluated by an additional question to demonstrate the severity of patient's life impairment. RESULTS: The questionnaire was answered by 78 patients pre- and post-operatively. LARS like symptoms were reported preoperatively in 34.6% (24.4% minor/10.2% major) and significantly increased postoperatively to 47.4% (28.2% minor/19.2% major; p = 0.011). Moderate to severe impairment of QoL correlated with LARS scores pre- (80%) and post-operatively (90%). Patients with two bowel anastomoses (mean score 18.6 pre- and 24.9 post-operatively, p = 0.041) showed a significant increase of the questionnaire score. CONCLUSIONS: Major LARS like symptoms appear in 10% of OC patients preoperatively and significantly increase to almost two-fold postoperatively. Multiple bowel anastomoses had a significant risk for higher postoperative LARS score. QoL impairment correlates linearly with LARS positive scoring, independent on the timing of the complaints.

Incidence and Prognostic Impact of Deleterious Germline Mutations in Primary Advanced Ovarian Carcinoma Patients.

Data on deleterious variants in genes other than BRCA1/2 remain limited. A retrospective cohort study was performed, including primary OC cases with TruRisk® germline gene panel testing between 2011 and 2020. Patients with testing after relapse were excluded. The cohort was divided into three groups: (A) no mutations, (B) deleterious BRCA1/2 mutations, and (C) deleterious mutations in other genes. A total of 702 patients met the inclusion criteria. Of these 17.4% (n = 122) showed BRCA1/2 mutations and a further 6.0% (n = 42) in other genes. Three-year overall survival (OS) of the entire cohort was significantly longer in patients with germline mutations (85%/82.8% for cohort B/C vs. 70.2% for cohort A, p < 0.001) and 3-year progression-free survival (PFS) only for cohort B (58.1% vs. 36.9%/41.6% in cohort A/C, p = 0.002). In multivariate analysis for the subgroup of advanced-stages of high-grade serous OC, both cohorts B/C were found to be independent factors for significantly better outcome, cohort C for OS (HR 0.46; 95% CI 0.25-0.84), and cohort B for both OS and PFS (HR 0.40; 95% CI 0.27-0.61 and HR 0.49; 95% CI 0.37-0.66, respectively). Germline mutations were detected in a quarter of OC patients, and a quarter of those in genes other than BRCA1/2. Germline mutations demonstrate in our cohort a prognostic factor and predict better prognosis for OC patients.

Implementing HRD Testing in Routine Clinical Practice on Patients with Primary High-Grade Advanced Ovarian Cancer.

The chemotherapy backbone for patients with high-grade advanced epithelial ovarian cancer (HG-AOC) is carboplatin and paclitaxel followed by a maintenance therapy either with bevacizumab, with a PARP inhibitor, or with a combination of both, which is defined by the presence of a homologous recombination deficiency (HRD) and by the BRCA1/2 status. This study included patients with a primary diagnosis of HG-AOC treated between December 2019 and December 2021. The HRD status was measured using the Myriad myChoice® test on all the patients with an indication for tumor HRD testing. Germline testing was conducted on all the patients using the TruRisk® panel as recommended by the national guidelines. HRD testing was requested for 190 patients, and, for 163 patients (85.8%), an HRD test result was available. An HRD test result could not be reported in 27 patients due to an insufficient tumor yield. The median time that it took to receive the HRD test results was 37 days (range of 8-97). In total, an HRD was present in 44.7% (73/163) of the patients based on a GIS ≥ 42 in 42.9% of the patients and based on a tumor BRCA1/2 mutation in 3 cases (all with a GIS < 42). The germline testing results were available for 148 patients, and, in 18 patients (12.2%), a deleterious germline mutation was detected. Of the 27 patients without sufficient HRD testing, BRCA1/2 germline testing results were available for 19 patients (70.4%), and a deleterious germline mutation was detected in 2 patients (7.4%). The implementation of HRD testing is feasible, and the results become available for treatment decisions in a timely manner for most patients. The prerequisite for HRD testing with the Myriad myChoice® test is a sufficient amount of tumor tissue. The cotesting of HRD and BRCA1/2 germline testing should be aimed for in order to enable optimal and timely treatment decisions on maintenance therapy as well as to test patients on whom the HRD test will not be evaluable.

Treatment strategies in patients with gynecological sarcoma: Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA-NOGGO RU1).

OBJECTIVE: Gynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study's objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease. METHODS: The German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021. RESULTS: A total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy. CONCLUSION: Our study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies.

Re-treatment with PARPi in patients with recurrent epithelial ovarian cancer: A single institutional experience.

INTRODUCTION: We aimed to evaluate real-life experiences with the re-challenge of poly(ADP-Ribose)Polymerase (PARP) inhibitors (PARPi) after a prior PARPi therapy in patients with recurrent EOC. METHODS: A retrospective descriptive study was conducted at a tertiary care center of excellence for ovarian cancer. Demographic, pathological, and therapeutic data were collected for patients with recurrent epithelial ovarian cancer who were re-treated with PARPi in their therapy course. RESULTS: Twenty-nine patients were included in the study. Twenty-six patients received the second PARPi as maintenance therapy after two different lines of therapy and three patients received the second PARPi as upfront therapy after progression. Most of the patients (57.7%) were exposed to first PARPi after a second-line therapy. The median progression-free survival under the first and second PARPi therapy was estimated at 15 and 7 months respectively. PFS under the second PARPi after platinum-based chemotherapy was better after a complete remission with a median PFS of 8.5 months, compared to patients with partial remission (5.5 months). A better PFS was noted in case of negative BRCA status under the second PARPi therapy (median PFS of 7.4 vs. 4.5 months, p = 0.11). The second PARPi therapy was mainly discontinued due to disease progression (84.6% of the cases). Discontinuation of treatment with the second PARP due to toxicity was needed in one case who developed a myelodysplastic syndrome. CONCLUSION: Real-life data support prospective evidence that patients with recurrent EOC may derive benefit of the re-treatment with PARPi in case of clear response to the last platinum-based therapy.

Self-reported physical, mental, and reproductive sequelae after treatment of abnormally invasive placenta: a single-center observational study.

OBJECTIVE: To analyze the types of treatment of abnormally invasive placenta (AIP) and to investigate the self-reported physical and mental short- and long-term sequelae. METHODS: This single-center observational study was performed between 2003 and 2017. Women with prenatal or intrapartum diagnosis of AIP were identified through the departmental database. Classification was performed according to the time of diagnosis establishment and the type of treatment. Medical complications overall and according to the type of treatment were analyzed. Data about women's perception of diagnosis, treatment, and short- and long-term sequelae were gathered by questionnaire. RESULTS: Cases were classified into four groups: prenatal diagnosis, cesarean hysterectomy (A, n = 10); prenatal diagnosis, expectant management (B, n = 19); intrapartum diagnosis, cesarean hysterectomy (C, n = 6); intrapartum diagnosis, conservative therapy (D, n = 20). Depth of invasion, total units of transfused red blood cells, and the need for reoperation differed between the treatment groups. Expectant management was successful in 94.7% of cases. Irrespective of the treatment group, 73.3% of women perceived the condition as serious or life-threatening; 30.0% utilized psychological support; and 36.7% reported persistent pain or problems. 37.5% of women after uterine preservation had another live birth, AIP recurred in 44.4% of cases. CONCLUSION: Conservative management of AIP is feasible in selected cases. The condition is perceived as life-threatening and has a lasting impact on the physical, mental, and reproductive health of those affected. This finding merits further investigation. AIP continues to be a condition with high morbidity.

Impact of hormone-associated resistance to activated protein C on the thrombotic potential of oral contraceptives: a prospective observational study.

INTRODUCTION: The increased thrombotic risk of oral contraceptives (OC) has been attributed to various alterations of the hemostatic system, including acquired resistance to activated protein C (APC). To evaluate to what extent OC-associated APC resistance induces a prothrombotic state we monitored plasma levels of thrombin and molecular markers specific for thrombin formation in women starting OC use. Elevated plasma levels of thrombin have been reported to characterize situations of high thrombotic risk such as trauma-induced hypercoagulability, but have not yet been studied during OC use. PATIENTS AND METHODS: Blood samples were collected prospectively from healthy women (n = 21) before and during three menstruation cycles after start of OC. APC resistance was evaluated using a thrombin generation-based assay. Plasma levels of thrombin and APC were directly measured using highly sensitive oligonucleotide-based enzyme capture assay (OECA) technology. Thrombin generation markers and other hemostasis parameters were measured additionally. RESULTS: All women developed APC resistance as indicated by an increased APC sensitivity ratio compared with baseline after start of OC (p = 0.0003). Simultaneously, plasma levels of thrombin, prothrombin fragment 1+2, and of thrombin-antithrombin complexes did not change, ruling out increased thrombin formation. APC plasma levels were also not influenced by OC use, giving further evidence that increased thrombin formation did not occur. CONCLUSIONS: In the majority of OC users no enhanced thrombin formation occurs despite the development of APC resistance. It cannot be ruled out, however, that thrombin formation might occur to a greater extent in the presence of additional risk factors. If this were the case, endogenous thrombin levels might be a potential biomarker candidate to identify women at high thrombotic risk during OC treatment. Large-scale studies are required to assess the value of plasma levels of thrombin as predictors of OC-associated thrombotic risk.

Tamoxifen induces resistance to activated protein C.

INTRODUCTION: The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet. MATERIALS AND METHODS: Blood samples were collected prospectively from women with breast cancer before (n=25) and monthly after start of adjuvant TAM treatment (n=75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally. RESULTS: APC sensitivity decreased by 41% (p=0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p=0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed. CONCLUSIONS: This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors.