Fibroblast Growth Factor Receptors and Ligands in Context of Bevacizumab Response in Ovarian Carcinoma: An Exploratory Analysis of AGO-OVAR11/ICON-7.

With more novel drugs being approved for the treatment of ovarian carcinoma, the question remains to what extent patients benefit from antiangiogenic treatment with bevacizumab, either in combination with poly-(ADP-ribose) polymerase inhibitors or as single-agent maintenance. As fibroblast growth factor receptors and their ligands (FGFRs/FGFs) are key players in angiogenic signaling and have been linked to resistance to several drugs, we investigated the prognostic or predictive potential of FGFs/FGFRs signaling in the context of bevacizumab treatment within the prospective phase III AGO-OVAR11/ICON-7 study. FGFR1, FGFR2, FGFR3, FGFR4, FGF1, and FGF19 gene expressions were determined in 380 ovarian carcinoma tumor samples collected from German centers in the multicenter phase III AGO-OVAR11 trial/ICON-7 trial. All patients received carboplatin and paclitaxel, administered every 3 weeks for 6 cycles, and were randomized to bevacizumab. Expressions of FGFR1, FGFR2, FGF1, and FGF19 were associated with progression-free survival in both uni- and multivariate (FGFR1: HR, 1.6, P < .001; FGFR2: HR, 1.6, P = .002; FGF1: HR, 2.3, P < .001; and FGF19: HR, 0.7; P = .007) analysis. A signature built by FGFR1, FGFR4, and FGF19 defined a subgroup (n = 62) of patients that derived the greatest bevacizumab-associated improvement of progression-free survival (HR, 0.3; P = .004). In this exploratory analysis of a prospective randomized phase III trial, we provide evidence that the expression of FGFRs/FGFs might have independent prognostic values. An FGFR/FGF-based gene signature identified in our study appears to predict long-term benefit from bevacizumab. This observation is hypothesis-generating and requires validation on independent cohorts.

Genetics and beyond: Precision Medicine Real-World Data for Patients with Cervical, Vaginal or Vulvar Cancer in a Tertiary Cancer Center.

Advances in molecular tumor diagnostics have transformed cancer care. However, it remains unclear whether precision oncology has the same impact and transformative nature across all malignancies. We conducted a retrospective analysis of patients with human papillomavirus (HPV)-related gynecologic malignancies who underwent comprehensive molecular profiling and subsequent discussion at the interdisciplinary Molecular Tumor Board (MTB) of the University Hospital, LMU Munich, between 11/2017 and 06/2022. We identified a total cohort of 31 patients diagnosed with cervical (CC), vaginal or vulvar cancer. Twenty-two patients (fraction: 0.71) harbored at least one mutation. Fifteen patients (0.48) had an actionable mutation and fourteen (0.45) received a recommendation for a targeted treatment within the MTB. One CC patient received a biomarker-guided treatment recommended by the MTB and achieved stable disease on the mTOR inhibitor temsirolimus for eight months. Factors leading to non-adherence to MTB recommendations in other patient cases included informed patient refusal, rapid deterioration, stable disease, or use of alternative targeted but biomarker-agnostic treatments such as antibody-drug conjugates or checkpoint inhibitors. Despite a remarkable rate of actionable mutations in HPV-related gynecologic malignancies at our institution, immediate implementation of biomarker-guided targeted treatment recommendations remained low, and access to targeted treatment options after MTB discussion remained a major challenge.

Galectin-10 Expression in Placentas of Women with Gestational Diabetes.

Galectins are known to play an important role in immunoregulatory processes and autoimmune diseases. Galectin-10 is a cytoplasmic protein of human eosinophils and is involved in various eosinophilic diseases. Since increased galectin expression is already detected in the placentas of mothers with gestational diabetes mellitus (GDM), this study focuses on the specific role of galectin-10 and hints at consequences for the diagnosis and therapeutic options of GDM. It is hypothesized that the difference in galectin-10 expression will raise the pathophysiological understanding of gestational diabetes. The study population consists of 80 women: 40 healthy mothers and 40 women suffering from gestational diabetes mellitus. The expression of galectin-10 was analyzed in the syncytiotrophoblast (SCT) and the decidua of the placenta via immunohistochemistry and immunofluorescence double staining. The immunoreactivity score (IRS) was used for evaluation. The results in this study were significant for an overexpression of galectin-10 in GDM placentas compared with the control group. The syncytiotrophoblast showed overexpression in the nucleus and the cytoplasm, whereas expression of galectin-10 in the decidua was significant in the cytoplasm only. This study identified the expression changes in galectin-10 in placental tissue between healthy and GDM mothers and intensified the understanding of gestational diabetes. Assuming that gestational diabetes mellitus is involved in inflammatory processes, galectin-10 might play a role in the development and maintenance of GDM. Further investigation is required to strengthen these findings.

Treatment and survival of patients with malignant ovarian sex cord-stromal cell tumours: An analysis of the Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) study group CORSETT database.

BACKGROUND: Malignant sex cord-stromal cell tumours (SCST) account for only 7% of ovarian malignancies. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) study group has established a clinicopathological database to provide an overview of the current treatment strategies and survival of SCST patients and to identify research needs. METHODS: Twenty centres provided mixed retro- and prospective data of patients with tumour specimens and second-opinion pathology review treated between 2000 and 2014. Descriptive analyses of treatment strategies, Kaplan-Meier curves and cox regression analyses were conducted. RESULTS: Two hundred and sixty-two SCST patients were included. One hundred and ninety-one Granulosa-cell tumour (GCT) and 17 Sertoli-Leydig cell tumour (SLCT) patients were stage I disease (>80%). Forty four GCT (18.7%) and two (8.3%) SLCT patients received adjuvant systemic treatment. After a median observation time of 78.2 months, 46% of all SCST patients experienced disease recurrence, treated predominantly with secondary debulking surgery (> 90%). Advanced FIGO stage, lymph node involvement and intra-operative capsule rupture were associated with disease recurrence on univariate analysis (all p < 0.05). Median OS time was not reached. DISCUSSION: In this analysis of SCST patients, adjuvant chemotherapy was unable to prevent disease recurrence. Despite high recurrence rates, overall survival rates were excellent.

PARP inhibitors: risk factors for toxicity and matching patients to the proper poly (ADP-ribose) polymerase inhibitor (PARPi) therapy.

The past 5 years have seen several fundamental advances in ovarian cancer, with important new insights towards novel therapeutic opportunities within the DNA repair pathway. With the incorporation of poly (ADP-ribose) polymerase inhibitors (PARPi) into maintenance treatment regimens, the management of short- and long-term adverse events are key clinical priorities. Currently, three different PARPi are clinically beneficial and have been approved for primary and recurrent ovarian cancer: olaparib, niraparib, and rucaparib. The duration of treatment with PARPi in patients with ovarian cancer varies; patients can receive treatment for up to 2 or 3 years in first-line setting, or continue treatment until unacceptable toxicity or progression occurs in recurrent disease. Despite their similar mechanisms of action, these three inhibitors have specific toxicity profiles, which may lead to dose interruptions or discontinuation of treatment. This review summarizes the current indications for PARPi, including their role in recurrent and first-line maintenance treatment for advanced ovarian cancer. We also outline dose modifications leading to treatment disruption and potential changes in quality of life after prolonged treatment. Finally, we highlight the patient groups most likely to benefit from each of the three different PARPi.

Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in BRCA1/2: results of the observational AGO-TR1 study (NCT02222883).

Variant-specific loss of heterozygosity (LOH) analyses may be useful to classify BRCA1/2 germline variants of unknown significance (VUS). The sensitivity and specificity of this approach, however, remains unknown. We performed comparative next-generation sequencing analyses of the BRCA1/2 genes using blood-derived and tumour-derived DNA of 488 patients with ovarian cancer enrolled in the observational AGO-TR1 trial (NCT02222883). Overall, 94 pathogenic, 90 benign and 24 VUS were identified in the germline. A significantly increased variant fraction (VF) of a germline variant in the tumour indicates loss of the wild-type allele; a decreased VF indicates loss of the variant allele. We demonstrate that significantly increased VFs predict pathogenicity with high sensitivity (0.84, 95% CI 0.77 to 0.91), poor specificity (0.63, 95% CI 0.53 to 0.73) and poor positive predictive value (PPV; 0.71, 95% CI 0.62 to 0.79). Significantly decreased VFs predict benignity with low sensitivity (0.26, 95% CI 0.17 to 0.35), high specificity (1.0, 95% CI 0.96 to 1.00) and PPV (1.0, 95% CI 0.85 to 1.00). Variant classification based on significantly increased VFs results in an unacceptable proportion of false-positive results. A significantly decreased VF in the tumour may be exploited as a reliable predictor for benignity, with no false-negative result observed. When applying the latter approach, VUS identified in four patients can now be considered benign. Trial registration number NCT02222883.

Risk of postpartum depressive symptoms is influenced by psychological burden related to the COVID-19 pandemic and dependent of individual stress coping.

PURPOSE: There are different studies worldwide, which have shown a higher risk of mental disorders due to the COVID-19 pandemic. One aim of this study was to identify influencing factors of the psychological burden related to the COVID-19 pandemic and the impact on the development of postpartum depression. Further, the role of individual stress and coping strategies was analyzed in this context. MATERIALS AND METHODS: Between March and October 2020, 131 women in obstetric care at the LMU Clinic Munich completed a questionnaire at consecutive stages during their perinatal period. The times set for the questionnaire were before birth, 1 month, 2 months, and 6 months after birth. The questionnaire was designed to evaluate the psychological burden related to the COVID-19 pandemic. For this a modified version of the Stress and coping inventory (SCI) and the Edinburgh Postnatal Depression Scale (EPDS) was used. RESULTS: We could show that the psychological burden related to the COVID-19 pandemic influenced the EPDS score 1, 2 and 6 months after birth. In addition, the prenatal stress and individual coping strategies affected the EPDS and the burden related to the COVID-19 pandemic before and after birth significantly. CONCLUSION: An association of the psychological burden related to the COVID-19 pandemic with the risk of developing postpartum depressive symptoms could be shown in this study. In this context, the separation of the partner and the family was recognized as an important factor. Furthermore, the SCI was identified as an effective screening instrument for identifying mothers with an increased risk of postpartum depression. Hereby allowing primary prevention by early intervention or secondary prevention by early diagnosis.

Trends among patients with endometriosis over a 7-year period and the impact of the COVID-19 pandemic: experience from an academic high-level endometriosis centre in Germany.

PURPOSE: Endometriosis is known to be an underestimated disease. Lately the awareness of the disease seems to have improved. Aim of this analysis is to provide an overview of the development of treatment of patients diagnosed with endometriosis. This includes a special scope on implications of the COVID-19 pandemic since in multiple settings postponed treatments resulting in negative impact on prognosis were reported. MATERIALS AND METHODS: We analysed the development of numbers of patients treated for endometriosis in an academic centre within a 7-year period, 01/2015-12/2021, performing a systematic analysis of ICD-10-Codes from our computer system used in clinical routine. RESULTS: Treatment numbers increased over the past 7 years, i.e., 239 treated cases in 2015 vs. 679 in 2021. Following restrictions for outpatient evaluation and surgical capacity at our centre, during COVID-19 pandemic the numbers of treated patients were reduced, especially in the first lockdown period (03/22/2020-05/05/2020 vs. same period in 2019: outpatient clinic (9 vs. 36; p < 0.001), patients surgically treated (27 vs. 52; p < 0,001)). The comparison of 2020 to 2019 showed a reduction in April 2020 of - 37% in outpatient department and up to - 90% for surgically treated patients. Comparing to 2019, we found a reduction of surgical interventions in 2020 by - 9% and an increase by 83% in 2021. CONCLUSIONS: Raising numbers of patients treated for endometriosis point to a new awareness for the disease. After the decline during the lockdown period numbers raised again, leading to a delay, but not an omission of treatment. A certified endometriosis centre with established and well-organized structures is required to improve not only treatment results but also quality of life of those affected.

PLA2G7/PAF-AH as Potential Negative Regulator of the Wnt Signaling Pathway Mediates Protective Effects in BRCA1 Mutant Breast Cancer.

Past studies have confirmed that aberrant activation of the Wnt/ß-catenin signaling is associated with tumorigenesis and metastasis in breast cancer, while the role of platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in this signaling pathway remains unclear. In this study, we analyze the functional impact of PAF-AH on BRCA1 mutant breast cancer and explore its relationship to the Wnt signaling pathway. By performing immunohistochemistry, PAF-AH expression and ß-catenin expression were examined in both BRCA1 WT and BRCA1 mutant breast cancer specimens. The BRCA1 mutant breast cancer cell line HCC1937 was used for in vitro experiments to assess the impact of PAF-AH on cellular functions. The intracellular distribution of ß-catenin depending on PLA2G7/PAF-AH expression was investigated by immunocytochemistry. Significantly higher nuclear expression levels of PAF-AH were found in BRCA1 mutant tissue specimens than in BRCA1 WT samples. Cell viability, proliferation, and the motility rate of HCC1937 were significantly enhanced after PLA2G7 silencing, which indicated a protective role of PAF-AH in breast cancer. Nuclear PAF-AH expressed correlatedly with membranous ß-catenin. PLA2G7 silencing provoked the ß-catenin translocation from the membrane to the nucleus and activated Wnt signaling downstream genes. Our data showed a protective effect of high PAF-AH expression in BRCA1 mutant breast cancer. PAF-AH may achieve its protective effect by negatively regulating the Wnt pathway. In conclusion, our research sheds new light on the regulatory pathways in BRCA1 mutant breast cancer.

Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer.

BACKGROUND: Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown. METHODS: We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or BRCA mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death. RESULTS: Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. CONCLUSIONS: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).

A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms.

BACKGROUND: Systematic pelvic and paraaortic lymphadenectomy has been widely used in the surgical treatment of patients with advanced ovarian cancer, although supporting evidence from randomized clinical trials has been limited. METHODS: We intraoperatively randomly assigned patients with newly diagnosed advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIB through IV) who had undergone macroscopically complete resection and had normal lymph nodes both before and during surgery to either undergo or not undergo lymphadenectomy. All centers had to qualify with regard to surgical skills before participation in the trial. The primary end point was overall survival. RESULTS: A total of 647 patients underwent randomization from December 2008 through January 2012, were assigned to undergo lymphadenectomy (323 patients) or not undergo lymphadenectomy (324), and were included in the analysis. Among patients who underwent lymphadenectomy, the median number of removed nodes was 57 (35 pelvic and 22 paraaortic nodes). The median overall survival was 69.2 months in the no-lymphadenectomy group and 65.5 months in the lymphadenectomy group (hazard ratio for death in the lymphadenectomy group, 1.06; 95% confidence interval [CI], 0.83 to 1.34; P = 0.65), and median progression-free survival was 25.5 months in both groups (hazard ratio for progression or death in the lymphadenectomy group, 1.11; 95% CI, 0.92 to 1.34; P = 0.29). Serious postoperative complications occurred more frequently in the lymphadenectomy group (e.g., incidence of repeat laparotomy, 12.4% vs. 6.5% [P = 0.01]; mortality within 60 days after surgery, 3.1% vs. 0.9% [P = 0.049]). CONCLUSIONS: Systematic pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer who had undergone intraabdominal macroscopically complete resection and had normal lymph nodes both before and during surgery was not associated with longer overall or progression-free survival than no lymphadenectomy and was associated with a higher incidence of postoperative complications. (Funded by Deutsche Forschungsgemeinschaft and the Austrian Science Fund; LION ClinicalTrials.gov number, NCT00712218.).

Clinical outcome of combined intracavitary / interstitial brachytherapy using a hybrid applicator in locally advanced cervical cancer.

OBJECTIVE: The aim of this study was to evaluate the clinical outcome in locally advanced cervical cancer (LACC) after image-guided adaptive brachytherapy (IGABT) with combined intracavitary and interstitial (IC/IS) techniques using the hybrid Venezia applicator (Elekta AB, Sweden). METHODS: LACC patients (UICC Stage IIB - IVB) treated with radiochemotherapy followed by IGABT with the hybrid IC/IS Venezia applicator at a single institution were retrospectively analyzed. Treatment comprised EBRT of the pelvis with 45 Gy and concomitant weekly cisplatin chemotherapy (40 mg/m2) followed by MRI-based IGABT. Dosimetry, oncological outcome and toxicity were investigated. RESULTS: Forty-six patients underwent a total of 184 fractions of IGABT between 2017 and 2020. Median follow-up was 24 months. Combined IC/IS techniques were used in 40 patients (87%). The median HRCTV volume was 31.2 cm3 and the median HRCTV D90% was 92.3 Gy (EQD210). The median D2cm3 was 74.8 Gy for bladder, 57.9 Gy for rectum, 60.0 Gy for sigmoid and 52.2 Gy for bowel (EQD23). The 3-yr actuarial rates were 97.6% for local control, 97.6% for pelvic control, 59.9% for distant metastasis-free survival and 81.6% for overall survival. The crude rate for G2 and G3 late toxicity was 21.7% and 4.3%. CONCLUSIONS: IGABT with the hybrid Venezia applicator and a pronounced use of a combined IC/IS technique achieved high target doses, while maintaining low doses to organs at risk, leading to excellent local control and overall survival rates with acceptable toxicity.

Changes in gynecologic and breast cancer diagnoses during the first wave of the COVID-19 pandemic: analysis from a tertiary academic gyneco-oncological center in Germany.

PURPOSE: With the beginning of 2021, the world has been suffering from the COVID-19 pandemic for more than 1 year. More and more, we are able to evaluate side effects of the pandemic in the healthcare sector. A negative impact on cancer diagnoses is one of them. Careful observation of trends in an academic gyneco-oncological context appears important to identify potential negative developments. METHODS: We analyzed the case number of gynecologic and breast cancer diagnoses in the period from January to June 2020 compared to 2019 and during the period of the first general German lockdown (March 22nd until May 5th 2020). Patients were characterized by age, tumor type, FIGO or TNM stage and presence of symptoms at initial hospital presentation. RESULTS: The frequency of newly diagnosed gynecologic and breast cancer cases from beginning of January until end of June changed by - 10% and by - 12% during the lockdown in 2020 compared to 2019. In both periods, reduction of breast cancer cases was relatively larger than decrease of gynecologic cancers. Moreover, median patient age decreased. For the first half of 2020, we found a shift towards higher tumor stages (N+/M1 or FIGO III-IV). During the lockdown period, the appearance of tumor-associated symptoms at diagnosis increased by about 12%. CONCLUSION: This analysis illustrates the anticipated general decrease in diagnoses of primary cancers during the lockdown periods in 2020 due to COVID-19 pandemic for gynecologic and breast cancer cases.

Galectin-8 and -9 as prognostic factors for cervical cancer.

PURPOSE: Galectins are carbohydrate-binding proteins with multiple effects on cell biology. Research shows that they play an important role in tumor development and progression. Therefore, in this study, the presence of Galectin-8 and -9 (Gal), both already known as prognostic factors in other tumor entities, were investigated in cervical cancer. Our aim was to examine the association of Gal-8 and -9 expression with histopathological markers and survival of the patients. METHODS: Gal-8 and -9 expression was investigated in 250 cervical cancer samples by immunohistochemistry. The staining was evaluated using the immunoreactive score (IRS). The results were correlated to clinical and pathological data. The correlation of Gal-8 and -9 expression with overall and relapse-free survival was analyzed. RESULTS: Expression of Gal-8 was associated with negative N-status and lower FIGO status. Detection of Gal-9 was connected to negative N-status and lower grading regarding all specimens. A correlation of Gal-9 with lower FIGO status was detected for squamous cell carcinoma (SCC) only. Expression of Gal-8 was associated with relapse-free survival of SCC patients in a positive manner. Gal-9 expression was associated with better overall survival. CONCLUSION: Our results suggest that expression of both galectins is inversely associated with tumor stage and progression. Gal-8 expression is associated with relapse-free survival of patients with SCC, while presence of Gal-9 in cervical cancer is associated with a better prognosis in regard of overall survival.

The role of resveratrol, Sirtuin1 and RXRα as prognostic markers in ovarian cancer.

OBJECTIVE: Ovarian cancer is the most lethal gynecologic cancer. Resveratrol (RSV) is known to alter metabolism in cancer. It affects the nuclear retinoid-X-receptor (RXR), which implies a modulating effect of RXR to gynaecologic cancers. Furthermore, RSV targets Sirtuin1 (Sirt1), a histone deacetylase. STUDY DESIGN: 123 tissue samples of patients with serous or mucinous ovarian cancer were examined for expression of Sirt1 and RXR. Ovarian cell lines were treated with RSV and consequences on viability and apoptosis were evaluated. The influence of RSV to Sirt1 and RXR expression was analyzed by western blotting RESULTS: A correlation of nuclear Sirt1 and RXRα expression could be detected (p = 0.006). Co-expression of nuclear RXRα and cytoplasmic (p = 0.026) or nuclear (p = 0.041) Sirt1 was associated with significantly increased overall survival in advanced tumour stages. Viability was decreased in all cell lines after stimulation with resveratrol, while cell apoptosis was increased. RSV treatment led to significant lower Sirt1 expression in A2780 cells (p = 0.025) and significant increased RXR expression in cisA2780 cells (p = 0.012) CONCLUSION: In order to use RSV as medical target, studies could be developed to improve the understanding of drug resistance mechanisms and consequently improve treatment outcome.

NGS-guided precision oncology in metastatic breast and gynecological cancer: first experiences at the CCC Munich LMU.

PURPOSE: Comprehensive genomic profiling identifying actionable molecular alterations aims to enable personalized treatment for cancer patients. The purpose of this analysis was to retrospectively assess the impact of personalized recommendations made by a multidisciplinary tumor board (MTB) on the outcome of patients with breast or gynecological cancers, who had progressed under standard treatment. Here, first experiences of our Comprehensive Cancer Center Molecular Tumor Board are reported. METHODS: All patients were part of a prospective local registry. 95 patients diagnosed with metastatic breast cancer or gynecological malignancies underwent extended molecular profiling. From May 2017 through March 2019, the MTB reviewed all clinical cases considering tumor profile and evaluated molecular alterations regarding further diagnostic and therapeutic recommendations. RESULTS: 95 patients with metastatic breast or gynecological cancers were discussed in the MTB (68% breast cancer, 20% ovarian cancer, 5% cervical cancer, 3% endometrial cancer and 4% others). Genes with highest mutation rate were PIK3CA and ERBB2. Overall, 34 patients (36%) received a biomarker-based targeted therapy recommendation. Therapeutic recommendations were implemented in nine cases; four patients experienced clinical benefit with a partial response or disease stabilization lasting over 4 months. CONCLUSION: In the setting of a multidisciplinary molecular tumor board, a small but clinically meaningful group of breast and gynecological cancer patients benefits from comprehensive genomic profiling. Broad and successful implementation of precision medicine is complicated by patient referral at late stage disease and limited access to targeted agents and early clinical trials. TRIAL REGISTRATION NUMBER: 284-10 (03.05.2018).

The effect of fertility-sparing surgery on sexuality and global quality of life in women with malignant ovarian germ cell and sex cord stromal tumors: an analysis of the CORSETT database of the AGO study group.

PURPOSE: Malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST) are ovarian neoplasms that affect disproportionally young women. Little is known about the impact of surgical and adjuvant management of these patient's sexual life. This study investigated the effect of fertility-sparing surgery on sexual activity and global quality of life (gQoL) in women with MOGCT and SCST. METHODS: CORSETT was an observational, multicenter, mixed retrospective/prospective cohort study of the AGO study group. Women of any age who had been diagnosed with MOGCTs and SCSTs between 2001 and 2011 were asked to complete the Sexual Activity Questionnaire (SAQ) and the EORTC QLQ-C30. RESULTS: In total, 355 patients were included. Of these, 152 patients with confirmed histological diagnosis had completed the questionnaires. A total of 106 patients were diagnosed with SCST and 46 with MOGCT. Totally, 83 women (55%) were sexually active. After fertility-sparing surgery, patients had a 2.6 fold higher probability for being sexually active than after non-fertility-conserving treatment (unadjusted odds ratio (OR) 2.6, p = 0.01). After adjustment for age, time since diagnosis, FIGO stage, histology and phase of disease, the OR dropped to 1.8 (p = 0.22). Of the sexually active patients, 35 (42%) reported high levels of discomfort during intercourse; 38% after fertility-sparing; and 58% after non-fertility-sparing surgery (adjusted OR 2.8, p = 0.18). Women with fertility-conserving treatment reported a significantly better global QoL (Fadj 2.1, 6.2 points difference, p = 0.03) but not more pleasure during intercourse than women without fertility-sparing surgery (Fadj 0.4, p = 0.52). CONCLUSION: Fertility preserving approaches should be offered to every patient, when oncologically acceptable.

Sirtuin 1 and Sirtuin 3 in Granulosa Cell Tumors.

Sirtuins (SIRTs) are NAD+-dependent deacetylases that regulate proliferation and cell death. In the human ovary, granulosa cells express sirtuin 1 (SIRT1), which has also been detected in human tumors derived from granulosa cells, i.e., granulosa cell tumors (GCTs), and in KGN cells. KGN cells are an established cellular model for the majority of GCTs and were used to explore the role of SIRT1. The SIRT1 activator SRT2104 increased cell proliferation. By contrast, the inhibitor EX527 reduced cell numbers, without inducing apoptosis. These results were supported by the outcome of siRNA-mediated silencing studies. A tissue microarray containing 92 GCTs revealed nuclear and/or cytoplasmic SIRT1 staining in the majority of the samples, and also, SIRT2-7 were detected in most samples. The expression of SIRT1-7 was not correlated with the survival of the patients; however, SIRT3 and SIRT7 expression was significantly correlated with the proliferation marker Ki-67, implying roles in tumor cell proliferation. SIRT3 was identified by a proteomic analysis as the most abundant SIRT in KGN. The results of the siRNA-silencing experiments indicate involvement of SIRT3 in proliferation. Thus, several SIRTs are expressed by GCTs, and SIRT1 and SIRT3 are involved in the growth regulation of KGN. If transferable to GCTs, these SIRTs may represent novel drug targets.

Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer.

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2 ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.

Sirtuin1 expression and survival in endometrial and clear-cell uterine cancer.

Several risk factors like obesity and hyperlipidemia were described for endometrial cancer. Here, the nuclear NAD-dependent histone-deacetylase Sirtuin1 (SIRT1) seems to be important. SIRT1 is also involved in cell regulatory mechanisms and can serve as tumor promotor or suppressor. Its role in tumor biology is not clear yet. In this study, we evaluated and correlated the SIRT1 expression with patients' tumor characteristics in endometrioid and clear-cell cancer of the uterus. 65 paraffin-embedded samples of patients with endometrial and clear-cell cancer of the uterus were immunohistochemically stained and SIRT1 expression was evaluated by immunoreactive score. The results were correlated to clinical and pathological tumor characteristics as well as to the expression of ARID1A and ß-Catenin. The staining was significantly more intensive in uterine endometrioid carcinoma compared to uterine clear-cell carcinoma (p = 0.007). The expression of SIRT1 correlated significantly with the membranous expression of ß-Catenin (p = 0.028) and ARID1A (p = 0.021). Patients with positive Sirtuin1 expression had a significantly better progression-free survival (p = 0.042), the overall survival showed a trend towards a better prognosis (p = 0.070). SIRT1 expression seems to be associated with improved progression-free survival in uterine cancer (endometrioid and clear-cell) and is correlated to the tumor suppressors ß-Catenin and ARID1A. Further studies are necessary to elucidate the role of SIRT1 in uterine and ovarian cancer and its potential as a therapeutic target.