Consensus on surgical technique for sentinel lymph node dissection in cervical cancer.

OBJECTIVE: The purpose of this study was to establish a consensus on the surgical technique for sentinel lymph node (SLN) dissection in cervical cancer. METHODS: A 26 question survey was emailed to international expert gynecological oncology surgeons. A two-step modified Delphi method was used to establish consensus. After a first round of online survey, the questions were amended and a second round, along with semistructured interviews was performed. Consensus was defined using a 70% cut-off for agreement. RESULTS: Twenty-five of 38 (65.8%) experts responded to the first and second rounds of the online survey. Agreement ≥70% was reached for 13 (50.0%) questions in the first round and for 15 (57.7%) in the final round. Consensus agreement identified 15 recommended, three optional, and five not recommended steps. Experts agreed on the following recommended procedures: use of indocyanine green as a tracer; superficial (with or without deep) injection at 3 and 9 o'clock; injection at the margins of uninvolved mucosa avoiding vaginal fornices; grasping the cervix with forceps only in part of the cervix is free of tumor; use of a minimally invasive approach for SLN biopsy in the case of simple trachelectomy/conization; identification of the ureter, obliterated umbilical artery, and external iliac vessels before SLN excision; commencing the dissection at the level of the uterine artery and continuing laterally; and completing dissection in one hemi-pelvis before proceeding to the contralateral side. Consensus was also reached in recommending against injection at 6 and 12 o'clock, and injection directly into the tumor in cases of the tumor completely replacing the cervix; against removal of nodes through port without protective maneuvers; absence of an ultrastaging protocol; and against modifying tracer concentration at the time of re-injection after mapping failure. CONCLUSION: Recommended, optional, and not recommended steps of SLN dissection in cervical cancer have been identified based on consensus among international experts. These represent a surgical guide that may be used by surgeons in clinical trials and for quality assurance in routine practice.

Tumor biology and impact on timing of surgery in advanced epithelial ovarian cancer.

Recent advances in epithelial ovarian cancer research have led to a shift in treatment strategy from the traditional 'organ-centric' to a personalized tumor biology-based approach. Nevertheless, we are still far behind an individualized approach for cytoreductive surgery in advanced ovarian cancer; the gold standard of primary treatment in combination with systemic agents. The impact of tumor biology on treatment sequence is still understudied. It is obvious, that response to platinum-based therapy is crucial for the success of neoadjuvant chemotherapy. While high-grade serous and endometrioid tumors are commonly characterized by an excellent response, other subtypes are considered poor responders or even resistant to platinum. Undoubtedly, neoadjuvant chemotherapy may filter poor responders, but to date, we still do not have appropriate alternatives to platinum-based chemotherapy in the neoadjuvant and first-line setting and 'adjusting' systemic treatment in cases of poor response to neoadjuvant chemotherapy remains elusive. Primary cytoreduction is still considered the gold standard for fit patients with operable tumor dissemination patterns, especially for those ovarian cancer subtypes that show poor response to platinum. Of note, even in high-grade serous ovarian cancer, approximately 20% of tumors are platinum resistant and the benefit of neoadjuvant chemotherapy in this subgroup is limited. Interestingly, these tumors are associated with the mesenchymal molecular subtype, which in turn correlates with high risk for residual disease after cytoreductive surgery and is characterized by the worst survival outcome among high-grade ovarian cancers. This leads to the question, how to best tailor surgical radicality at the onset of patients' presentation to avoid associated morbidity and with a moderate benefit. Here, we give an overview of recent advances of interaction between tumor biology and surgery in ovarian cancer.

Social media ambassadors and collaboration with OncoAlert: a European Network of Young Gynae Oncologists study of comparative Twitter analysis of #ESGO2021 and #ESGO2022.

OBJECTIVE: The primary objective was to reveal the impact of social media ambassadors and the collaboration between the European Society of Gynaecological Oncology (ESGO) and the OncoAlert Network on Twitter during the ESGO 2022 Congress by comparing it with the ESGO 2021 Congress. We also aimed to share our experience on how to organize a social media ambassador program and evaluate the potential benefits for the society and the ambassadors. METHODS: We defined the impact as promoting the congress, sharing the knowledge, change in follower count, and change in tweet, retweet, and reply counts. We used the Academic Track Twitter Application Programming Interface to retrieve data from ESGO 2021 and ESGO 2022. We used the keywords of ESGO2021 and ESGO2022 to retrieve data for each of the conferences. The time range in our study captured interactions from before, during, and after conferences. We collected the ambassadors', ESGO's, and the European Network of Young Gynae Oncologists' (ENYGO's) follower data on Twitter from November 2021 to November 2022 for comparative analysis. RESULTS: There was a 7.23-fold increase in the use of the official congress hashtag in 2022 compared with 2021. Compared with #ESGO2021 data, the main interventions of the Social Media Ambassadors and OncoAlert partnership determined 7.79-, 17.36-, 5.50-, 10.58-, and 8.50-fold increases with #ESGO2022 data in the mentions, mentions in retweet, tweet, retweet, and replies, respectively. Similarly, all other most commonly used hashtags in the top 10 list indicated a range from 2.56- to 7.00-fold increase. Compared to the ESGO 2021 congress month, ESGO and the majority (83.3%, n=5) of ambassadors gained more followers during ESGO 2022 congress month. CONCLUSIONS: An official social media ambassadors program and collaboration with influential accounts in the field of interest are beneficial for congress-related engagement on a social media platform (Twitter). Individuals participating in the program can also benefit from gaining higher visibility among specific audience.

Enhanced recovery after cesarean section (ERAC): Where are we in Austria?

OBJECTIVE: Enhanced recovery after surgery (ERAS) recommendations for cesarean section (ERAC), likely the most common reason for laparotomy in women, were issued in 2018-19. We examined how current perioperative management at cesarean section in Austrian hospitals aligns with ERAS recommendations. STUDY DESIGN: We surveyed the 21 largest public obstetric units in Austria for alignment with 20 of the 31 strong ERAS recommendations regarding perioperative maternal care at cesarean section. We also looked at how the German-language clinical guideline for cesarean section (AWMF Guideline Sectio caesarea) aligns with ERAS recommendations. RESULTS: The 21 obstetric units cared for about 51% of all births in Austria in 2019. Cesarean section rates ranged from 17.7% to 50.4%. All 21 units implemented the five strong recommendations regarding patient information and counselling, regional anesthesia, euvolemia and multimodal analgesia. The least implemented strong recommendation was the one for the use of pneumatic compression stockings to prevent thromboembolic disease (0/21 units). Overall, all 21 units implemented ≥11 and 13 (62%) implemented ≥15 (≥75%) of the 20 strong recommendations; no unit implemented all 20 strong recommendations. There were no differences in the implementation of strong recommendations according to hospital volume. CONCLUSIONS: Even in the absence of formal adoption of ERAS program for cesarean section many perioperative ERAS recommendations are already implemented in Austria. The least implemented recommendations were the use of pneumatic compression stockings (0 of 21 units) and immediate catheter removal (4 of 21 units). Only 10 of the 20 ERAS recommendations we looked at are included in the current German-language clinical guideline for cesarean section.

An angiogenic tumor phenotype predicts poor prognosis in ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), shows efficacy in different lines of OC therapy. This study investigates the clinical impact of tumoral expression of angiogenesis-related genes and their association with bevacizumab response in OC in retrospective analysis of three independent cohorts. METHODS: mRNA expression of seven angiogenic genes (VEGF, VEGFR2, PDGFA, PDGFB, PDGFRA, PDGFRB, KIT) was quantified in an inception OC cohort (n = 195) and a transcriptional tumor angiogenesis score from 0 to 3 was established and linked to progression-free survival (PFS) and overall survival (OS). This score was corroborated in an independent publicly available cohort from The Cancer Genome Atlas (TCGA, n = 582) and prediction of therapeutic efficacy of bevacizumab by the angiogenesis score was analyzed in the Gene Expression Omnibus (GEO) dataset GSE140082 (n = 380) from the ICON7-trial. RESULTS: The tumor angiogenesis score prognosticated PFS and OS in patients with OC from the inception cohort (p < 0.001, respectively). Tumoral PDGFA expression (PFS: HR 2.46, p = 0.005; OS: HR 2.26, p = 0.011) and a high tumoral transcriptional angiogenesis score (PFS: HR 1.41, p = 0.018) were identified as independent predictors of clinical outcome. The transcriptional angiogenesis score exhibited a significant though smaller effect size on PFS in the TCGA cohort. However, in the ICON7-trial, the angiogenesis score was not associated with benefit of bevacizumab treatment. CONCLUSIONS: Our study indicates that tumoral expression of angiogenic genes is unfavorable in OC. The established score could be used to identify patients who respond to targeted angiogenic therapies, a concept that warrants prospective controlled clinical trials.

Austria-based real-world data on bevacizumab in newly diagnosed epithelial ovarian cancer.

BACKGROUND: Front-line maintenance therapy with bevacizumab demonstrates high efficacy and safety in epithelial ovarian cancer, as already shown in large phase III trials; however, the corresponding study populations are often not fully representative of patients in clinical routine. In this Austria-based multicenter study, we aimed to explore the real-world outcomes of bevacizumab use in front-line treatment of ovarian cancer, including patients with comorbidities and poor performance status. PATIENTS: This study is an open label single arm multicenter noninterventional trial and included patients with newly diagnosed advanced epithelial ovarian cancer, who were treated with platinum-based chemotherapy and were candidates for receiving bevacizumab according to the product label. Data collection started in the third quarter of 2012 and ended in the third quarter of 2018. RESULTS: In this study 50 patients were included and 575 adverse events were reported for 90% of the patients. The majority of the adverse events were mild (47%) or moderate (37%). The most common adverse events were hypertension (60%), anemia (48%), leukopenia (42%), thrombocytopenia (36%), neutropenia (36%) and proteinuria (26%). A relation to bevacizumab was documented only for 10.3% of all adverse events. In almost 50% of all adverse events, no intervention was needed and bevacizumab treatment had to be interrupted only in 3.3% of all adverse events. The median progression-free survival was 1.3 years (95% CI 1.1-1.8). CONCLUSION: The routine use of front-line bevacizumab for advanced ovarian cancer is associated with high efficacy comparable with that obtained in randomized phase III clinical trials; however, hypertension and proteinuria were reported significantly more often in our Austria-based real-world population.

Dubious effects of methadone as an "anticancer" drug on ovarian cancer cell-lines and patient-derived tumor-spheroids.

BACKGROUND: The opioid agonist D,L-methadone exerts analgesic effects via the mu opioid receptor, encoded by OPRM1 and therefore plays a role in chronic pain management. In preclinical tumor-models D,L-methadone shows apoptotic and chemo-sensitizing effects and was therefore hyped as an off-label "anticancer" drug without substantiation from clinical trials. Its effects in ovarian cancer (OC) are completely unexplored. METHODS: We analyzed OPRM1-mRNA expression in six cisplatin-sensitive, two cisplatin-resistant OC cell-lines, 170 OC tissue samples and 12 non-neoplastic control tissues. Pro-angiogenetic, cytotoxic and apoptotic effects of D,L-methadone were evaluated in OC cell-lines and four patient-derived tumor-spheroid models. RESULTS: OPRM1 was transcriptionally expressed in 69% of OC-tissues and in three of eight OC cell-lines. D,L-methadone exposure significantly reduced cell-viability in five OC cell-lines irrespective of OPRM1 expression. D,L-methadone, applied alone or combined with cisplatin, showed no significant effects on apoptosis or VEGF secretion in cell-lines. Notably, in two of the four spheroid models, treatment with D,L-methadone significantly enhanced cell growth (by up to 121%), especially after long-term exposure. This is consistent with the observed attenuation of the inhibitory effects of cisplatin in three spheroid models when adding D,L-methadone. The effect of methadone treatment on VEGF secretion in tumor-spheroids was inconclusive. CONCLUSIONS: Our study demonstrates that certain OC samples express OPRM1, which, however, is not a prerequisite for D,L-methadone function. As such, D,L-methadone may exert also detrimental effects by stimulating the growth of certain OC-cells and abrogating cisplatin's therapeutic effect.

The impact of COVID-19 pandemic on the rate of newly diagnosed gynecological and breast cancers: a tertiary center perspective.

PURPOSE: The aim of the present study was to assess the impact of postponed screening examinations and lockdown measures on gynecological and breast cancer diagnoses throughout the year 2020 in a gynecological oncological center in Austria. METHODS: Data of 889 patients with either newly diagnosed gynecological or breast cancer between January 2019 and December 2020 were collected. Clinical parameters including symptoms, performance status, comorbidities and referral status were compared in patients, who were newly diagnosed with cancer in the period of the first lockdown from March 2020 to April 2020 and the second lockdown from November 2020 to December 2020 and compared to the same period in 2019. RESULTS: Our results showed a strong decline in newly diagnosed cancers during the lockdown periods: -45% in gynecological cancer and -52% in breast cancer compared to the same period in 2019. Compared to the analogue period of 2019, breast cancer patients reported significantly more tumor-associated symptoms (55% vs. 31%, p = 0.013) during and in between (48% vs. 32%, p = 0.022) the lockdowns. During the lockdown, periods in the group of breast cancer patients' tumor stage varied significantly compared to 2019 (T2-T4; p = 0.047). CONCLUSION: Both lockdowns led to a strong decrease in newly diagnosed gynecological and breast cancers. Treatment delays in potentially curable disease could lead to inferior clinical outcomes, with the risk of missing the optimal treatment window. As the COVID-19 pandemic will be a challenge for some time to come, new strategies in patient care are needed to optimize cancer screening and management during the pandemic.

Clinical impact of EZH2 and its antagonist SMARCA4 in ovarian cancer.

SMARCA4 and EZH2 are two functional key players of their respective antagonizing chromatin remodeling complexes SWI/SNF and PRC2. EZH2 inhibitory drugs may abrogate pro-oncogenic features of PRC2 and turn the balance to cell differentiation via SWI/SNF activity in cancers. SMARCA4 and EZH2 expression was assessed by RT-PCR in 238 epithelial ovarian cancers (OCs) and put in relation to clinico-pathological parameters and patients' outcome. Optimal thresholds for high and low expression of both variables were calculated by the Youden's index based on receiver operating characteristic (ROC) curves. High SMARCA4 mRNA expression was independently associated with favorable progression-free survival (PFS) (P = 0.03) and overall survival (OS) (P = 0.018). As Youden's threshold determination for EZH2 yielded a S-shaped ROC-curve, two cut-off points (29th and 94th percentile) predicting opposite features were defined. Whereas EZH2 mRNA levels beyond the 29th percentile independently predicted poor PFS (P = 0.034), Cox-regression in EZH2 transcripts above the 94th percentile revealed a conversion from unfavorable to favorable PFS and OS (P = 0.009 and P = 0.032, respectively). High SMARCA4 expression associates with improved survival, whereas moderate/high EZH2 expression predicts poor outcome, which converts to favorable survival in ultra-high expressing OCs. This small OC subgroup could be characterized by REV7-abrogated platinum hypersensitivity but concomitant PARP-inhibitor resistance.

Decrease in gynecological cancer diagnoses during the COVID-19 pandemic: an Austrian perspective.

BACKGROUND: On March 16, 2020, the federal government of Austria declared a nationwide lockdown due to the COVID-19 pandemic. Since the lockdown, screening examinations and routine checkups have been restricted to prevent the spread of the virus and to increase the hospitals' bed capacity across the country. This resulted in a severe decline of patient referrals to the hospitals. OBJECTIVE: To assess the impact of the COVID-19 pandemic on the rate of newly diagnosed gynecological and breast cancers in Austria. METHODS: Data of 2077 patients from 18 centers in Austria with newly diagnosed gynecological or breast cancer between January and May 2019 and January and May 2020 were collected. Clinical parameters, including symptoms, performance status, co-morbidities, and referral status, were compared between the time before and after the COVID-19 outbreak. RESULTS: Our results showed a slight increase of newly diagnosed cancers in January and February 2020 as compared with 2019 (+2 and +35%, respectively) and a strong decline in newly diagnosed tumors since the lockdown: -24% in March 2020 versus March 2019, -49% in April 2020 versus April 2019, -49% in May 2020 versus May 2019. Two-thirds of patients diagnosed during the pandemic presented with tumor-specific symptoms compared with less than 50% before the pandemic (p<0.001). Moreover, almost 50% of patients in 2020 had no co-morbidities compared with 35% in 2019 (p<0.001). Patients, who already had a malignant disease, were rarely diagnosed with a new cancer in 2020 as compared with 2019 (11% vs 6%; p<0.001). CONCLUSIONS: The lockdown led to a decreased number of newly diagnosed gynecological and breast cancers. The decreased accessibility of the medical services and postponed diagnosis of potentially curable cancers during the COVID-19 pandemic may be a step backwards in our healthcare system and might impair cancer treatment outcomes. Therefore, new strategies to manage early cancer detection are needed to optimize cancer care in a time of pandemic in the future.

The miR-34 family and its clinical significance in ovarian cancer.

The tumor suppressor miR-34 family is transcriptionally induced by p53. Clinical significance of the various miR-34 family members has not been studied in ovarian cancer. In 228 ovarian cancers and in 19 non-neoplastic fallopian tube samples we analysed miR-34 a/b/c expression in relation to clinicopathological characteristics and clinical outcome. We found significantly lower levels of miR-34 a/b/c in ovarian cancers as compared to control-tissues (P=0.002, P<0.001, P<0.001, respectively). Expression of miR-34 b/c revealed an inverse correlation with BRCA1/2 mRNA-expression (BRCA1: miR34 b/c P=0.002 each; BRCA2: miR-34 b/c P<0.001 each), the same was true for miR-34a and BRCA2 mRNA-expression (P<0.001). The miR-34 family expression was found to be significantly lower in type 2 in comparison to type 1 cancers (P<0.001) and in TP53-mutated compared with TP53-wild-type ovarian cancers (P<0.001, P=0.002, P=0.004, respectively). When low grade serous ovarian cancers were compared with high grade serous cancers the respective miR-34 a/b/c expression was 2.6-, 40.8- and 32.3-fold higher. The expression of each of the miR-34 family members was revealed to be of independent prognostic relevance regarding progression free survival (PFS); miR-34a: HR 0.6, P=0.033; miR-34b: HR 0.2, P=0.001 and miR-34c: HR 0.3, P=0.002, respectively). For overall survival (OS) independency of the prognostic value was confined to miR-34b (HR 0.4, P=0.016) and miR-34c (HR 0.6, P=0.049). The independency of the prognostic value of our identified thresholds was confirmed for PFS for miR-34c in a publicly available dataset (NCBI Gene Expression Omnibus GSE73582). Our findings suggest that downregulation of miR-34 family is a crucial part in ovarian cancer development. Low miR-34 levels are linked to a worse overall survival and progression free survival and may indicate a more aggressive disease.

Hopes and failures in front-line ovarian cancer therapy.

Through the last three decades, the combination of paclitaxel and carboplatin remains the standard of care chemotherapy in newly diagnosed epithelial ovarian cancer (EOC). Based on a single trial, first-line maintenance therapy with angiogenesis inhibitor bevacizumab was approved in Europe and widely applied. In 2018, based on a second trial bevacizumab was approved for first-line maintenance in the United States. Despite complete remission upon chemotherapy, the majority of the patients recur. A large number of randomized trials were conducted to explore the optimal front-line therapy regimen, but neither dose-densing, nor adding of a third chemotherapy agent or intraperitoneal administration could improve overall survival (OS). Also implementation of hyperthermic intraperitoneal chemotherapy (HIPEC) or the neoadjuvant approach failed to improve OS. Recently, maintenance therapy with PARP inhibitors showed encouraging results in patients with BRCA1/2 mutation. Further trials with targeted therapies are ongoing. Here we review the achievements of front-line therapy in primary advanced EOC through the last three decades and discuss future treatment strategies.

Clinical Impact of RANK Signalling in Ovarian Cancer.

Ovarian cancer (OC) is a gynaecological malignancy with poor clinical outcome and limited treatment options. The receptor activator of nuclear factor-κB (RANK) pathway, activated by RANK ligand (RANKL), critically controls bone metabolism, tumourigenesis and tumour immune responses. Denosumab, a monocloncal RANKL antibody, exerts tumour-suppressive effects in mice and humans. Here, we investigated the relevance of RANK signalling in OC. RANK, RANKL and OPG expression in 192 epithelial OC tissues was compared to expression in 35 non-malignant control tissues and related to clinico-pathological characteristics. Findings were validated in a cohort of 563 OC patients from The Cancer Genome Atlas (TCGA). The expression of RANK, RANKL and OPG was studied in four OC cell lines and the impact of RANK ligation or blockade on OC cell proliferation was determined. RANK, RANKL and OPG were expressed in epithelial and stromal cells in OC. RANKL expression was elevated in OC tissue, particularly in BRCA1/2 mutated tumours. High RANKL expression independently predicted reduced progression-free (PFS, p = 0.017) and overall survival (OS, p = 0.007), which could be validated in the TCGA cohort (PFS, p = 0.022; OS, p = 0.046, respectively). Expression of RANK and OPG in OC cells was induced by inflammatory cytokines IL-1ß and TNFα. Neither recombinant RANK ligation nor denosumab treatment affected OC cell proliferation. Our study independently links RANKL expression with poor clinical outcome in two unrelated OC cohorts. These findings implicate RANK signalling in the immunopathogenesis of OC and warrant clinical trials with denosumab in OC.

NADPH oxidase 4 expression in the normal endometrium and in endometrial cancer.

The aim of this study was to explore the role of NOX4 in the biology of the normal endometrium and endometrial cancer. NOX4 plays a key role in other adenocarcinomas and has been implicated in the pathogenesis of diabetes and obesity, which are important risk factors for endometrial cancer. NOX4 expression was assessed in 239 endometrial cancer and 25 normal endometrium samples by quantitative real-time polymerase chain reaction, in situ hybridization, and immunohistochemistry. DNA methylation of the NOX4 promoter was determined by means of MethyLight PCR. Data were correlated with clinicopathological parameters and analyzed in the context of diabetes and body mass index. In the normal endometrium, NOX4 microRNA expression was significantly higher in the secretory transformed compared with proliferative endometrium ( p = 0.008). In endometrial cancer specimens, NOX4 expression did not differ between diabetic and non-diabetic patients, but was the highest in patients with a body mass index ≤ 26 ( p = 0.037). The lowest NOX4 expression was found in carcinosarcomas ( p = 0.007). High NOX4 expression predicted poorer clinical outcome with regard to overall survival, especially in non-diabetic patients and those with a body mass index > 20. Independent prognostic significance of NOX4 transcripts was retained in type I endometrial cancer and was the most meaningful in patients with a body mass index > 20. No prognostic impact was shown for NOX4 promoter methylation in endometrial cancer. For the first time, we demonstrate that NOX4 plays a considerable role in the cycle-dependent changes in the normal endometrium and in the biology of endometrial cancer.

Tumor necrosis factor receptor modulator spermatogenesis-associated protein 2 is a novel predictor of outcome in ovarian cancer.

Inflammation plays a crucial role in the pathogenesis of cancer with tumor necrosis factor-α (TNF-α) as a key mediator. Recently, spermatogenesis-associated protein 2 (SPATA2) was identified as a TNF receptor modulator which is required for TNF-induced inflammation and apoptosis. The available data on TNF-α in ovarian cancer (OC) are inconsistent, and SPATA2 is completely uncharacterized in tumorigenesis. We analyzed expression of SPATA2 and TNFA by quantitative real-time polymerase chain reaction in tissues of 171 patients with low-grade serous (LGSOC), high-grade serous (HGSOC), endometrioid and clear cell OC compared with 28 non-malignant control tissues. We stimulated OC cells (OVCAR3) with pro-inflammatory (TNF-α, interleukin [IL]-1ß) and mitogenic stimuli (IL-6, lysophosphatidic acid) to establish a direct effect between inflammatory signaling and SPATA2. Pro-inflammatory, but not mitogenic stimuli, potently induced SPATA2 expression in OC cells. Expression of TNFA and SPATA2 was higher in OC compared with control tissues (P = 0.010 and P = 0.001, respectively) and correlated with each other (P = 0.034, rs  = 0.198). When compared with grade 1 cancers, SPATA2 was expressed higher in grade 2 and 3 tumors (P = 0.011) as well as in HGSOC compared with LGSOC (P = 0.024). Multivariate survival analyses revealed that OC with high SPATA2 expression were associated with reduced progression-free survival (P = 0.048) and overall survival (P < 0.001). In conclusion, SPATA2 expression is regulated by TNF-α and IL-1ß and is found to independently affect clinical outcome in OC patients. These data implicate a role of SPATA2 in tumorigenesis which warrants further investigation in gynecological malignancies.

Immunotherapy in ovarian cancer: fake news or the real deal?

Cancer immunotherapy has emerged as one of the most promising approaches in oncology, and comprises the activation of the immune system to induce tumor immune surveillance or to reverse the tumor immune escape. Different therapeutic strategies for ovarian carcinoma have evolved over the years. Already 30 years ago, the first clinical studies focused on modulating the tumor cytokine network with special attention to interferon-mediated immune responses. With the exploration of specific tumor antigens such as NY-ESO-1, which is expressed in ovarian carcinoma and other malignancies, the development of therapeutic cancer vaccines has been pursued initiating the era of personalized anti-cancer medicine. Almost at the same time, the adoptive transfer of genetically modified autologous tumor-reactive T-cells occurred, but response rates in ovarian carcinoma were disappointing. Today, probably the most promising therapeutic approach in this context is the blockade of immune checkpoints, such as programed cell death protein 1 (PD-1) and one of its ligands (PD-L1) or cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4), which has demonstrated impressive response rates in malignant melanoma and non-small cell lung cancer. Despite increasing availability of treatment approaches that target tumor immune surveillance in ovarian carcinoma, selecting patient groups that particularly benefit from these treatment modalities is clinically challenging as predictive biomarkers are lacking. Here, we summarize different immunotherapy approaches in ovarian cancer and discuss why immunotherapy in ovarian cancer is still in its infancy.

BRCA1 and BRCA2 mRNA-expression prove to be of clinical impact in ovarian cancer.

BACKGROUND: Mutations in BRCA1 and BRCA2 are associated with better survival in ovarian cancer (OC) patients due to a better response to platinum-based chemotherapy. However, the impact of the BRCA1/2 mRNA-expression is not well characterized in OC. PATIENTS AND METHODS: We investigated BRCA1/2 mRNA-expression in 12 non-neoplastic fallopian tubes and 201 epithelial OCs in relation to their clinical characteristics. RESULTS: We found higher BRCA1/2 mRNA-expression in OCs compared to controls (P = 0.011, P < 0.001, respectively). BRCA1 mutated OCs exhibited lower BRCA1 (P = 0.014) but higher BRCA2 mRNA-expression (P = 0.001). Low BRCA1-expression was associated with favorable overall survival (OS) (P = 0.012) and low BRCA2-expression with better progression-free survival (PFS) and OS (P = 0.004, P = 0.001, respectively). A subgroup-analysis showed that this effect was confined only to the BRCA1-wildtype cancers. Cox-regression confirmed the prognostic significance of BRCA1-expression for OS (P = 0.028). Independency of the prognostic value of BRCA2-expression for PFS (P = 0.045) and OS (P = 0.015) was restricted to high-grade serous OCs. Fully platinum-sensitivity was characterized by lower BRCA1/2 mRNA-expression in BRCA1-wildtype cancers in comparison to platinum-refractory OC. CONCLUSION: Our findings may reflect higher platinum-sensitivity due to reduced capacity of DNA damage repair in tissues with low BRCA1/2-expression. In this context, especially in BRCA-wildtype cancers both parameters could also be potential predictors for PARP-sensitivity.