Ovarian cancer relies on the PDGFRß-fibronectin axis for tumorsphere formation and metastatic spread.

High-grade serous ovarian cancer (HGSOC) is the deadliest gynecological malignancy. The most common form of metastatic spread of HGSOC is transcoelomic dissemination. In this process, detached cells from the primary tumor aggregate as tumorspheres and promote the accumulation of peritoneal ascites. This represents an early event in HGSOC development and is indicative of poor prognosis. In this study, based on tumorspheres isolated from ascitic liquid samples from HGSOC patients, ovarian cancer spheroid 3D cultures, and in vivo models, we describe a key signal for tumorsphere formation in HGSOC. We report that platelet-derived growth factor receptor beta (PDGFRß) is essential for fibronectin-mediated cell clustering of ovarian cancer cells into tumorspheres. This effect is mediated by the kinase NUAK family SNF1-like kinase 1 (NUAK1) and blocked by PDGFRß pharmacological or genetic inhibition. In the absence of PDGFRß, ovarian cancer cells can be provided with fibronectin by cancer-associated fibroblasts to generate chimeric spheroids. This work provides new insights that uncover potential targets to prevent peritoneal dissemination, the main cause of advanced disease in HGSOC patients.

Prognostic factors in young women with epithelial ovarian cancer: the Young Ovarian Cancer-Care (YOC-Care) study.

OBJECTIVE: To determine oncological outcomes and to identify prognostic factors in women aged <45 years with epithelial ovarian cancer. METHODS: A multicenter retrospective study was performed of patients treated for epithelial ovarian cancer aged <45 years between January 2010 and December 2019. RESULTS: A total of 998 patients with epithelial ovarian cancer from 55 different institutions in Spain were collected. The median age of the study population was 40.8 years (range 35.6-43.4). The grouped International Federation of Gynecology and Obstetrics (FIGO) stage distribution was 508 (50.9%) patients in initial stages (I and II) and 490 (49.1%) with advanced stages (III and IV). Three hundred and twenty-five (32.6%) patients presented with recurrent disease after a median follow-up of 33.1 months (range 16.1-66.4). The type of staging surgery (incomplete vs complete), type of initial treatment modality (primary cytoreduction vs interval surgery), and amount of residual disease were all significantly associated with overall survival. Tumor rupture was noted in 288 (27.9%) cases, but it was not associated with oncologic outcomes (p=0.11 for overall survival). In the multivariate analysis, the response based on radiological findings (HR 3.24, 95% CI 2.14 to 4.91 for partial response; HR 6.93, 95% CI 4.79 to 10.04 for progression), neoadjuvant chemotherapy (HR 1.42, 95% CI 1.04 to 1.94), and FIGO stage (HR 1.68, 95% CI 1.40 to 2.02) were identified as independent prognostic factors associated with worse oncologic outcomes (p<0.001). CONCLUSION: The partial and progression radiology-based response after chemotherapy, neoadjuvant chemotherapy, and advanced FIGO stage are independent prognostic factors associated with worse oncological outcomes in women aged <45 years with epithelial ovarian cancer.

Robotic-assisted para-aortic lymphadenectomy: Technique and indications in gynecological oncology.

The benefits of minimally-invasive surgeries have been documented, and they have been established as the preferred approach for gynecological surgeries. With the development of robotic surgery, many highly complex surgeries can benefit from these advantages. Due to the complexity of aortocaval lymphadenectomy, surgical technique protocols have been described to reduce risks by maximizing benefits. We describe the technique using five ports (4 robotic arms and an assistant) to work the upper abdominal field, and different instruments recommended in each of their positions to reduce errors and optimize surgical time. After the "step by step" description, we summarize indications of aortocaval lymphadenectomy for every gynecological cancer in different stages.

Oncological outcomes among young women with non-epithelial ovarian cancer: the YOC-Care study (Young Ovarian Cancer - Care).

OBJECTIVE: To determine oncological outcomes and associated prognostic factors in women younger than 45 years diagnosed with non-epithelial ovarian cancer. METHODS: A retrospective, multicenter Spanish study was performed including women with non-epithelial ovarian cancer younger than 45 years between January 2010 and December 2019. All types of treatments and stages at diagnosis with at least 12 months of follow-up were collected. Women with missing data, epithelial cancers, borderline or Krukenberg tumors, and benign histology, as well as patients with previous or concomitant cancer, were excluded. RESULTS: A total of 150 patients were included in this study. The mean±SD age was 31.45±7.45 years. Histology subtypes were divided into germ cell (n=104, 69.3%), sex-cord (n=41, 27.3%), and other stromal tumors (n=5, 3.3%). Median follow-up time was 58.6 (range: 31.10-81.91) months. Nineteen (12.6%) patients presented with recurrent disease with a median time to recurrence of 19 (range: 6-76) months. Progression-free survival and overall survival did not significantly differ among histology subtypes (p=0.09 and 0.26, respectively) and International Federation of Gynecology and Obstetrics (FIGO) stage (I-II vs III-IV) with p=0.08 and p=0.67, respectively. Univariate analysis identified sex-cord histology with the lowest progression-free survival. Multivariate analysis showed that body mass index (BMI) (HR=1.01; 95% CI 1.00 to 1.01) and sex-cord histology (HR=3.6; 95% CI 1.17 to 10.9) remained important independent prognostic factors for progression-free survival. Independent prognostic factors for overall survival were BMI (HR=1.01; 95% CI 1.00 to 1.01) and residual disease (HR=7.16; 95% CI 1.39 to 36.97). CONCLUSIONS: Our study showed that BMI, residual disease, and sex-cord histology were prognostic factors associated with worse oncological outcomes in women younger than 45 years diagnosed with non-epithelial ovarian cancers. Even though the identification of prognostic factors is relevant to identify high-risk patients and guide adjuvant treatment, larger studies with international collaboration are essential to clarify oncological risk factors in this rare disease.

Generation and Integrated Analysis of Advanced Patient-Derived Orthoxenograft Models (PDOX) for the Rational Assessment of Targeted Therapies in Endometrial Cancer.

Clinical management of endometrial cancer (EC) is handicapped by the limited availability of second line treatments and bona fide molecular biomarkers to predict recurrence. These limitations have hampered the treatment of these patients, whose survival rates have not improved over the last four decades. The advent of coordinated studies such as The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA_UCEC) has partially solved this issue, but the lack of proper experimental systems still represents a bottleneck that precludes translational studies from successful clinical testing in EC patients. Within this context, the first study reporting the generation of a collection of endometrioid-EC-patient-derived orthoxenograft (PDOX) mouse models is presented that is believed to overcome these experimental constraints and pave the way toward state-of-the-art precision medicine in EC. The collection of primary tumors and derived PDOXs is characterized through an integrative approach based on transcriptomics, mutational profiles, and morphological analysis; and it is demonstrated that EC tumors engrafted in the mouse uterus retain the main molecular and morphological features from analogous tumor donors. Finally, the molecular properties of these tumors are harnessed to assess the therapeutic potential of trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor with growing interest in EC, using patient-derived organotypic multicellular tumor spheroids and in vivo experiments.

The Impact of Surgical Practice on Oncological Outcomes in Robot-Assisted Radical Hysterectomy for Early-Stage Cervical Cancer, Spanish National Registry.

This study aimed to assess whether surgical practice had a significant impact on oncological outcomes among women who underwent robot-assisted radical hysterectomy for early-stage cervical cancer (≤IB1 or IIA1, FIGO 2009). The secondary objective was to audit the pre-surgical quality indicators (QI) proposed by the European Society of Gynaecological Oncology (ESGO). The top 5 of 10 centers in Spain and Portugal were included in the analysis. The hospitals were divided into group A (n = 118) and group B (n = 97), with recurrence rates of <10% and >10%, respectively. After balancing both groups using the propensity score, the ORs for all events were higher and statistically significant for group B (recurrences OR = 1.23, 95% CI = 1.13-1.15, p-value = 0.001; death OR = 1.10, 95% CI = 1.02-1.18, p-value = 0.012; disease-specific mortality ORr = 1.11, 95% CI = 1.04-1.19, p-value = 0.002). A higher surgical volume, higher participation in clinical trials, higher rate of MRI use for diagnosis, greater use of sentinel lymph node biopsies, and a favorable learning curve with low rates of early recurrences were observed among the centers with better oncological outcomes. These factors might have a significant impact on oncological outcomes not only after robot-assisted surgery, but also after laparoscopies and open surgeries in the treatment of cervical cancer.

Combined use of ICG and technetium does not improve sentinel lymph node detection in endometrial cancer: Results of the COMBITEC study.

OBJECTIVE: There is scarce evidence available about the benefit of combining technetium (99mTc) and indocyanine green (ICG) for sentinel lymph node (SLN) biopsy in endometrial cancer. The aim of this study was to compare the overall and bilateral pelvic detection rates of SLNs in two retrospective cohorts: ICG exclusive vs. combined ICG+99mTc. METHODS: The COMBITEC study (COMBined ICG and Technetium for SLN detection in Endometrial Cancer) consisted of a multicentre retrospective study (February 2015-June 2020) including patients diagnosed with endometrial atypical hyperplasia or early-stage endometrial carcinoma who underwent SLN biopsy by cervical injection of ICG with or without 99mTc in four different referral centers in Spain. RESULTS: A total of 180 patients were included, 51% (n = 92) in ICG group and 49% (n = 88) in ICG+99mTc group. Eighty-seven percent of the patients presented endometrioid histology, and over 99% of the procedures were performed by a minimally invasive approach. Both groups were comparable regarding their basal characteristics, except for a higher body mass index in ICG+99mTc group and a bigger proportion of robotic-assisted procedures in ICG group. Overall detection rate was 92.8% without significant differences between groups (ICG: 94.6% vs ICG+99mTc: 90.9%, p = .34). No significant differences were observed neither in bilateral pelvic nor aortic mapping rate. When 99mTc was used, surgical procedures were significantly longer. In 7.3% of mapped patients, at least one positive SLN was found (ICG: 10.3% vs ICG+99mTc: 3.9%, p = .109). Empty node packet rates and number of SLNs retrieved per patient were also similar between cohorts. CONCLUSION: Combining preoperative 99mTc to intraoperative ICG did not improve SLN detection in endometrial cancer, but resulted in longer procedures.

TGFß Controls Ovarian Cancer Cell Proliferation.

There have been no major improvements in the overall survival of ovarian cancer patients in recent decades. Even though more accurate surgery and more effective treatments are available, the mortality rate remains high. Given the differences in origin and the heterogeneity of these tumors, research to elucidate the signaling pathways involved is required. The Transforming Growth Factor (TGFß) family controls different cellular responses in development and cell homeostasis. Disruption of TGFß signaling has been implicated in many cancers, including ovarian cancer. This article considers the involvement of TGFß in ovarian cancer progression, and reviews the various mechanisms that enable the TGFß signaling pathway to control ovarian cancer cell proliferation. These mechanistic explanations support the therapeutic use of TGFß inhibitors in ovarian cancer, which are currently in the early phases of development.

Robotic Transperitoneal Infrarenal Para-Aortic Lymphadenectomy With Double Docking: Technique, Learning Curve, and Perioperative Outcomes.

Para-aortic lymphadenectomy (PAL) is a challenging procedure performed by minimally invasive surgery in very few centers, owing to its intrinsic technical complexity. We describe and assess the feasibility and learning curve of robotic double-docking transperitoneal infrarenal PAL combined with oncological pelvic surgery. Fifty patients who underwent this procedure using the Da Vinci S surgical system between March 2010 and May 2013 were included. The mean operating time for PAL surgery was 76 minutes (range, 32-150 minutes), and the mean number of lymph nodes per patient was 11.8 (range, 1-44). There were no conversions to laparotomy or laparoscopy. The mean length of hospital stay was 2 days (range, 1-25 days). Statistically significant decreases were noted for mean table rotation time (17 ± 6.8 minutes vs 13 ± 3.6 minutes; p = .02) and mean PAL operating time (85.4 ± 25.8 minutes vs 69.8 ± 24.6 minutes; p = .04) when comparing the first 20 patients and the last 30 patients. The number of nodes was similar in the first 20 patients and last 30 patients. The double-docking transperitoneal infrarenal PAL technique combined with oncological pelvic surgery is feasible, with minimal morbidity and a short learning curve.

BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer.

Germline mutations in the BRCA1 or BRCA2 genes are associated with an increased risk of breast and ovarian cancer development. Both genes are involved in DNA repair, and tumors harboring genetic defects in them are thought to be more sensitive to DNA-damaging agents used in chemotherapy. However, as only a minority of breast and ovarian cancer patients carry BRCA1 or BRCA2 mutations, few patients are likely to benefit from these pharmacogenetic biomarkers. Herein, we show that, in cancer cell lines and xenografted tumors, BRCA1 CpG island promoter hypermethylation-associated silencing also predicts enhanced sensitivity to platinum-derived drugs to the same extent as BRCA1 mutations. Most importantly, BRCA1 hypermethylation proves to be a predictor of longer time to relapse and improved overall survival in ovarian cancer patients undergoing chemotherapy with cisplatin.

Lurbinectedin (PM01183), a new DNA minor groove binder, inhibits growth of orthotopic primary graft of cisplatin-resistant epithelial ovarian cancer.

PURPOSE: Epithelial ovarian cancer (EOC) is the fifth leading cause of death in women diagnosed with gynecologic malignancies. The low survival rate is because of its advanced-stage diagnosis and either intrinsic or acquired resistance to standard platinum-based chemotherapy. So, the development of effective innovative therapeutic strategies to overcome cisplatin resistance remains a high priority. EXPERIMENTAL DESIGN: To investigate new treatments in in vivo models reproducing EOCs tumor growth, we generated a preclinical model of ovarian cancer after orthotopic implantation of a primary serous tumor in nude mice. Further, matched model of acquired cisplatin-resistant tumor version was successfully derived in mice. Effectiveness of lurbinectedin (PM01183) treatment, a novel marine-derived DNA minor groove covalent binder, was assessed in both preclinical models as a single and a combined-cisplatin agent. RESULTS: Orthotopically perpetuated tumor grafts mimic the histopathological characteristics of primary patients' tumors and they also recapitulate in mice characteristic features of tumor response to cisplatin treatments. We showed that single lurbinectedin or cisplatin-combined therapies were effective in treating cisplatin-sensitive and cisplatin-resistant preclinical ovarian tumor models. Furthermore, the strongest in vivo synergistic effect was observed for combined treatments, especially in cisplatin-resistant tumors. Lurbinectedin tumor growth inhibition was associated with reduced proliferation, increased rate of aberrant mitosis, and subsequent induced apoptosis. CONCLUSIONS: Taken together, preclinical orthotopic ovarian tumor grafts are useful tools for drug development, providing hard evidence that lurbinectedin might be a useful therapy in the treatment of EOC by overcoming cisplatin resistance.