Multimodale prädiktive und prognostische Faktoren zum klinischen Verlauf von Patientinnen mit Ovarialkarzinom

Although a plethora of biomarkers have been analyzes in the last decades and ultrasound criteria have been developed, ovarian cancer is mostly diagnosed in advanced stages. Despite more extensive surgical procedures and improvement in surgical outcome, ovarian cancer remains a deadly disease with most of the patients developing relapse and platinum resistance. Although progresses in understanding the molecular biology of EOC have been done in the last years, targeted therapies failed to improve overall survival rates in ovarian cancer patients. The here presented data focuses on three major bottle necks of multimodal management of ovarian cancer: predictive biomarkers for early diagnosis of EOC, role and limitations of BRCA1 epigenetic changes and predictive biomarkers and clinical parameters for clinical outcome. Borderline tumors of the ovary (BOT) are a special entity of epithelial tumors, usually having a benign behavior. Nevertheless, optimal surgical staging is mandatory, as BOT could be a precursor of low grade serous ovarian cancers. Using ultrasound, BOT together with some benign tumors, are the most difficult pelvic tumors to be assessed. They have both malignant as also benign characteristics. In our study, presented here, we analyzed the role of HE4 and CA125 alone and in combination within ROMA algorithm to predict the presence of BOT in pelvic mass patients. Our results showed that HE4 and ROMA (an algorithm combining CA125, Both biomarkers together with ROMA had poor sensitivity and specificity. Therefore there is still an urgent need of new diagnostic strategies with regards to BOT. Furthermore we analyzed the role of GLYCOV for the diagnosis of early ovarian cancer. GLYCOV is a newly discovered biomarker panel, formed by 11 N-glycan biomarkers, more specific four high- mannose and seven complex-type fucosylated N-glycans. Regarding to available data CA125 is increased in up to 80% of ovarian cancer patients, but only in 50% of early stages. Therefore CA125 remains a poor biomarker for early detection. In our study, GLYCOV had a better sensitivity and specificity than CA125 alone, with an AUC of 0.992 in detecting early stages EOC (FIGO stage I and II). This study included 20 FIGO I and II ovarian cancer patients, therefore further validation studies are needed. Homologous recombination deficiency (HRD) has been reported in up to 50% of high grade serous ovarian cancer patients. Mutations in BRCA1 and 2 genes are usually responsible for HRD. Epigenetic changes of BRCA1/2 promoter as also functional loss of proteins involved in HDR showed similar behavior as BRCA1/2 mutant tumors. Current trials showed that PARP inhibition increased progression free survival in BRCA mutant tumors. Therefore understanding inactivation mechanisms of the BRCA1 gene is of high clinical importance. In our study, we showed that methylation of BRCA1 promoter gene in HGSOC was not associated with platinum response, or with better overall or progression free survival rates. Hyper- methylation was associated with younger age at first diagnosis. No significant correlation between methylation status and surgical outcome have been detected. Residual mass after primary tumor debulking is an important prognostic factor. Optimal surgery can be achieved in ca. 60-70% of the patients, if primary debulking is performed in high volume centers. Nevertheless in a sub-group of patients optimal surgical outcome cannot be achieved. Until now there are no predictive biomarkers or clinical parameters for residual tumor mass. We analyzed the role of CA125 and HE4 in predicting surgical outcome in primary EOC. CA125 performed better than HE4 alone, but the combination of both biomarkers increased the sensitivity and specificity. When looking at different histological subtypes, we found out that in early stages, type I tumors have better survival rates, less extensive surgery, less extensive tumor spread. This was mostly due to diagnosis in early stages. Nevertheless when analyzing only the advanced FIGO stages, there was no differences in survival rates between type I and type II EOC. In advanced stages, tumor residuals together with positive lymph nodes and extrapelvic dissemination were independent prognostic factors for PFS and OS. If surgery is well accepted for primary situation, controversial discussions are surrounding the indication of secondary debulking surgery for ovarian cancer relapse. In our presented data, we analyzed the differences in surgical outcome and dissemination pattern in paired primary and relapse ovarian cancer patients. Complete tumor resection was significantly more often achieved in primary debulked patients as in first relapse. Residual mass at first surgery correlated with surgical outcome at relapse. No clinical parameters could predict surgical outcome in relapse situation. Dissemination pattern differed between primary and relapsed situation: with higher incidence of ascites at first diagnosis, and significant more involvement of upper abdomen in recurrent setting. In relapsed ovarian cancer diffuse mesenterial and peritoneal spread have been reported, leading to sub-optimal surgical outcome. There were no significant differences within postoperative complications. Looking for the classical biomarkers, HE4 and CA125, and their ability to predict surgical outcome, our study showed that both HE4 and CA125 are correlating with tumor residuals in patients with first platinum sensitive relapses. Nevertheless the sensitivity and specificity was poor, so further prospective multicentric studies evaluating biomarkers in combination with clinical parameters (eg. ECOG status, ascites, residual mass after primary debulking surgery) are needed. Furthermore, HE4 together with response to first platinum based chemotherapy were the only independent prognostic factors for OS. These data are the fundament for further validation and discovery studies towards personalized management of ovarian cancer patients.Obwohl in den letzten Jahren eine Vielzahl von Biomarkern und Ultraschallkriterien etabliert wurden, wird Eierstockkrebs noch immer meist in fortgeschrittenen Stadien diagnostiziert. Trotz Verbesserung der chirurgischen Techniken und des surgical outcome, bleibt Eierstockkrebs eine tödliche Erkrankung, während welcher die Patientinnen Rezidive und Platinresistenzen entwickeln. Obwohl in den letzten Jahren Fortschritte im Verständnis für die molekularen Zusammenhänge der Erkrankung verzeichnet wurden, konnten mittels gezielter Therapieansätze („targeted therapy“) keine Verbesserungen der Gesamtüberlebensraten bei Eierstockkrebspatientinnen erreicht werden. Die hier präsentierten Daten konzentrieren sich auf die drei Schwerpunkte einer multimodalen Therapiestrategie bei Eierstockkrebs: prädiktive Biomarker für eine frühzeitige Diagnosestellung, die Rolle und Limitationen von epigenetischen Veränderungen von BRCA1 und prädiktiver Biomarker sowie klinische Parameter für die Evaluation des klinischen Outcome. Borderlinetumoren des Ovars (BOT) sind eine spezielle Entität von epithelialen Tumoren, welche üblicherweise von benigner Dignität sind. Trotzdem ist ein optimales chirurgisches Staging unerlässlich, da die BOT Vorstufen des low grade serösen Eierstockkrebs darstellen können. Dabei sind BOT zusammen mit anderen benignen Tumoren am schwierigsten von allen Beckentumoren sonographisch zu diagnostizieren, da sie sowohl maligne als auch benigne Charakteristika tragen. In unserer Studie analysierten wir die Rolle des HE4 und CA125 allein und in Kombination mit dem ROMA Algorithmus, um das Vorliegen von BOT in Patientinnen mit unklarem Beckentumor zu prognostizieren. Unsere Ergebnisse zeigten, dass HE4 und ROMA sowohl einzeln als auch gemeinsam betrachtet eine schlechte Sensitivität und Spezifität aufzeigten. Daher besteht ein dringender Bedarf für die Etablierung neuer diagnostischer Strategien bezüglich des BOT. Weiterhin analysierten wir die Rolle von GLYCOV für die Diagnostik von Eierstockkrebs im Frühstadium. GLYCOV ist ein neu entwickelter Score, welcher aus 11 Bereichen (4 High- Mannose- und sieben fukosylierten N- Glykanen vom komplexen Typ) des N- glycan- Biomarker errechnet wird. Nach aktueller Datenlage ist CA125 in bis zu 80% der Ovarialkarzinompatientinnen erhöht, bei frühen Stadien jedoch nur in 50%. Daher bleibt CA125 ein schwacher Biomarker für die Krebsfrüherkennung. In unserer Studie wies GLYCOV eine bessere Sensitivität und Spezifität auf als CA125 allein mit einem AUC von 0.992 für die Erkennung von EOC in Frühstadien (FIGO- Studien I und II). Diese Studie umfasst 20 FIGO I und II Ovarialkarzinompatientinnen, sodass weitere Validierungsstudien notwendig sind. Ein Defizit in der der Homologen Rekombinationsreparatur (HRR) wurde in bis zu 50% der Patientinnen mit high grade serösem Ovarialkarzinom (HGSOC) berichtet. Dafür sind meist Mutationen des BRCA1 und 2- Gens verantwortlich. Epigenetische Veränderungen der BRCA1/2- Promoter sowie Funktionsverluste von Proteinen durch defiziente HRR zeigten ähnliches Verhaltensmuster wie Tumoren mit BRCA1/2- Mutationen. Aktuelle Studien zeigten, dass PARP- Inhibitoren das progressionsfreie Überleben in BRCA- mutierten Tumoren erhöhen. Daher ist das Verständnis bezüglich der Inaktivierungsmechanismen des BRCA1- Gens von hoher klinischer Relevanz. In unserer Studie zeigten wir, dass die Methylierung des BRCA- Promotorgens in HGSOC nicht mit der Platinsensitivität, der Verbesserung des Gesamtüberlebens oder des progressionsfreien Überlebens assoziiert ist. Es konnte weiterhin keine Korrelation zwischen Methylierungsstatus und chirurgischem Outcome festgestellt werden. Der Tumorrest nach primärem Tumordebulking ist ein wichtiger prognostischer Faktor. Diesbezüglich kann ein optimales Ergebnis in ca. 60-70% der Patientinnen erreicht werden, sofern das primäre Debulking in einem hierfür spezialisierten Tumorzentrum durchgeführt wird. Nichtsdestotrotz kann bei einem Teil der Patientinnen kein optimales Ergebnis erzielt werden. Bis heute gibt es keine prädiktiven Biomarker oder klinischen Parameter für den Verbleib von Tumorrest. Wir analysierten die prädiktive Rolle von CA125 und HE4 bezüglich des Surgical Outcomes bei primärem EOC. Dabei schnitt CA125 besser ab als HE4 und die Kombination aus beiden Biomarkern erhöhte die Sensitivität und Spezifität nochmals. Bei der Betrachtung der verschiedenen histologischen Subtypen konnten wir zeigen, dass in frühen Stadien die Typ I- Tumoren bessere Überlebensraten, weniger ausgedehnte Operationen und geringeren Tumorbefall aufwiesen. Bei der Analyse der fortgeschrittenen FIGO Stadien, zeigte sich kein Unterscheid in den Überlebensraten zwischen Typ I und Typ II EOC. Bei fortgeschrittenen Stadien stellten Tumorrest gemeinsam mit positivem Lymphknotenstatus und extrapelviner Tumorausbreitung unabhängige prognostische Faktoren für das progressionsfreie Überleben und das Gesamtüberleben dar. Im Gegensatz zur allgemein anerkannten Operation in der Primärsituation, bestehen Kontroversen bezüglich der Indikation zur sekundären Debulkingoperation bei Ovarialkarzinomrezidiv. Wir analysierten die Unterschiede im Surgical Outcome und Tumorbefallsmuster in gepaarten Patientinnen mit jeweils primärem und rezidiviertem Ovarialkarzinom. Tumorfreiheit konnte signifikant häufiger in primären Debulkingoperationen als bei Rezidivoperationen erreicht werden. Der Tumorrest korrelierte bei primärer Operation mit dem surgical outcome und Auftreten von Rezidiven. Es gab keine klinischen Parameter, welche das surgical outcome in der Rezidivsituation beurteilen konnten. Auch der Tumorbefall unterschied sich in der Primär- und Rezidivsituation, indem bei Ersterer ein höherer Aszitesanteil bei Erstdiagnose und ein signifikant höherer Tumorbefall des Oberbauches bestand. In der Rezidivsituation zeigten sich vermehrt eine diffuse mesenterielle und peritoneale Tumorausbreitung, welche zu einem suboptimalem surgical outcome führten. Es gab keine signifikanten Unterschiede bezüglich der postoperativen Komplikationen. Bezüglich der klassischen Biomarker HE4 und CA125 und deren prädiktiven Aussage bezüglich des surgical outcomes zeigte unsere Studie, das Beide mit dem Tumorrest bei Patientinnen mit erstem platinsensitivem Rezidiv korrelierten. Trotzdem war die Sensitivität und die Spezifität gering, sodass weitere prospektive multizentrische Studien zur Evaluation von Biomarkern in Kombination mit klinischen Parametern (z.B.- ECOG Status, Aszites, Tumorrest nach primärer Debulkingoperation) benötigt werden. HE4 stellte zusammen mit der Platinsensitivität der ersten Chemotherapie die einzigen unabhängigen prognostischen Faktoren für das Gesamtüberleben dar. Diese Daten stellen die Grundlage für weitere Validierungs- und Entwicklungsstudien hinsichtlich eines personalisierten Managements von Patientinnen mit Ovarialkarzinom dar

Immunoglobulin G Subclass-Specific Glycosylation Changes in Primary Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) was previously shown to be associated with glycosylation changes of total serum and total IgG proteins. However, as a majority of previous studies analyzed released glycan profiles, still little is known about IgG subclass-specific alterations in ovarian cancer. Hence, in this study, we investigated EOC-related glycosylation changes of the three most abundant IgG subclasses, namely, IgG1, IgG2 and IgG3 isolated from sera of 87 EOC patients and 74 age-matched healthy controls. In order to separate IgG2 and IgG3, we performed a two-step affinity purification employing Protein A and Protein G Sepharose. After tryptic digestion, IgG glycopeptides were enriched and measured by MALDI-TOF-MS. Finally, EOC-related glycosylation changes were monitored at the level of total agalactosylation, monogalactosylation, digalactosylation, sialylation, bisection and fucosylation, which were calculated separately for each IgG subclass. Interestingly, aside from an EOC-related increase in agalactosylation/decrease in monogalactosylation and digalactosylation observed in all IgG subclasses, some subclass-specific trends were detected. Glycosylation of IgG1 was found to be most strongly affected in EOC, as it exhibited the highest number of significant differences between healthy controls and EOC patients. Specifically, IgG1 was the only subclass that showed a significant decrease in sialylation and a significant increase in fucosylation in EOC patients. Interestingly, IgG2 and IgG3 that were often investigated collectively in previous studies, were found to have distinct glycosylation patterns. IgG3 displayed stronger EOC-related increase in agalactosylation/decrease in digalactosylation and was characterized by notably higher sialylation, which consequently decreased in EOC patients. In conclusion, our study indicates that IgG subclasses exhibit subtly distinct glycosylation patterns of EOC-related alterations and that IgG1 and IgG3 agalactosylation show the strongest association with CA125, the routine diagnostic marker. Additionally, our results show that simultaneous analyses of IgG2 and IgG3 might lead to wrong conclusions as these two subclasses exhibit noticeably different glycosylation phenotypes

Prevalence of human papillomavirus detection in ovarian cancer: a meta-analysis

We conducted a meta-analysis of published data to update and estimate the prevalence of HPV in ovarian cancer. A comprehensive literature search was performed according to the PRISMA guidelines. Eligible articles published from 1989 until 2020 by searching Web of Sciences, Pubmed, Embase, and the Cochrane Library Central databases were gathered. A pooled estimation of HPV prevalence with a 95% confidence interval (CI) was calculated based on a random effect model. Quantitative assessment of heterogeneity was explored using Cochrane test and I-2. Additionally, publication bias, sensitivity, meta-regression, and subgroup analyses were also performed. Twenty-nine studies involving 2280 patients with ovarian cancer were included. The statistical heterogeneity was high (I-2 = 88%, P<0.0001). The pooled prevalence of HPV in ovarian cancer cases was 15.9% (95% CI, 11-22). In subgroup analyses, the highest prevalence of HPV was reported by studies from Asia (30.9%; 95% CI, 20-44) and Eastern Europe (29.3%; 95% CI, 4.4-78). Furthermore, the most frequently detected HPV genotype was HPV16 (54%; 95% CI, 27.9-55), followed by HPV18 (23.2%; 95% CI, 18.8-28.2). Our meta-analysis suggests a great difference in the prevalence of HPV detected in ovarian cancer by different studies, which is not seen in strongly HPV-associated cancers such as cervical cancer. However, the prevalence varied markedly by geographic region. Considering the substantial heterogeneity found, more studies with control groups and precise assays measuring HPV mRNA expression are needed to further evaluate the link and causative aetiology between HPV and ovarian cancer

Discovery and Validation of Novel Biomarkers for Detection of Epithelial Ovarian Cancer

Detection of epithelial ovarian cancer (EOC) poses a critical medical challenge. However, novel biomarkers for diagnosis remain to be discovered. Therefore, innovative approaches are of the utmost importance for patient outcome. Here, we present a concept for blood-based biomarker discovery, investigating both epithelial and specifically stromal compartments, which have been neglected in search for novel candidates. We queried gene expression profiles of EOC including microdissected epithelium and adjacent stroma from benign and malignant tumours. Genes significantly differentially expressed within either the epithelial or the stromal compartments were retrieved. The expression of genes whose products are secreted yet absent in the blood of healthy donors were validated in tissue and blood from patients with pelvic mass by NanoString analysis. Results were confirmed by the comprehensive gene expression database, CSIOVDB (Ovarian cancer database of Cancer Science Institute Singapore). The top 25% of candidate genes were explored for their biomarker potential, and twelve were able to discriminate between benign and malignant tumours on transcript levels (p < 0.05). Among them T-cell differentiation protein myelin and lymphocyte (MAL), aurora kinase A (AURKA), stroma-derived candidates versican (VCAN), and syndecan-3 (SDC), which performed significantly better than the recently reported biomarker fibroblast growth factor 18 (FGF18) to discern malignant from benign conditions. Furthermore, elevated MAL and AURKA expression levels correlated significantly with a poor prognosis. We identified promising novel candidates and found the stroma of EOC to be a suitable compartment for biomarker discovery

High-grade ovarian serous carcinoma patients exhibit profound alterations in lipid metabolism

Ovarian cancer is a very severe type of disease with poor prognosis. Treatment of ovarian cancer is challenging because of the lack of tests for early detection and effective therapeutic targets. Thus, new biomarkers are needed for both diagnostics and better understanding of the cellular processes of the disease. Small molecules, consisting of metabolites or lipids, have shown emerging potential for ovarian cancer diagnostics. Here we performed comprehensive lipidomic profiling of serum and tumor tissue samples from high-grade serous ovarian cancer patients to find lipids that were altered due to cancer and also associated with progression of the disease. Ovarian cancer patients exhibited an overall reduction of most lipid classes in their serum as compared to a control group. Despite the overall reduction, there were also specific lipids showing elevation, and especially alterations in ceramide and triacylglycerol lipid species were dependent on their fatty acyl side chain composition. Several lipids showed progressive alterations in patients with more advanced disease and poorer overall survival, and outperformed CA-125 as prognostic markers. The abundance of many serum lipids correlated with their abundance in tumor tissue samples. Furthermore, we found a negative correlation of serum lipids with 3-hydroxybutyric acid, suggesting an association between decreased lipid levels and fatty acid oxidation. In conclusion, here we present a comprehensive analysis of lipid metabolism alterations in ovarian cancer patients, with clinical implications.Peer reviewe

Deregulation of hydroxybutyric acid metabolism provides diagnostic and prognostic biomarkers in ovarian high-grade serous carcinomas

Ovarian cancer is a heterogeneous disease of low prevalence but poor survival. Early diagnosis is critical for patients’ survival but often challenging because ovarian cancer symptoms are unclear and appear only in advanced stages of the disease. Finding more robust disease markers is therefore a clinical priority. Metabolomics is an emerging diagnostic tool that enables the detection of biomarkers reflecting alterations of tumor metabolism, a hallmark of cancer. We performed metabolomics profiling of serum and tumor tissue of high grade serous ovarian cancer (HGSOC) patients, and report novel diagnostic and prognostic biomarkers which indicate deregulation of hydroxybutyric acid (HBA) metabolism. The accumulation of HBA metabolites was associated with lower expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal-transition (EMT) gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our work reports the first comprehensive metabolomic investigation of HGSOC and proposes a new set of metabolites that can be used as diagnostic and prognostic biomarkers of the disease.This work was supported by the Academy of Finland post-doctoral fellow grants: MH decision 138201 and PG 265966. TA was supported by Academy of Finland (grants 272437, 269862, 279163, 292611) and Cancer Society of Finland. EIA is participant in the Charité Clinical Scientist Program funded by the Charité Universitätsmedizin Berlin and the Berlin Institute of Health

Efficacy of individualised starting dose (isd) and fixed starting dose (fsd) of niraparib per investigator assessment (ia) in newly diagnosed advanced ovarian cancer (oc) patients

Niraparib is a poly(ADP-ribose) polymerase inhibitor approved for maintenance treatment of patients with newly diagnosed or recurrent OC that responded to platinumbased chemotherapy and treatment in heavily-pretreated recurrent OC. Here we report efficacy in patients receiving the FSD and ISD in the PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016)

HE4 as a serum biomarker for the diagnosis of pelvic masses: a prospective, multicenter study in 965 patients

Background: To evaluate the diagnostic value of adding human epididymis protein 4 (HE4), cancer antigen 125 (CA125) and risk of malignancy algorithm (ROMA) to ultrasound for detecting ovarian cancer in patients with a pelvic mass. Methods: This was a prospective, observational, multicenter study. Patients aged > 18 years who were scheduled to undergo surgery for a suspicious pelvic mass had CA125 and HE4 levels measured prior to surgery, in addition to a routine transvaginal ultrasound scan. The diagnostic performance of CA125, HE4 and ROMA for distinguishing between benign and malignant adnexal masses was assessed using receiver operating characteristic (ROC) analysis and the corresponding area under the curve (AUC). Results: Of 965 evaluable patients, 804 were diagnosed with benign tumors and 161 were diagnosed with ovarian cancer. In late-stage ovarian cancer, CA125, HE4 and ROMA all had an excellent diagnostic performance (AUC > 0.92), whereas in stage I and II, diagnostic performance of all three biomarkers was less adequate (AUC < 0.77). In the differential diagnosis of ovarian cancer and endometriosis, ROMA and HE4 performed better than CA125 with 99 and 98.1% versus 75.0% sensitivity, respectively, at 75.4% specificity. Conclusions: ROMA and HE4 could be valuable biomarkers to help with the diagnosis of ovarian cancer in premenopausal patients in order to differentiate from endometriosis, whereas CA125 may be more adequate for postmenopausal patients

Exploring the clonal evolution of CD133/aldehyde-dehydrogenase-1 (ALDH1)-positive cancer stem-like cells from primary to recurrent high-grade serous ovarian cancer (HGSOC). A study of the Ovarian Cancer Therapy–Innovative Models Prolong Survival (OCTIPS) Consortium

Background High-grade serous ovarian cancer (HGSOC) causes 80% of all ovarian cancer (OC) deaths. In this setting, the role of cancer stem-like cells (CSCs) is still unclear. In particular, the evolution of CSC biomarkers from primary (pOC) to recurrent (rOC) HGSOCs is unknown. Aim of this study was to investigate changes in CD133 and aldehyde dehydrogenase-1 (ALDH1) CSC biomarker expression in pOC and rOC HGSOCs. Methods Two-hundred and twenty-four pOC and rOC intrapatient paired tissue samples derived from 112 HGSOC patients were evaluated for CD133 and ALDH1 expression using immunohistochemistry (IHC); pOCs and rOCs were compared for CD133 and/or ALDH1 levels. Expression profiles were also correlated with patients' clinicopathological and survival data. Results Some 49.1% of the patient population (55/112) and 37.5% (42/112) pOCs were CD133+ and ALDH1+ respectively. CD133+ and ALDH1+ samples were detected in 33.9% (38/112) and 36.6% (41/112) rOCs. CD133/ALDH1 coexpression was observed in 23.2% (26/112) and 15.2% (17/112) of pOCs and rOCs respectively. Pairwise analysis showed a significant shift of CD133 staining from higher (pOCs) to lower expression levels (rOCs) (p < 0.0001). Furthermore, all CD133 + pOC patients were International Federation of Gynaecology and Obstetrics (FIGO)-stage III/IV (p < 0.0001) and had significantly worse progression-free interval (PFI) (p = 0.04) and overall survival (OS) (p = 0.02). On multivariate analysis, CD133/ALDH1 coexpression in pOCs was identified as independent prognostic factor for PFI (HR: 1.64; 95% CI: 1.03–2.60; p = 0.036) and OS (HR: 1.71; 95% CI: 1.01–2.88; p = 0.045). Analysis on 52 pts patients with known somatic BRCA status revealed that BRCA mutations did not influence CSC biomarker expression. Conclusions The study showed that CD133/ALDH1 expression impacts HGSOC patients' survival and first suggests that CSCs might undergo phenotypic change during the disease course similarly to non stem-like cancer cells, providing also a first evidence that there is no correlation between CSCs and BRCA status

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

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