Survival In Ovarian Carcinoma Research Articles

High density of CXCL12-positive immune cell infiltration predicts chemosensitivity and recurrence-free survival in ovarian carcinoma

BackgroundOvarian carcinoma is the most lethal gynecologic malignancy because of its late diagnosis, extremely high recurrence rate, and limited curative treatment options. In clinical practice, high-grade serous carcinoma (HGSC) predominates due to its frequency, high aggressiveness, and rapid development of drug resistance. Recent evidence suggests that CXCL12 is an important immunological factor in ovarian cancer progression. Therefore, we investigated the predictive and prognostic significance of the expression of this chemokine in tumor and immune cells in patients with HGSC.MethodsWe studied a cohort of 47 primary high-grade serous ovarian carcinomas and their associated recurrences. A tissue microarray was constructed to evaluate the CXCL12 immunostained tumor tissue. CXCL12 expression was evaluated and statistically analyzed to correlate clinicopathologic data, overall survival, and recurrence-free survival.ResultsA high proportion of CXCL12 + positive immune cells in primary ovarian serous carcinoma correlated significantly with chemosensitivity (p = 0.005), overall survival (p = 0.021), and longer recurrence-free survival (p = 0.038). In recurrent disease, high expression of CXCL12 was also correlated with better overall survival (p = 0.040). Univariate and multivariate analysis revealed that high CXCL12 + tumor-infiltrating immune cells (TICs) (HR 0.99, p = 0.042, HR 0.99, p = 0.023, respectively) and combined CXCL12 + /CD66b + infiltration (HR 0.15, p = 0.001, HR 0.13, p = 0.001, respectively) are independent favorable predictive markers for recurrence-free survival.ConclusionA high density of CXCL12 + TICs predicts a good response to chemotherapy, leading to a better overall survival and a longer recurrence-free interval. Moreover, with concomitant high CXCL12/CD66b TIC density, it is an independent favorable predictor of recurrence-free survival in patients with ovarian carcinoma.

P53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR]=2.18, 95% confidence interval [CI] 1.36-3.47, p=0.0011) and with CCC (HR=1.57, 95% CI 1.11-2.22, p=0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Profile of HER2/neu Expression in Surface Epithelial Ovarian Tumours: A Clinicomorphological Study

Introduction: Surface Epithelial Ovarian Tumours (SEOT) are most prevalent tumours and account for about two third of all ovarian cancers. Survival of ovarian carcinoma is poor despite optimal surgical and chemotherapeutic management. Evaluation of new diagnostic and prognostic Immunohistochemical (IHC) markers will be essential in this aspect. Aim: To evaluate quantitatively the profile of Human Epidermal growth factor Receptor 2 (HER2)/neu IHC expression with standard scoring system in SEOTs and their association with various clinicpathologic variables (age, laterality, CA 125 levels, histological subtype and FIGO staging). Materials and Methods: The present ambispective study was done in the Department of Pathology, SRM Medical College Hospital and Research Centre, Kattankulathur, Tamil Nadu, India, from August 2020 to August 2022 with a sample size of 166 cases. All the histopathological samples of SEOT during the study period from August 2020 to August 2022 (prospective) and all borderline, malignant and few benign cases from June 2016 to August 2020 (retrospective) were also included in the study. Cases for which slides and blocks were not available and patient treated with neo adjuvant chemotherapy or radiotherapy were excluded in the study. For prospective cases after getting clinical history and Cancer Antigen 125 (CA 125) level, specimens were fixed, processed and Haematoxylin and Eosin (H&E), IHC staining was done as per standard lab protocol, for retrospective cases clinical history, CA 125 levels, pathological diagnosis and tissue blocks were retrieved, IHC performed and finally both prospective and retrospective cases HER2/neu IHC expression association was studied related to clinicopathological parameters. Results: Out of total sample, SEOT was the most common (n=184, 76.98%) tumour cases, followed by germ cell tumours (n=42, 17.57%) cases and least common was sex cord stromal tumour (n=13, 5.43%). HER2/neu had higher IHC expression in malignant tumours and showed statistically significant positive association with age (p-value=0.001), CA 125 level (p-value0.001), and histological diagnosis (p-value <0.001), but there is no significant association with size of tumour (p-value=0.786), parity (p-value=0.717), laterality (p-value=0.514) and the International Federation of Gynecology and Obstetrics (FIGO) grading (p-value=0.274). Conclusion: Malignant tumours had high HER2/neu IHC expression, thus emphasising its carcinogenic role and helps in the diagnostic differentiation of benign and borderline tumours with malignant potential from actual malignant tumours and can be a therapeutic target in future.

Does Timing of Treatment Have an Effect on Survival in Ovarian Carcinoma?

Background and Purpose: Optimal cytoreduction (CRS) is the main treatment modality in epithelial ovarian cancer (OC). Inoperable OC at the time of diagnosis may become eligible for CRS after neoadjuvant chemotherapy (NACT). We aimed to investigate the effect of the time between NACT-CRS and CRS-adjuvant chemotherapy on survival in OC patients.
 Materials and Methods: Demographic and clinicopathological characteristics of sixty-nine patients with OC who underwent CRS after NACT between December 2009 and May 2020 were analyzed retrospectively.
 Results: The median age was 61.1, and the median overall survival (OS) was 75.8 months. The median time from the end of NACT to CRS was 6.53 weeks, and the median time from CRS to initiation of adjuvant therapy was 4.8 weeks. The mean OS was 123.4 months in patients with a NACT-CRS interval of 6.53 weeks or less, and it was 61.6 months in patients above this period (p>0.05). The OS was 75.7 months in patients with an interval between CRS and adjuvant therapy of 4.8 weeks or less and 55.1 months compared to those with 4.8 weeks or more (p>0.05). 
 Conclusion: It was shown numerically, although not statistically significant, that a long time between NACT and CRS and CRS-adjuvant therapy had a negative effect on OS.

Impact of substage and histologic type in stage I ovarian carcinoma survival: a multicenter retrospective observational study

ObjectiveThis international study aimed to investigate the impact of substage, histological type and other prognostic factors on long-term survival for stage I ovarian carcinoma.MethodsOur study was a retrospective multicenter cohort...

Arachidonic acid, a clinically adverse mediator in the ovarian cancer microenvironment, impairs JAK‐STAT signaling in macrophages by perturbing lipid raft structures

Survival of ovarian carcinoma is associated with the abundance of immunosuppressed CD163highCD206high tumor‐associated macrophages (TAMs) and high levels of arachidonic acid (AA) in the tumor microenvironment. Here, we show that both associations are functionally linked. Transcriptional profiling revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine‐triggered signaling, mirrored by an impaired transcriptional response to interferons and IL‐6 in monocyte‐derived macrophages by AA. This inhibition of pro‐inflammatory signaling is caused by dysfunctions of the cognate receptors, indicated by the inhibition of JAK1, JAK2, STAT1, and STAT3 phosphorylation, and by the displacement of the interferon receptor IFNAR1, STAT1 and other immune‐regulatory proteins from lipid rafts. AA exposure led to a dramatic accumulation of free AA in lipid rafts, which appears to be mechanistically crucial, as the inhibition of its incorporation into phospholipids did not affect the AA‐mediated interference with STAT1 phosphorylation. Inhibition of interferon‐triggered STAT1 phosphorylation by AA was reversed by water‐soluble cholesterol, known to prevent the perturbation of lipid raft structure by AA. These findings suggest that the pharmacologic restoration of lipid raft functions in TAMs may contribute to the development new therapeutic approaches.

Survival in Advanced Epithelial Ovarian Cancer Associated with Cardiovascular Comorbidities and Type 2 Diabetes Mellitus.

Background: Ovarian carcinoma (OC) is usually diagnosed at an advanced stage, necessitating a multimodal approach that includes surgery and systemic therapy. The incidence of OC is approximately five times higher in women over 65 years of age. Cardiovascular comorbidities and type 2 diabetes mellitus, both prevalent at this age, can influence therapeutic strategy and have an adverse effect on survival. Objectives: Our study aimed to determine the impact of cardiovascular diseases and diabetes mellitus on survival in advanced ovarian cancer. Materials and methods: From 2004 to 2012, we retrospectively studied 104 patients with advanced epithelial ovarian cancer (FIGO stage II–IV) who underwent surgical treatment at the Gynecology Clinic, St. Anna University Hospital, Varna, Bulgaria. Patients were followed for an average of 90 (52–129) months. We divided the study population into two groups: those with concurrent cardiovascular diseases and type 2 diabetes mellitus (CVD) and those without these comorbidities (No-CVD group). Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were compared between groups using Kaplan–Meier survival analysis. Cardiovascular comorbidities and diabetes mellitus were evaluated for their prognostic value for survival using multivariate Cox proportional regression analysis adjusted for age, stage of OC, grade and histological type of the tumor, ascites presence, residual tumor size (RT), performance status, and type of hysterectomy. Results: The Kaplan–Meier analysis showed reduced OS and DSS in the CVD group compared to the No-CVD group. The median OS was 24.5 months (95% CI 18.38 months) and 38 months (95% CI 26, not reached), respectively (Log-rank p = 0.045). The median DSS was 25.5 months (95% CI 19.39 months) and 48 months (95% CI 28, not reached), respectively (Log-rank p = 0.033). The Cox regression multivariate analysis established a lower (by 68%) overall survival rate for the CVD patient group than the No-CVD group, approaching statistical significance (HR 1.68, 95% CI 0.99, 2.86, p = 0.055). Cardiovascular diseases and diabetes were associated with a 79% reduction in DSS (HR 1.79, 95% CI 1.02, 3.13, p = 0.041) and a twofold increase in the risk of disease progression (HR 2.05, 95% CI 1.25, 3.37, p = 0.005). Conclusions: According to our study, cardiovascular comorbidities and diabetes may adversely affect OC survival. Optimal control of cardiovascular diseases, diabetes mellitus, and their risk factors may be beneficial for patients with advanced OC. Further research involving a larger patient population is necessary to establish these comorbidities as independent prognostic factors.

Ferroptosis-Related Gene Model to Predict Overall Survival of Ovarian Carcinoma.

Background Ovarian cancer (OC) is the eighth most common cause of cancer death and the second cause of gynecologic cancer death in women around the world. Ferroptosis, an iron-dependent regulated cell death, plays a vital role in the development of many cancers. Applying expression of ferroptosis-related gene to forecast the cancer progression is helpful for cancer treatment. However, the relationship between ferroptosis-related genes and OC patient prognosis is still vastly unknown, making it still a challenge for developing ferroptosis therapy for OC. Methods The Cancer Genome Atlas (TCGA) data of OC were obtained and the datasets were randomly divided into training and test datasets. A novel ferroptosis-related gene signature associated with overall survival (OS) was constructed according to the training cohort. The test dataset and ICGC dataset were used to validate this signature. Results We constructed a model containing nine ferroptosis-related genes, namely, LPCAT3, ACSL3, CRYAB, PTGS2, ALOX12, HSBP1, SLC1A5, SLC7A11, and ZEB1, and predicted the OS of OC in TCGA. At a suitable cutoff, patients were divided into low risk and high risk groups. The OS curves of the two groups of patients had significant differences, and the time-dependent receiver operating characteristics (ROCs) were as high as 0.664, respectively. Then, the test dataset and the ICGC dataset were used to evaluate our model, and the ROCs of test dataset were 0.667 and 0.777, respectively. In addition, functional analysis and correlation analysis showed that immune-related pathways were significantly enriched. Meanwhile, we also integrated with other clinical factors and we found the synthesized clinical factors and ferroptosis-related gene signature improved prognostic accuracy relative to the ferroptosis-related gene signature alone. Conclusion The ferroptosis-related gene signature could predict the OS of OC patients and improve therapeutic decision-making.

Patterns of clinicopathological features and outcome in epithelial ovarian cancer patients: 35 years of prospectively collected data.

Investigate the clinical landscape of ovarian carcinoma (OC) over time. Register-based prospectively collected data. South East Scotland. A total of 2805 OC patients diagnosed in 1981-2015. Survival times were visualised using the Kaplan-Meier method; median survival, 5-year survival probabilities and associated restricted mean survival time analyses were used to quantify survival differences. Disease-specific survival. A significant increase in disease-specific survival (DSS) from 1981-1985 to 2011-2015 was observed (median 1.73 versus 4.23years, P<0.0001). Corresponding increase in progression-free survival (PFS) was not statistically significant (median 1.22 versus 1.58years, P=0.2568). An increase in the proportion of cases with low residual disease volume (RD) (<2cm RD) following debulking was observed (54.0% versus 87.7%, P<0.0001). The proportion of high grade serous (HGS) cases increased (P<0.0001), whereas endometrioid and mucinous cases decreased (P=0.0005 and P=0.0002). Increases in stage IV HGS OCincidence (P=0.0009) and stage IV HGSOC DSS (P=0.0122) were observed. Increasing median age at diagnosis correlated with increasing Eastern Cooperative Oncology Group Performance Status (ECOG PS) over time (r=0.86). OC DSS has improved over the last 35years. PFS has not significantly increased, highlighting that improvement in outcome has been limited to extending post-relapse survival. Distribution of stage at diagnosis, histological subtype and RD following debulking has changed over time, reflecting evolution in tumour classification, staging and optimal debulking definitions (from low RD to minimal or zero RD). Histology, stage, RD and ECOG PS remain reliable outcome predictors. Increasing median age at diagnosis and ECOG PS indicates demographic shifts in the clinical population. Significant improvement in ovarian carcinoma survival has been seen over time. Most of this improvement is due to an extension of survival following disease relapse.

Subcellular localization of FANCD2 is associated with survival in ovarian carcinoma.

Objective: Ovarian cancer is a leading cause of death from gynecological cancers. Late diagnosis and resistance to therapy results in mortality and effective screening is required for early diagnosis and better treatments. Expression of the Fanconi Anemia complementation group D2 protein (FANCD2) is reduced in ovarian surface epithelial cells (OSE) in patients with ovarian cancer. FANCD2 has been studied for its role in DNA repair; however multiple studies have suggested that FANCD2 has a role outside the nucleus. We sought to determine whether subcellular localization of FANCD2 correlates with patient outcome in ovarian cancer.Methods: We examined the subcellular localization of FANCD2 in primary OSE cells from consenting patients with ovarian cancer or a normal ovary. Ovarian tissue microarray was stained with anti-FANCD2 antibody by immunohistochemistry and the correlation of FANCD2 localization with patient outcomes was assessed. FANCD2 binding partners were identified by immunoprecipitation of cytoplasmic FANCD2.Results: Nuclear and cytoplasmic localization of FANCD2 was observed in OSEs from both normal and ovarian cancer patients. Patients with cytoplasmic localization of FANCD2 (cFANCD2) experienced significantly longer median survival time (50 months), versus patients without cytoplasmic localization of FANCD2 (38 months; p < 0.05). Cytoplasmic FANCD2 was found to bind proteins involved in the innate immune system, cellular response to heat stress, amyloid fiber formation and estrogen mediated signaling.Conclusions: Our results suggest that the presence of cytoplasmic FANCD2 modulates FANCD2 activity resulting in better survival outcome in ovarian cancer patients.

Overexpression of SLC12A5 is associated with tumor progression and poor survival in ovarian carcinoma

IntroductionThe solute carrier family 12 member 5 (SLC12A5) gene is playing a putative oncogenic role in colorectal carcinoma. However, the status of SLC12A5 amplification and expression in ovarian carcinoma and...

Abstract 3038: Implication of DYRK1B Kinase in ovarian cancers and utilization of DYRK1B Inhibitors as a novel therapeutic strategy for ovarian cancer

Abstract Majority of tumors consist of two populations of cancer cells: actively proliferating and those in the reversible dormant or quiescent state, which contribute to the resistance of human tumors to chemotherapies. Conventional chemotherapeutic agents have limited efficacy in ovarian adenocarcinoma patients: while the appropriate chemotherapeutic agent kills proliferating cancer cells, dormant cancer cells survive the treatments and result in recurrent disease. The presence of dormant cancer cells is not revealed by standard H&amp;E staining and morphological tumor analysis. CDK inhibitor p27 is known to be a marker of the dormant state. DYRK1B kinase (serine/threonine-protein kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1B) is associated with survival of many types of cancers and was shown to play a key role in maintaining the cancer cells in quiescent state by stabilizing p27 and by inducing the breakdown of cyclin D isoforms. In this study, we investigated the functional and therapeutic relevance of DYRK1B in ovarian carcinomas. We have conducted an immunohistochemical study of 70 human ovarian tumors (35 primary/treatment-naive and 35 recurrent/standard chemotherapy resistant ones) and 20+ cases of normal and benign ovarian tissues for expression of DYRK1B, p27 and Ki-67. All FFPE tissue samples have been obtained from the consented patients and under the IRB-approved protocols clinical network, groups have been normalized for age and the disease type/stage. High levels of DYRK1B and p27 proteins expression in malignant treatment-naïve tumors and their significant correlation indicates the presence of dormant cancer cells mixed up with the proliferating ones within patient’s tumors. This effect was detected regardless of the tumor histological subtype (endometrial, serous, mucinous, etc.) and/or stage. While all advanced stage tumors (Stage IIIC and IV) overexpress both markers of dormancy; the early stage tumors (Stage I-II) also presented a higher number of cases with greatly positive scores. Tissue microarray and immunohistochemistry analysis in the literature showed that higher expression levels of DYRK1B correlated with a worse prognosis. We suggest that specific immunostaining of DYRK1B in tumor and endothelial cells can be explored as a predictive risk factor of time to progression/death in patients with primary ovarian tumors. Inhibition of DYRK1B kinase activity with FX9847, specific and selective DYRK1B inhibitor, inhibited ovarian cancer cell growth and induced apoptosis. Moreover, combination of FX9847 with chemotherapeutic agents such as taxanes or vinca alkaloids demonstrated an increased anti-cancer effect on ovarian cancer cells. Together, these findings suggest that DYRK1B is critically involved in the survival of ovarian carcinoma providing a new rationale for their treatment with the kinase inhibitors. Citation Format: Alexandra Kuznetsova, Arianna Damiani, Lita De Leon, Michael Frid, Menelik Duey, Jason Law, Olga Potapova, Maria Vilenchik. Implication of DYRK1B Kinase in ovarian cancers and utilization of DYRK1B Inhibitors as a novel therapeutic strategy for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3038.

Lymphocyte-specific protein tyrosine kinase expression predicts survival in ovarian high-grade serous carcinoma

Objective: Cellular immune response, specifically tumor-infiltrating lymphocytes (TILs), correlates with survival in ovarian carcinoma; however, specific gene expression patterns for this response remain poorly understood. Our objective was to evaluate the impact of a subset of immune-related gene expression on prognosis ovarian high-grade serous carcinoma (OHGSC), with a focus on lymphocyte specific kinase (LCK). Prognostic value of LCK status was compared to the previously validated metric of cytolytic activity score (CYT).

Targeted blockade of HSP90 impairs DNA-damage response proteins and increases the sensitivity of ovarian carcinoma cells to PARP inhibition

ABSTRACTPharmacological inhibition of PARP is a promising approach in treating high grade serous ovarian carcinoma (HGSOC). PARP inhibitors (PARPi) are most active in patients with defects in DNA damage repair (DDR) mechanisms, such as alterations in expression/function of DNA repair and homologous recombination (HR) genes/proteins, including BRCA1 and BRCA2. Benefit of PARPi could be extended towards HR-proficient patients by combining PARPi with agents that functionally abrogate HR. An attractive molecular target for this purpose is heat shock protein 90 (HSP90), which mediates the maturation and stability of several key proteins required for DDR. Here, we tested the hypothesis that targeted inhibition of HSP90 with a small-molecule inhibitor ganetespib would sensitize non-BRCA mutant ovarian carcinoma (OC) cells to PARP inhibition by talazoparib. We used commercially available cell lines, along with several novel HGSOC OC cell lines established in our laboratory. Ganetespib treatment destabilized HSP90 client proteins involved in DNA damage response and cell cycle checkpoint, and disrupted γ-irradiation-induced DNA repair. The effects of the combination of ganetespib and talazoparib on OC cell viability and survival were also analyzed, and among the non-BRCA mutant cell lines analyzed, the combination was synergistic in several cell lines (OVCAR-3, OC-1, OC-16). Together, our data suggest that ganetespib-mediated inhibition of HSP90 effectively disrupts critical DDR pathway proteins and may sensitize OC cells without ‘BRCAness’ to PARPi. From a clinical perspective, this suggests that HSP90 inhibition has the potential to sensitize some HGSOC patients without HR pathway alterations to PARPi, and potentially other DNA-damage inducing agents.

Comparative surgical resection of the ligamentum teres hepatis in a cadaveric model and a patient with ovarian cancer

Resection of all tumor implants with the aim of maximal cytoreduction is the main predictor of overall survival in ovarian carcinoma. However, there are high risk sites of tumor recurrence, and the perihepatic region, especially the point where the ligamentum teres hepatis enters the liver parenchyma under the hepatic bridge (pont hepatique), is one of them. This video demonstrates the resection of the ligamentum teres hepatis both in a cadaveric model and in a patient with ovarian cancer.

Tumor infiltrating lymphocytes and homologous recombination deficiency are independently associated with improved survival in ovarian carcinoma

ObjectiveThe presence of tumor infiltrating lymphocytes (TIL) and defects in homologous recombination (HR) are each important prognostic factors in ovarian carcinoma (OC). We characterized the association between HR deficiency (HRD) and the presence of TILs in a cohort of OC patients and the relative contribution to overall survival. MethodsPatients with carcinoma of the ovary, fallopian tube, or peritoneum were prospectively enrolled. Malignant neoplasm and serum samples were collected. Immunohistochemistry for CD3+ T cells and CD68+ tumor associated macrophages (TAMs) was performed on specimens collected at primary surgery. Damaging germline and somatic mutations in genes in the HR-mediated repair (HRR) pathway were identified using BROCA sequencing. HRD was defined as a damaging mutation in one of 12 genes in the HRR pathway or promoter hypermethylation in BRCA1 or RAD51C. ResultsNinety-eight of 250 patients included in the analysis had HRD OC (39.2%). HRD OC were enriched for CD3+ TILs and CD68+ TAMs. High CD3+ TIL was present in 65.3% of HRD OC compared to 43.4% of non-HRD OC (P = 0.001). High CD68+ TAM was present in 66.3% of HRD OC compared to 50.7% of non-HRD OC (P = 0.015). Patients with HRD OC and high CD3+ TILs had the longest median overall survival compared to non-HRD OC with low CD3+ TILs (70.9 vs. 35.8 months, adjusted HR 0.38, 95% CI (0.25–0.59)). ConclusionsPatients that have both CD3+ TILs and HRD OC are afforded the greatest improvement in overall survival. This finding may have therapeutic implications for OC patients treated with emerging immunotherapies.

Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma.

Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion, and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth. Cancer Res; 77(17); 4589-601. ©2017 AACR.

Abstract AP28: BRCA1 and RAD51C Promoter Hypermethylation Confer Sensitivity to PARP Inhibitors in Patients with Platinum Sensitive Ovarian Carcinoma

Abstract Germline and somatic mutations in BRCA1 and BRCA2 (BRCA) confer PARP inhibitor sensitivity. Promoter hypermethylation is an alternate mechanism of gene down-regulation, and BRCA1 promoter methylation is relatively common in sporadic ovarian cancer. The clinical significance of BRCA1 methylation is less clear than for mutations, as the Cancer Genome Atlas (TCGA) and others have failed to show improved survival in ovarian carcinomas with BRCA1 methylation. No one has previously tested whether BRCA1 methylation confers in vivo sensitivity to PARP inhibitors in patients with ovarian cancer. ARIEL2 is a phase 2 study of the PARP inhibitor rucaparib in patients with recurrent platinum sensitive high-grade ovarian, peritoneal or fallopian tube carcinoma. At enrollment, ARIEL2 required pre-treatment tumor biopsies with the goal of developing tissue predictors of PARP inhibitor sensitivity other than BRCA mutations. The number of women with known germline mutations was capped at 15 patients in order to predominantly enroll BRCA wildtype cases. As presented at ASCO 2016, in cases with no BRCA mutations, a high fraction of genomic loss of heterozygosity (LOH) significantly predicted a better progression-free survival (the primary endpoint), longer duration of response, and a higher fraction of responders compared to cases with low LOH. We assessed BRCA1 and RAD51C promoter hypermethylation using methylation-sensitive polymerase chain reaction in paired archival and pre-treatment biopsies from patients on ARIEL2. Of 165 cases for which methylation analyses were completed, 21 (12.7%) were methylated at the BRCA1 promoter and four (2.4%) at the RAD51C promoter. Methylation of BRCA1 and RAD51C was mutually exclusive with mutation in BRCA or other homologous recombination genes. All four cases with RAD51C methylation and 15/19 (78.9%) with BRCA1 methylation were associated with high LOH. In 90 paired samples archival and pre-treatment tissues, RAD51C methylation was 100% concordant and BRCA1 methylation was highly concordant (p&amp;lt;0·001). For 13 cases with BRCA1 methylation in the archival specimen, 4 (30·8%) were unmethylated in the paired pretreatment tumor, but for 77 unmethylated archival specimens, gain of methylation in the pretreatment biopsy was observed just once. Confirmed RECIST responses were seen in 52.4% (11/21) BRCA1 methylated and 75.0% (3/4) RAD51C methylated cases. In conclusion, BRCA1 and RAD51C methylation in ovarian carcinomas correlates with a high response rate to PARP inhibitors. If methylation was to be used as a predictor of PARP inhibitor sensitivity, it would need to be assessed in a pre-treatment (not archival) specimen. The loss of BRCA1 methylation in recurrent ovarian carcinoma, which was common even in these platinum sensitive cases, could explain why BRCA1 methylation is associated with similar survival to methylated cases, despite initial improved therapeutic sensitivity. Citation Format: Elizabeth Swisher, Maria Harrell, Kevin K. Lin, Clare Scott, Sandra Goble, Amit Oza, Robert L. Coleman, Gottfried Konecny, Anna V. Tinker, David M. O'Malley, Rebecca Kristeleit, Ling Ma, James Brenton, Katherine Bell-McGuinn, Ana Oaknin, Alexandra Leary, Elaina Mann, Heidi Giordano, Mitch Rapon, Iain McNeish, Scott H. Kaufmann. BRCA1 and RAD51C Promoter Hypermethylation Confer Sensitivity to PARP Inhibitors in Patients with Platinum Sensitive Ovarian Carcinoma [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP28.

MAP3K3 overexpression is associated with poor survival in ovarian carcinoma

Mitogen-activated protein kinase kinase kinase 3 (MAP3K3) is ubiquitously expressed in numerous tissues and is activated by various extracellular stimuli to regulate processes, such as cell proliferation and differentiation. Recent studies have identified potentially pathologic conditions of MAP3K3 as an oncogene that promotes tumor progression and metastasis in a number of malignancies. However, the clinical significance of MAP3K3 expression in ovarian carcinoma (OC) remains unclear. In this study, the correlation between MAP3K3 expression and OC prognosis was assessed by immunohistochemistry. MAP3K3 overexpression was observed in 59.1% (55/93) of OCs and was significantly associated with histological type and grade, chemotherapy response, and challenge model (P < .05, respectively). MAP3K3 overexpression was also used as an independent prognostic marker for decreased disease-free survival and overall survival. In OC cell lines, MAP3K3 expression was evaluated by Western blot analysis, quantitative real-time polymerase chain reaction, and immunofluorescence. High MAP3K3 expression is significantly detected in SKOV3, C13*, and A2780 cells. All these findings suggested that MAP3K3 overexpression is an independent poor prognostic indicator of OC and can be a clinically effective biomarker of OC.

Epithelial ovarian cancer with CD117 phenotype is highly aggressive and resistant to chemotherapy.

CD117 expression has a pathogenic role in many malignancies, including ovarian carcinoma. The aim of the present study was to examine the correlation of stemness-associated marker CD117 with the clinicopathologic features of epithelial ovarian cancer and patient survival. The analysis included 240 primary ovarian carcinomas (OC) diagnosed during the period from 2005 to 2011 in the region of South Serbia. Age, pathohistological characteristics, presence and size of residual tumor, choice of therapy and response to the therapy were studied. Residual tumors were more frequently present in the patients with positive CD117 expression (18.1% vs 8.0%; P < 0.05). Chemotherapy according to paclitaxel/carboplatin protocol was more frequent in the patients with positive CD117 expression (70.9% vs 54.2%; P < 0.05), while carboplatin monotherapy was more frequent in the patients with negative CD117 expression (18.0% vs 6.4%; P < 0.05). Median survival time in patients with CD117-positive mucinous and endometrioid OC was significantly shorter, at 20 and 26.8 months, respectively. Median survival in serous OC was not related to CD117 expression. Residual tumors and chemotherapy treatment were more frequent in patients with positive CD117 expression. The outcome was dependent on the type of OC; a worse outcome, including a shorter survival, was documented in the mucinous and endometrioid OC cases.