Evaluation of Angiogenesis-Related Genes as Prognostic Biomarkers of Bevacizumab Treated Ovarian Cancer Patients: Results from the Phase IV MITO16A/ManGO OV-2 Translational Study

Background. Epithelial ovarian cancer (EOC) is a rare, highly lethal disease. In a subset of high grade EOC patients, maintenance therapy with the antiangiogenic drug Bevacizumab (BEV) is a valuable option. To date, no validated predictive or prognostic biomarkers exist for selecting EOC patients that might benefit from BEV treatment. Methods. Immunohistochemistry and RT-qPCR evaluated the expression of seven angiogenesis-related proteins and of a twelve microRNAs angio-signature in EOC patients, treated in first line with chemotherapy plus BEV (MITO16A/ManGO OV-2 phase IV trial). Centralized statistical analyses assessed the associations between each biomarker, clinical prognostic factors and survival outcomes. Results. High miR-484 expression was associated with longer progression-free and overall survival. Notably, the combined expression of miR-484 and its target VEGFB identified a subset of patients that might mostly benefit from BEV treatment. No other significant correlations were found between the other analyzed biomarkers and patients’ survival. The application of a shrinkage procedure to adjust for over-fitting hazard ratio estimates reduced the association significance. Conclusions. The analysis of angiogenesis related biomarkers in EOC patients homogenously treated with BEV in first line provides novel insight in their prognostic value and suggests that some of them might merit to be tested as predictive markers of drug activity in dedicated randomized trials.

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Poly (ADP-ribose) polymerase inhibitors in combination with anti-angiogenic agents for the treatment of advanced ovarian cancer

Future Oncology ◽

10.2217/fon-2021-0059 ◽

2021 ◽

Author(s):

Olivia Le Saux ◽

Hélène Vanacker ◽

Fatma Guermazi ◽

Mélodie Carbonnaux ◽

Clémence Roméo ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Advanced Ovarian Cancer ◽

Cost Effective ◽

Preclinical Study ◽

The Body ◽

Synergistic Activity ◽

High Grade ◽

First Line ◽

Homologous Recombination Deficiency

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.

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Predicting STAT1 as a prognostic marker in patients with solid cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920917558 ◽

2020 ◽

Vol 12 ◽

pp. 175883592091755

Author(s):

Jinguo Zhang ◽

Fanchen Wang ◽

Fangran Liu ◽

Guoxiong Xu

Keyword(s):

Ovarian Cancer ◽

Prognostic Value ◽

Renal Carcinoma ◽

The Cancer Genome Atlas ◽

Solid Cancer ◽

Lower Grade ◽

High Grade ◽

Large Tumor ◽

Normal Tissues ◽

Tumor Types

Background: Aberrant activities of signal transducer and activator of transcription 1 (STAT1) have been implicated in cancer development. However, the prognostic value of STAT1 remains unclear. This report identified the role of STAT1 in prognosis in patients with solid cancer through open literature and The Cancer Genome Atlas (TCGA) database. Methods: Published articles were obtained from PubMed, Web of Science, and Embase databases according to a search strategy up to October 2019. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted to assess the prognostic factors of patients. TCGA datasets were used to explore the prognostic value of STAT1 in various cancers. Results: A total of 15 studies incorporating 2839 patients with solid cancers were included. Pooled data showed that overexpressed STAT1 favored long overall survival (OS) (HR = 0.604, 95% CI = 0.431–0.846, p = 0.003) and disease-specific survival (DSS) (HR = 0.650, 95% CI = 0.512–0.825, p = 0.000). In subgroup analyses, highly expressed STAT1 was correlated with long OS of patients with high-grade serous ovarian cancer and oral squamous cell carcinoma. Data extracted from TCGA datasets unveiled that STAT1 expression was significantly higher in 12 cancers (e.g. bladder and breast) than their adjacent normal tissues. Again, highly expressed STAT1 favored long OS of patients with ovarian cancer as well as rectum adenocarcinoma, sarcoma, and skin cutaneous melanoma. However, in renal carcinoma, brain lower grade glioma, lung adenocarcinoma, and pancreatic cancer, highly expressed STAT1 was correlated with poor OS of patients. Particularly in renal carcinoma, increased STAT1 expression was associated with high grade, later stage, large tumor size, and lymph node and distant metastasis. Conclusion: STAT1 has been identified to have prognostic value in patients with solid cancer. Highly expressed STAT1 may predict prognosis in cancer patients based on their tumor types.

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The Prognostic Value of PARP Expression in High-Grade Epithelial Ovarian Cancer

Pathology & Oncology Research ◽

10.1007/s12253-020-00856-6 ◽

2020 ◽

Vol 26 (4) ◽

pp. 2549-2555

Author(s):

Szabolcs Molnár ◽

Lívia Beke ◽

Gábor Méhes ◽

Róbert Póka

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Prognostic Value ◽

High Grade

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Combined Immunoscore of CD103 and CD3 Identifies Long-Term Survivors in High-Grade Serous Ovarian Cancer

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000672 ◽

2016 ◽

Vol 26 (4) ◽

pp. 671-679 ◽

Cited By ~ 28

Author(s):

Hans-Christian Bösmüller ◽

Philipp Wagner ◽

Janet Kerstin Peper ◽

Heiko Schuster ◽

Deborah Lam Pham ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Clinical Outcome ◽

Prognostic Value ◽

Intraepithelial Lymphocytes ◽

High Grade ◽

Serous Ovarian Cancer ◽

Term Survival ◽

Cell Counts

ObjectiveIncreased numbers of tumor-infiltrating lymphocytes (TILs) in high-grade serous ovarian cancer (HGSC) are associated with improved clinical outcome. Intraepithelial localization of TILs might be regulated by specific homing receptors, such as CD103, which is widely expressed by intraepithelial lymphocytes. Given the emerging role of CD103+ TILs, we aimed to assess their contribution to the prognostic value of immunoscoring in HGSC.MethodsThe density of intratumoral CD3+ and CD103+ lymphocytes was examined by immunohistochemistry on a tissue microarray of a series of 135 patients with advanced HGSC and correlated with CD4+, CD8+, CD56+, FoxP3+, and TCRγ+ T-cell counts, as well as E-cadherin staining and conventional prognostic parameters and clinical outcome.ResultsBoth the presence of CD103+ cells, as well as high numbers of intraepithelial CD3+ lymphocytes (CD3E), showed a significant correlation with overall survival, in the complete series, as well as in patients with optimal debulking and/or platinum sensitivity. Combining CD3 and CD103 counts improved prognostication and identified 3 major subgroups with respect to overall survival. The most pronounced effect was demonstrated for patients with optimally resected and platinum-sensitive tumors. Patients with CD3high/CD103high tumors showed a 5-year survival rate at 90%, CD3low/CD103high at 63%, and CD3low/CD103low at 0% (P < 0.001).ConclusionsThese results suggest that combined assessment of CD103 and CD3 counts improves the prognostic value of TIL counts in HGSC and might identify patients with early relapse or long-term survival based on the type and extent of the immune response.

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Do DWI and quantitative DCE perfusion MR have a prognostic value in high-grade serous ovarian cancer?

La radiologia medica ◽

10.1007/s11547-019-01075-z ◽

2019 ◽

Vol 124 (12) ◽

pp. 1315-1323

Author(s):

Francesca De Piano ◽

Valentina Buscarino ◽

Dulia Maresca ◽

Patrick Maisonneuve ◽

Giovanni Aletti ◽

...

Keyword(s):

Ovarian Cancer ◽

Prognostic Value ◽

High Grade ◽

Serous Ovarian Cancer ◽

Perfusion Mr

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Prognostic value of the rate of rise of CA 125 after first line chemotherapy for survival in patients with relapsed ovarian cancer

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.5544 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 5544-5544

Author(s):

V. Karavasilis ◽

K. Thomas ◽

M. Harrison ◽

P. Papadopoulos ◽

D. Barton ◽

...

Keyword(s):

Ovarian Cancer ◽

Prognostic Value ◽

Ca 125 ◽

First Line ◽

Line Chemotherapy

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Prognostic Value of Human Epidermal Growth Factor Receptor 2 (Her-2)/neu in Patients With Advanced Ovarian Cancer Treated With Platinum/Paclitaxel as First-Line Chemotherapy: A Retrospective Evaluation of the AGO-OVAR 3 Trial by the AGO OVAR Germany

International Journal of Gynecological Cancer ◽

10.1111/igc.0b013e3181991a7c ◽

2009 ◽

Vol 19 (1) ◽

pp. 109-115 ◽

Cited By ~ 7

Author(s):

Jacobus Pfisterer ◽

Andreas Du Bois ◽

Eva-Katrin Bentz ◽

Friedrich Kommoss ◽

Philipp Harter ◽

...

Keyword(s):

Ovarian Cancer ◽

Epidermal Growth Factor Receptor ◽

Prognostic Value ◽

Growth Factor Receptor ◽

Advanced Ovarian Cancer ◽

Advanced Stage ◽

First Line ◽

Her 2 ◽

Epidermal Growth ◽

Line Chemotherapy

Objectives:Results on the prognostic value of human epidermal growth factor receptor 2 (HER-2)/neu in ovarian cancer are inconsistent. This exploratory analysis evaluates Her-2/neu as a prognostic factor in a large cohort of patients with advanced-stage ovarian cancer treated with platinum/paclitaxel as first-line chemotherapy within a prospective randomized trial.Methods:Her-2/neu expression was assessed by immunohistochemistry in 359 patients (46%) treated within the AGO-OVAR 3 trial (n = 783). Patients received either cisplatin/paclitaxel or carboplatin/paclitaxel according to the study protocol. Immunohistochemistry results were scored according to the Dako score.Results:Her-2/neu Dako scores of 0 or 1+ was found in 337 patients (94%) and a score of 2+ or 3+ in 22 patients (6%). Her-2/neu overexpression (2+/3+) was associated with a higher International Federation of Gynecology and Obstetrics stage and larger postoperative residual disease. There were no significant differences in response to chemotherapy between the Her-2/neu score subgroups and in progression-free survival time. In a multivariate analysis, the Her-2/neu score had no significant impact on overall survival time.Conclusions:In the present study, Her-2/neu overexpression in patients with advanced-stage ovarian cancer was rare and provided no evidence for a prognostic value of Her-2/neu in patients with advanced ovarian cancer treated with platinum/paclitaxel.

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Prognostic value of primary tumor resection in synchronous metastatic colorectal cancer (mCRC): Individual patient data (IPD) analysis of first-line randomized trials from the ARCAD database.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.658 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 658-658

Author(s):

Miriam Koopman ◽

Qian Shi ◽

Kaitlyn K.H. Goey ◽

Erin Green ◽

Volker Heinemann ◽

...

Keyword(s):

Primary Tumor ◽

Prognostic Value ◽

Randomized Trials ◽

Performance Status ◽

Tumor Resection ◽

Primary Tumor Resection ◽

Lung Involvement ◽

First Line ◽

Resection Group ◽

Anti Vegf

658 Background: In patients (pts) with mCRC with an asymptomatic primary tumor, there is limited evidence regarding the indication for primary tumor resection. The primary objective was to evaluate the prognostic value of primary tumor resection in synchronous mCRC pts. Methods: In this IPD analysis, a total of 3,423 pts from 8 first-line randomized trials (RCTs) with systemic therapy in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analyzed. Five RCTs included targeted (anti-VEGF and/or anti-EGFR) agents. Synchronous mCRC was defined as distant metastases occurring ≤ 6 months of the initial CRC diagnosis. Overall survival (OS) and progression-free survival (PFS) were compared by stratified multivariate Cox models. Results: There were 710 (21%), 1,705 (50%) and 1,008 (29%) pts with non-resected and resected synchronous mCRC and metachronous mCRC, respectively. Compared to the non-resection group, pts in the synchronous resection group were associated with female gender, colon tumor, isolated liver/lung involvement, single metastatic site, and lower LDH (all p<.001). Adjusted for age, gender, performance status and prior chemotherapy, the non-resection group had a significantly worse median OS (16.4m) compared to the resection (22.2m; HR 1.60, 95% CI 1.43-1.78) and metachronous (22.4m; HR 1.81, 95% CI 1.58-2.07) groups. Similarly, PFS was significantly worse for the non-resection group (7.9m) compared to the resection (9.7m; HR 1.31, 95% CI 1.19-1.44) and metachronous group (8.9m; HR 1.47, 95% CI 1.30-1.66). Similar trends were observed in pts treated with non-targeted vs targeted agents, and anti-VEGF vs anti-EGFR therapy. In a subset analysis (n= 526), the observed associations remained after additional adjustment for primary tumor location, liver/lung involvement, number of metastatic sites, BMI and LDH. Conclusions: In this largest IPD analysis of mCRC trials to date, primary tumor resection is associated with better OS and PFS in synchronous mCRC pts. These results may be subject to bias since reasons for (non)resection were not available. Prospective RCTs on this topic are ongoing.

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NOGGO Ov-42/MAMOC: Rucaparib maintenance after bevacizumab maintenance following carboplatin-based first line-chemotherapy in ovarian cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps6102 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS6102-TPS6102

Author(s):

Elena Ioana Braicu ◽

Pauline Wimberger ◽

Rolf Richter ◽

Maren Keller ◽

Petra Krabisch ◽

...

Keyword(s):

Ovarian Cancer ◽

Maintenance Therapy ◽

Residual Tumor ◽

Phase Iii ◽

High Grade ◽

First Line ◽

Tumor Mass ◽

Antiangiogenic Drugs ◽

Line Chemotherapy ◽

Residual Tumor Mass

TPS6102 Background: Ovarian cancer (OC) is associated with the highest mortality rates among gynecological malignancies, with most patients being diagnosed in advanced stages. The most common histological subtype is high grade serous OC, which is characterized by deficiency in homologous recombination. Debulking surgery, followed by platinum based chemotherapy and bevacizumab (bev), followed by maintenance therapy with bev, is the standard therapy for advanced BRCA wild type (BRCAwt) OC patients in Germany. BRCA mutant patients will receive maintenance with olaparib, according to SOLO1 data. The anticancer effects of PARP inhibitors (PARPi) seem to be increased by the addition of antiangiogenic drugs. Preclinical data showed increased HRD in tumors pretreated with bev, and clinical trials showed a benefit of the combination of antiangiogenic drugs and PARPi vs. PARPi alone. NOGGO Ov-42/MAMOC trial (NCT04227522) is a phase III, randomized, placebo-controlled study evaluating rucaparib maintenance following bevacizumab maintenance for the treatment of advanced primary high grade BRCAwt OC. Methods: 190 patients with histologically confirmed advanced (FIGO stage IIIA- IV of the 2014 FIGO classification) high grade serous or high grade endometrioid (based on local histopathological findings) OC, fallopian tube cancer, primary peritoneal cancer or clear cell carcinoma of the ovary will be randomized 2:1 to receive either rucaparib 600mg BID or placebo as maintenance therapy following first line chemotherapy with 6 cycles of Carboplatin/Paclitaxel and at least 12 cycles of bev, given together with chemotherapy and as maintenance. Only BRCAwt patients will be included in the trial. Randomization is stratified by surgery planned timepoint (neoadjuvant vs. adjuvant), surgical outcome (no residual tumor mass vs. residual tumor mass), response to chemotherapy followed by bev (CR/NED vs. PR/SD) and study center. Treatment will continue for 24 months or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint is PFS in BRCAwt patients per RECIST v1.1. Secondary endpoints are PFS2, quality of life (EORTC QLQ-C30/OV28, FSI, SF-12, PROC-CTCAE, every day memory questionnaire), daily activity, time to next medical intervention, time to next subsequent therapy, safety assessments and OS. Clinical trial information: NCT04227522.

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