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Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 25241

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Dr. Francesco Plotti

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Department of Obstetrics and Gynecology, Campus Bio-Medico University of Rome, 00128 Rome, Italy
Interests: gynecology; gynecologic oncology; minimally invasive surgery; urogynecology
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In the last 10 years, the “Human Epididymis protein 4 (HE4)” marker for the management of gynecological tumors has entered powerfully in the world’s literature. The HE4 gene product is an N-glycosylated protein which is secreted into the extracellular environment and can be detected in the bloodstream of patients with ovarian cancer. Diagnostic strategies for discriminate benign neoplasm from malignant EOC use tumor markers, imaging exams, and combination algorithms. Ca125 is the best documented circulating marker and the most frequently recommended by clinical practice guidelines, despite its low specificity. To compensate for the low sensitivity of Ca125, new markers were studied: HE4 is one of the most promising; HE4 has demonstrated good sensitivity and specificity in detecting EOC, overcoming the traditional role of Ca125. In recent years, however, these markers (HE4 and Ca125) have assumed an important significance in the assessment of prognosis, follow-up, and response to chemotherapy. The current standard of care for ovarian cancer is a combination of optimal cytoreductive surgery and platinum-based chemotherapy. However, in an age when great advances have been made in understanding the genetics and molecular biology of this heterogeneous disease, the introduction of novel targeted therapies will have a major impact on ovarian cancer management. The aim of this comprehensive review is to gather all the evidence reported in literature analyzing the potential value of tumor markers in every step of the management of ovarian cancer and evaluate new possible strategies for targeting growth-dependent mechanisms involved in its pathogenesis.

Dr. Francesco Plotti
Guest Editor

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Keywords

ovarian cancer
tumor markers
HE4
ovarian cancer follow-up
ovarian cancer prognosis
target therapy
PARP inhibitors
anti-angiogenic therapy

Published Papers (9 papers)

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Research

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10 pages, 7799 KiB

Open AccessArticle

Patient-Specific Variables Determine the Extent of Cellular Senescence Biomarkers in Ovarian Tumors In Vivo

by Paweł Uruski, Justyna Mikuła-Pietrasik, Eryk Naumowicz, Kamila Kaźmierczak, Andrey N. Gaiday, Jan Królak, Błażej Nowakowski, Rafał Moszyński, Andrzej Tykarski and Krzysztof Książek

Biomedicines 2021, 9(4), 330; https://doi.org/10.3390/biomedicines9040330 - 24 Mar 2021

Cited by 3 | Viewed by 2251

Abstract

The mechanisms and clinical significance of the cellular senescence of tumor cells are a matter of ongoing debate. Recently, the triggers and molecular events underlying spontaneous, replicative senescence of primary epithelial ovarian cancer cells were characterized. In this study, we reanalyzed tumors obtained from ovarian cancer patients with respect to the expression of the senescence biomarkers SA-β-Gal and γ-H2A.X and the proliferative antigen Ki67. The results showed that the tumors displayed strong heterogeneity with respect to the expression of analyzed markers. The expression of SA-β-Gal and γ-H2A.X in the oldest patients (61–85 y.o.) was significantly higher than in the younger age groups. Conversely, the area of Ki67-positive cancer cells was greater in younger individuals. At the same time, there was a positive correlation between SA-β-Gal expression and calendar age in FIGO III–IV and malignant ascites-positive patients. The γ-H2A.X positively correlated with age in the whole group, FIGO III–IV, and ascites-positive patients. Ki67 levels correlated negatively with the age of patients among those same groups. Collectively, our study indicated that organismal aging may determine the development of the senescence phenotype in ovarian tumors, particularly in patients with advanced disease and those accumulating malignant ascites. Full article

(This article belongs to the Special Issue Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer)

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12 pages, 304 KiB

Open AccessArticle

Integrin α2β1 Represents a Prognostic and Predictive Biomarker in Primary Ovarian Cancer

by Katharina Dötzer, Friederike Schlüter, Franz Edler von Koch, Christine E. Brambs, Sabine Anthuber, Sergio Frangini, Bastian Czogalla, Alexander Burges, Jens Werner, Sven Mahner and Barbara Mayer

Biomedicines 2021, 9(3), 289; https://doi.org/10.3390/biomedicines9030289 - 12 Mar 2021

Cited by 7 | Viewed by 2182

Abstract

Currently, the same first-line chemotherapy is administered to almost all patients suffering from primary ovarian cancer. The high recurrence rate emphasizes the need for precise drug treatment in primary ovarian cancer. Being crucial in ovarian cancer progression and chemotherapeutic resistance, integrins became promising therapeutic targets. To evaluate its prognostic and predictive value, in the present study, the expression of integrin α2β1 was analyzed immunohistochemically and correlated with the survival data and other therapy-relevant biomarkers. The significant correlation of a high α2β1-expression with the estrogen receptor alpha (ERα; p = 0.035) and epithelial growth factor receptor (EGFR; p = 0.027) was observed. In addition, high α2β1-expression was significantly associated with a low number of tumor-infiltrating immune cells (CD3 intratumoral, p = 0.017; CD3 stromal, p = 0.035; PD-1 intratumoral, p = 0.002; PD-1 stromal, p = 0.049) and the lack of PD-L1 expression (p = 0.005). In Kaplan–Meier survival analysis, patients with a high expression of integrin α2β1 revealed a significant shorter progression-free survival (PFS, p = 0.035) and platinum-free interval (PFI, p = 0.034). In the multivariate Cox regression analysis, integrin α2β1 was confirmed as an independent prognostic factor for both PFS (p = 0.021) and PFI (p = 0.020). Dual expression of integrin α2β1 and the hepatocyte growth factor receptor (HGFR; PFS/PFI, p = 0.004) and CD44v6 (PFS, p = 0.000; PFI, p = 0.001; overall survival [OS], p = 0.025) impaired survival. Integrin α2β1 was established as a prognostic and predictive marker in primary ovarian cancer with the potential to stratify patients for chemotherapy and immunotherapy, and to design new targeted treatment strategies. Full article

(This article belongs to the Special Issue Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer)

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17 pages, 3946 KiB

Open AccessArticle

BECN1 and BRCA1 Deficiency Sensitizes Ovarian Cancer to Platinum Therapy and Confers Better Prognosis

by Amreen Salwa, Alessandra Ferraresi, Menaka Chinthakindi, Letizia Vallino, Chiara Vidoni, Danny N. Dhanasekaran and Ciro Isidoro

Biomedicines 2021, 9(2), 207; https://doi.org/10.3390/biomedicines9020207 - 18 Feb 2021

Cited by 16 | Viewed by 2625

Abstract

Background: BRCA1, BECN1 and TP53 are three tumor suppressor genes located on chromosome 17 and frequently found deleted, silenced, or mutated in many cancers. These genes are involved in autophagy, apoptosis, and drug resistance in ovarian cancer. Haploinsufficiency or loss-of-function of either TP53, BRCA1 or BECN1 correlates with enhanced predisposition to cancer development and progression, and chemoresistance. Expectedly, the combined altered expression of these three tumor suppressor genes worsens the prognosis of ovarian cancer patients. However, whether such a genotypic pattern indeed affects the chemo-responsiveness to standard chemotherapy thus worsening patients’ survival has not been validated in a large cohort of ovarian cancer patients. Aim: We interrogated datasets from the TCGA database to analyze how the expression of these three tumor suppressor genes impacts on the clinical response to platinum-based chemotherapy thus affecting the survival of ovarian cancer patients. Results and conclusion: Compared to EOC with homozygous expression of BECN1 and BRCA1, tumors expressing low mRNA expression of these two tumor suppressor genes (either because of shallow (monoallelic) co-deletion or of promoter hypermethylation), showed higher sensitivity to platinum-based therapies and were associated with a better prognosis of ovarian cancer-bearing patients. This outcome was independent of TP53 status, though it was statistically more significant in the cohort of patients with mutated TP53. Thus, sensitivity to platinum therapy (and probably to other chemotherapeutics) correlates with low expression of a combination of critical tumor suppressor genes. Our study highlights the importance of thoroughly assessing the genetic lesions of the most frequently mutated genes to stratify the patients in view of a personalized therapy. More importantly, the present findings suggest that targeting the function of both BECN1 and BRCA1 could be a strategy to restore chemosensitivity in refractory tumors. Full article

(This article belongs to the Special Issue Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer)

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12 pages, 2573 KiB

Open AccessArticle

Clinicopathological and Functional Evaluation Reveal NBS1 as a Predictor of Platinum Resistance in Epithelial Ovarian Cancers

by Adel Alblihy, Muslim L. Alabdullah, Reem Ali, Mashael Algethami, Michael S. Toss, Nigel P. Mongan, Emad A. Rakha and Srinivasan Madhusudan

Biomedicines 2021, 9(1), 56; https://doi.org/10.3390/biomedicines9010056 - 08 Jan 2021

Cited by 5 | Viewed by 2209

Abstract

Platinum resistance seriously impacts on the survival outcomes of patients with ovarian cancers. Platinum-induced DNA damage is processed through DNA repair. NBS1 is a key DNA repair protein. Here, we evaluated the role of NBS1 in ovarian cancers. NBS1 expression was investigated in clinical cohorts (protein level (n = 331) and at the transcriptomic level (n = 1259)). Pre-clinically, sub-cellular localization of NBS1 at baseline and following cisplatin therapy was tested in platinum resistant (A2780cis, PEO4) and sensitive (A2780, PEO1) ovarian cancer cells. NBS1 was depleted and cisplatin sensitivity was investigated in A2780cis and PEO4 cells. Nuclear NBS1 overexpression was associated with platinum resistance (p = 0.0001). In univariate and multivariate analysis, nuclear NBS1 overexpression was associated with progression free survival (PFS) (p-values = 0.003 and 0.017, respectively) and overall survival (OS) (p-values = 0.035 and 0.009, respectively). NBS1 mRNA overexpression was linked with poor PFS (p = 0.011). Pre-clinically, following cisplatin treatment, we observed nuclear localization of NBS1 in A2780cis and PEO4 compared to A2780 and PEO1 cells. NBS1 depletion increased cisplatin cytotoxicity, which was associated with accumulation of double strand breaks (DSBs), S-phase cell cycle arrest, and increased apoptosis. NBS1 is a predictor of platinum sensitivity and could aid stratification of ovarian cancer therapy. Full article

(This article belongs to the Special Issue Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer)

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12 pages, 1221 KiB

Open AccessArticle

Role of BRCA Mutation and HE4 in Predicting Chemotherapy Response in Ovarian Cancer: A Retrospective Pilot Study

by Francesco Plotti, Corrado Terranova, Federica Guzzo, Carlo De Cicco Nardone, Daniela Luvero, Martina Bartolone, Camilla Dionisi, Domenico Benvenuto, Silvia Fabris, Massimo Ciccozzi, Violante Di Donato, Pierluigi Benedetti Panici and Roberto Angioli

Biomedicines 2021, 9(1), 55; https://doi.org/10.3390/biomedicines9010055 - 08 Jan 2021

Cited by 9 | Viewed by 2062

Abstract

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in BRCA mutated patients and in BRCA wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to BRCA mutation test, patients were further divided into BRCA wild-type (53 patients), and BRCA mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the BRCA WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the BRCA WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the BRCA mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the BRCA mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios. Full article

(This article belongs to the Special Issue Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer)

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11 pages, 2373 KiB

Open AccessArticle

Anti-HER2/neu Antibody Reduces Chemotherapy-Induced Ovarian Toxicity—From Bench to Bedside

by Mattan Levi, Tal Goshen-Lago, Rinat Yerushalmi, Tal Granot, Salomon M. Stemmer, Ruth Shalgi and Irit Ben-Aharon

Biomedicines 2020, 8(12), 577; https://doi.org/10.3390/biomedicines8120577 - 07 Dec 2020

Cited by 8 | Viewed by 1861

Abstract

Background: Trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (HER2/neu) antibody, is considered a standard treatment in addition to chemotherapy in the adjuvant setting for HER2/neu-positive breast cancer, yet its impact on fertility and ovarian reserve remains obscure. We aimed to study the effect of anti-HER2/neu on chemotherapy-induced ovarian toxicity in both clinical and preclinical settings. Methods: We prospectively enrolled breast cancer patients below the age of 42 years who were treated with chemotherapy with or without trastuzumab into the study. Anti-Müllerian hormone (AMH) was measured 6 and 12 months post-chemotherapy as an ovarian reserve indicator. In the animal model, pubertal mice were injected with cyclophosphamide or paclitaxel with or without anti-HER2/neu, or saline, and sacrificed 1 week or 3 months later. Ovarian apoptosis, proliferation and vascularity were measured by immunohistochemistry and ovarian reserve was measured by morphometric analysis and serum-AMH. Results: Thirty-three patients with early breast cancer were enrolled into the study. Nineteen patients had HER2/neu negative cancer and were treated with chemotherapy and 14 had HER2/neu positive cancer and were treated with chemotherapy and trastuzumab. In all patients, AMH levels declined to undetectable values immediately post-treatment, but regained for 57.1% of the HER2/neu positive cohort and 36.8% of the negative cohort (p < 0.05). In the preclinical setting, anti-HER2/neu antibody, in combination with chemotherapy, displayed lessened ovarian and vascular damage. Conclusions: Our results indicate that trastuzumab may alleviate chemotherapy-induced ovarian toxicity that may be mediated via its effect on ovarian vasculature. Full article

(This article belongs to the Special Issue Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer)

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Review

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21 pages, 407 KiB

Open AccessReview

Ovarian Cancer: Biomarkers and Targeted Therapy

by Mihaela Raluca Radu, Alina Prădatu, Florentina Duică, Romeo Micu, Sanda Maria Creţoiu, Nicolae Suciu, Dragoş Creţoiu, Valentin Nicolae Varlas and Viorica Elena Rădoi

Biomedicines 2021, 9(6), 693; https://doi.org/10.3390/biomedicines9060693 - 18 Jun 2021

Cited by 28 | Viewed by 5587

Abstract

Ovarian cancer is one of the most common causes of death in women as survival is highly dependent on the stage of the disease. Ovarian cancer is typically diagnosed in the late stage due to the fact that in the early phases is mostly asymptomatic. Genomic instability is one of the hallmarks of ovarian cancer. While ovarian cancer is stratified into different clinical subtypes, there still exists extensive genetic and progressive diversity within each subtype. Early detection of the disorder is one of the most important steps that facilitate a favorable prognosis and a good response to medical therapy for the patients. In targeted therapies, individual patients are treated by agents targeting the changes in tumor cells that help them grow, divide and spread. Currently, in gynecological malignancies, potential therapeutic targets include tumor-intrinsic signaling pathways, angiogenesis, homologous-recombination deficiency, hormone receptors, and immunologic factors. Ovarian cancer is usually diagnosed in the final stages, partially due to the absence of an effective screening strategy, although, over the times, numerous biomarkers have been studied and used to assess the status, progression, and efficacy of the drug therapy in this type of disorder. Full article

(This article belongs to the Special Issue Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer)

11 pages, 4749 KiB

Open AccessReview

Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer

by David Schweer, J. Robert McCorkle, Jurgen Rohr, Oleg V. Tsodikov, Frederick Ueland and Jill Kolesar

Biomedicines 2021, 9(1), 70; https://doi.org/10.3390/biomedicines9010070 - 12 Jan 2021

Cited by 7 | Viewed by 3400

Abstract

Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance. This article summarizes recent clinical developments related to mithramycin and postulates a role for the use of mithramycin, or its analog, in the treatment of platinum-resistant ovarian cancer. Full article

(This article belongs to the Special Issue Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer)

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13 pages, 345 KiB

Open AccessReview

Reproductive Outcomes and Fertility Preservation Strategies in Women with Malignant Ovarian Germ Cell Tumors after Fertility Sparing Surgery

by Francesca Maria Vasta, Miriam Dellino, Alice Bergamini, Giulio Gargano, Angelo Paradiso, Vera Loizzi, Luca Bocciolone, Erica Silvestris, Micaela Petrone, Gennaro Cormio and Giorgia Mangili

Biomedicines 2020, 8(12), 554; https://doi.org/10.3390/biomedicines8120554 - 30 Nov 2020

Cited by 19 | Viewed by 2203

Abstract

Malignant ovarian germ cell tumors are rare tumors that mainly affect patients of reproductive age. The aim of this study was to investigate the reproductive outcomes and fertility preservation strategies in malignant ovarian germ cell tumors after fertility-sparing surgery. Data in literature support that fertility-sparing surgery is associated with an excellent oncological outcome not only in early stages malignant ovarian germ cell tumors but also in advanced stages. Moreover, the possibility of performing conservative treatment should be considered even in case of relapse or advanced disease, given the high chemosensitivity. Indeed, available data have shown that menstrual function is maintained after platinum-based regimens in over 85–95% of patients with malignant ovarian germ cell tumors and rate of premature menopause reported in literature ranges between 3% and 7.4%, while premature ovarian failure rates are between 3.4% and 5%. Moreover, reproductive outcomes are about 80% with no increase in the risk of teratogenicity compared to general population. Therefore, conservative surgery for malignant ovarian germ cell tumors currently may represent a therapeutic option in patients who wish to preserve fertility but must be available for extended follow-up and after subscribing to informed consent. Full article

(This article belongs to the Special Issue Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer)

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