research paper on ovarian cancer

Advances in Ovarian Cancer Research

An ovarian tumor grown in a mouse using human cells. Special techniques were used to create the high-resolution, 3-D view of the cancer’s cell structure and inner workings.

Ovarian cancers include cancers that begin in the epithelial cells that line the fallopian tubes or peritoneum as well as the ovaries , and they are collectively called epithelial ovarian cancers . Other types of ovarian cancer arise in other cells, including germ cell tumors , which start in the cells that make eggs, and stromal cell tumors , which start in supporting tissues. 

NCI-funded researchers are working to advance our understanding of how to prevent, detect early, and treat ovarian cancer.

This page highlights some of what’s new in the latest research in ovarian cancer, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.

Prevention of Ovarian Cancer

Women who carry certain mutations in the BRCA1 or BRCA2 genes are at increased risk of developing ovarian cancer. Scientists are looking at ways to reduce the risk in women with these mutations. Surgery to remove the ovaries and fallopian tubes in these women is the recommended method to reduce their risk of getting ovarian cancer. However, removing the ovaries results in immediate menopause, which may cause other health problems. 

Research has shown that the most common type of ovarian cancer begins in the fallopian tubes , not in the ovaries. This discovery has led doctors to reconsider ways of preventing ovarian cancer.

• Removing fallopian tubes only. An ongoing NCI-sponsored clinical trial is testing whether removing the fallopian tubes but delaying removal of the ovaries will be as effective to reduce the risk of ovarian cancer in women with BRCA1 mutations as removing both the ovaries and fallopian tubes at the same time. This would allow women to maintain premenopausal levels of hormones produced by the ovaries and delay many of the complications associated with menopause.
• Removal of fallopian tubes in people seeking to prevent pregnancy. The discovery that epithelial ovarian cancers most often start in the fallopian tubes has also led to changes in the way some gynecologists approach surgery to prevent pregnancy. Women seeking tubal ligation to prevent pregnancy (often called having your tubes tied) may be offered the option of having their tubes removed instead. Doing so might reduce the possibility of ovarian cancer in the future. 
• Testing relatives for gene mutations. NCI is funding efforts to test the relatives of women who have been diagnosed with ovarian cancer in the past.  Researchers are locating women diagnosed with ovarian cancer with the hope to test them and/or their family members for ovarian cancer-related gene mutations, so that family members who learn they carry a mutation may take steps to reduce their risk. The overall goal is not only to prevent ovarian cancer, but also to find the best ways to communicate sensitive genetic information to ovarian cancer patients and their family members.

Ovarian Cancer Treatment

Surgery and chemotherapy are the main treatments for ovarian cancer. The location and type of cells where the cancer begins, and whether the cancer is high-grade or low-grade , may influence the success of treatment. Surgery can cure most people with early-stage ovarian cancer that has not spread beyond the ovaries. For advanced ovarian cancer, the goal of surgery is to remove as much of the cancer as possible, called surgical debulking . 

Platinum-based chemotherapy drugs, such as cisplatin or carboplatin (Paraplatin) , often given in combination with other drugs, are usually effective in treating epithelial ovarian cancer at any stage. However, in most people with advanced ovarian cancer, the cancer usually comes back. Treating the cancer again with platinum drugs may work, but eventually the tumors become resistant to the drugs.

Targeted Therapy

Targeted therap y uses drugs or other agents to attack specific types of cancer cells. PARP inhibitors are a type of targeted therapy that can stop a cancer cell from repairing its damaged DNA, causing the cell to die. Cancers in people who have certain mutations in the BRCA genes are considered particularly susceptible to PARP inhibitors. That’s because BRCA genes are involved in the repair of some types of DNA damage, so cancers with BRCA gene alterations already have defects in DNA repair.

The use of PARP inhibitors has transformed treatment for people with advanced epithelial ovarian cancer and harmful mutations in a BRCA gene. Since the 2014 approval of olaparib (Lynparza) , the first PARP inhibitor, the number of PARP inhibitors has grown and their uses for people with ovarian cancer have expanded. For example, researchers are testing PARP inhibitors as maintenance therapy to prevent cancer from coming back or growing.

Clinical trials have shown that using PARP inhibitors as long-term therapy in women with advanced epithelial ovarian cancer delayed progression of the cancer. 

Treatment after Cancer Progression

Typically, chemotherapy and targeted therapies are stopped once ovarian cancer begins to come back. But clinical trials for patients previously treated with the drug bevacizumab (Avastin) have found that resuming a treatment regimen with bevacizumab and a platinum-based chemotherapy even after the cancer started to grow again slowed the growth of platinum-sensitive disease . And in women who no longer benefited from platinum-based chemotherapy, non–platinum-based chemotherapy combined with bevacizumab kept the cancer in check longer than chemotherapy alone.

Researchers are also testing an experimental drug called adavosertib in women with relapsed or treatment-resistant ovarian cancer. Adavosertib blocks a protein in cells called Wee1 that helps regulate how cells grow and divide. In a clinical trial, combining adavosertib and gemcitabine improved how long women with recurrent or treatment-resistant epithelial ovarian cancer lived before their cancer got worse. 

Targeted therapies may also be helpful for people with low-grade ovarian cancer. A trial of the drug trametinib in women with low-grade serous ovarian cancer that had come back showed that it delayed the cancer’s growth compared with treating the cancer with chemotherapy again.

Secondary Surgery

Several clinical trials have studied the use of secondary surgery for women with advanced epithelial ovarian cancer that has come back after being in remission, or to remove more tumor after their initial surgery. 

• An NCI-funded phase 3 clinical trial found that secondary surgery followed by chemotherapy did not increase overall survival compared with chemotherapy alone. 
• A trial done in China that tested secondary surgery followed by chemotherapy, however, did show improvements in how long women with recurrent epithelial ovarian cancer lived without their cancer growing .
• In a third trial, conducted in Europe, women who underwent secondary surgery followed by chemotherapy lived an average of nearly 8 months longer than women who only received chemotherapy.
• In the Chinese and European trials, and in an analysis of 64 clinical trials and other studies , the benefits of secondary surgery were observed only in women who had all of their visible cancer removed.

Hyperthermic Intraperitoneal (HIPEC) Chemotherapy

Doctors have used chemotherapy injected into the peritoneal cavity to treat ovarian cancer for decades. Now, researchers are studying the usefulness of infusing heated drugs directly into the peritoneal cavity in a procedure called HIPEC (hyperthermic intraperitoneal chemotherapy). HIPEC treatment involves washing the abdominal cavity with heated high-dose chemotherapy immediately after surgery to help kill any remaining cancer.

A large clinical trial found that people with stage 3 ovarian cancer treated with HIPEC during surgery lived almost a year longer than those who received only intravenous chemotherapy after surgery. Studies are underway to confirm this finding.

NCI-Supported Research Programs

Many NCI-funded researchers at the National Institutes of Health campus, and across the United States and the world, are seeking ways to address ovarian cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of ovarian cancer and the social factors that affect cancer risk. And some is more clinical, seeking to translate this basic information into improving patient outcomes.

The Women’s Malignancies Branch in NCI’s Center for Cancer Research conducts basic and clinical research in breast and gynecologic cancers, including early-phase clinical trials at the NIH Clinical Center in Bethesda, Maryland. 

The Ovarian Specialized Programs of Research Excellence (SPOREs) promote collaborative translational cancer research. This group works to improve prevention and treatment approaches, along with molecular diagnostics , in the clinical setting to help people with ovarian cancer.

The Ovarian Cancer Cohort Consortium , part of the NCI Cohort Consortium, is an international consortium of more than 20 cohort studies that follow people with ovarian cancer to improve understanding of ovarian cancer risk, early detection, tumor differences, and prognosis. 

NCI’s clinical trials programs, the National Clinical Trials Network , Experimental Therapeutics Clinical Trials Network , and NCI Community Oncology Research Program , all conduct or sponsor clinical studies of ovarian cancer.

Clinical Trials for Ovarian Cancer

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for the treatment of ovarian cancer.

Ovarian Cancer Research Results

The following are some of our latest news articles on ovarian cancer research:

Implanted “Drug Factories” Deliver Cancer Treatment Directly to Tumors

Trametinib Is a New Treatment Option for Rare Form of Ovarian Cancer

When Ovarian Cancer Returns, Surgery May Be a Good Choice for Selected Patients

How Does Ovarian Cancer Form? A New Study Points to MicroRNA

Ovarian Cancer Studies Aim to Reduce Racial Disparities, Improve Outcomes

Surgery for Recurrent Ovarian Cancer Does Not Improve Survival

View the full list of Ovarian Cancer Research Results and Study Updates .

• Open access
• Published: 18 April 2024

ALKBH5 modulates macrophages polarization in tumor microenvironment of ovarian cancer

• Yuanyuan An 1 &
• Hua Duan 1  

Journal of Ovarian Research volume  17 , Article number:  84 ( 2024 ) Cite this article

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Macrophages play an essential role in regulating ovarian cancer immune microenvironment. Studies have shown that m6A methylation could influence immune microenvironment in cancer. In this study, we investigated the roles of m6A demethylase ALKBH5 and m6A recognition protein IGF2BP2 played in regulating macrophages polarization in ovarian cancer.

In this study, we first explored the differentially expressed m6A methylation enzymes in M0 and M2 macrophages according to two independent GEO datasets. TIMER2.0 and GSCA database were used to explore the immune analysis of ALKBH5 and IGF2BP2 in ovarian cancer. K-M plotter and TIMER2.0 databases were used to evaluate the prognostic role of ALKBH5 and IGF2BP2 in ovarian cancer. For CNV mutation analysis of ALKBH5 and IGF2BP2, cBioPortal and GSCA databases were used. For single-cell analysis, sc-TIME and HPA softwares were used to analyze the roles of ALKBH5 and IGF2BP2 played in immune cells in ovarian cancer. To identify the role of ALKBH5 played in macrophage polarization, RT-PCR was used to verify the macrophage polarization related markers in vitro study. The function of ALKBH5 played in ovarian cancer was further analyzed through GO and KEGG analysis.

In this study, we found that ALKBH5 and IGF2BP2 were up-regulated in M2 macrophages, which showed closely correlation with immune cells expressions in ovarian cancer, especially with macrophages. Ovarian cancer patients with higher expression of ALKBH5 and IGF2BP2 showed worse prognosis, possibly because of their close correlation with immune response. ALKBH5 also correlated with macrophage phenotypes in single-cell levels analysis. However, the expression level of IGF2BP2 in ovarian cancer immune microenvironment was very low. The results of RT-PCR indicated the potential role of ALKBH5 in M2 polarization of macrophages.

Interpretation

ALKBH5 participated in regulating macrophage M2 polarization in ovarian cancer immune microenvironment.

Introduction

Ovarian cancer is one of the most common gynecologic malignant tumors, with a relatively high mortality rate. The statistics showed that 5-year survival rate of ovarian cancer patients was less than 44% [ 1 ]. The first-line treatment for ovarian cancer remains tumor cell reduction surgery combined with post-operative chemotherapy. However, the recurrence rate of ovarian cancer is as high as 70%. Studies have shown that tumor microenvironments (TME) participated in regulating the immune response and inflammatory response of cancer through various mechanisms [ 2 , 3 , 4 ]. Therefore, immunotherapy targeting TME has attracted extensive attentions.

TME refers to the tumor microenvironment which surrounds and nourishes the tumor cells, including blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, various signaling molecules and extracellular matrix. Macrophages are one of the most important immune cells in TME, which mainly work as recognition, phagocytosis and degradation of foreign bodies, bacteria and dead cells, etc. In addition, macrophages can also play a role in presenting antigens to T cells to initiate adaptive immune response, which means macrophages not only participate in innate immunity, but also adaptive immunity. Macrophages can be divided into M1 and M2 polarization phenotypes, tumor-associated macrophages (TAMs) are a type of macrophages, which status is similar to M2 macrophages [ 5 ]. Here, we aimed to explore the role of m6A methylation enzymes ALKBH5 and IGF2BP2 in regulating macrophage polarization in ovarian cancer microenvironment.

M6A methylation is one of the most common RNA modifications, and participates in all stages of RNA life cycle, including RNA transcription, translation and degradation [ 4 ]. In fact, m6A methylation also participates in cancer progression. ALKBH5 is one of the most important and classical demethylases. In many cancers, ALKBH5 functions as an oncogene . In GBM, ALKBH5 worked as an oncogene and influences the self-renewal and proliferation of cancer stem cells [ 6 ]. In ovarian cancer, ALKBH5 was up-regulated to enhance the stability of BCL-2, thus inhibiting the autophagy, and promoting the invasion and proliferation of cancer cells [ 7 ]. In addition, ALKBH5-HOXA10 loop could promote the cisplatin resistance in epithelial ovarian cancer through demethylating JAK2 [ 8 ]. As an important m6A recognition protein, IGF2BP2 mainly acts to promote the stability and translation of mRNA. In ovarian cancer, the knockdown of circ-0001756 could suppress IGF2BP2 mediated RAB5A expression, thus inhibiting malignant progression of ovarian cancer [ 9 ]. As for the role that IGF2BP2 plays in immune response, study showed that IGF2BP2 could affect the immune-related biological pathways in oral squamous cell carcinoma, thus leading to the worse prognosis for cancer [ 10 ]. However, few studies have focused on the role of ALKBH5 and IGF2BP2 in regulating macrophage polarization in ovarian cancer.

Compared to the M0 macrophages, we first identified that ALKBH5 and IGF2BP2 were up-regulated in M2 macrophages. To deepen our understanding the role of ALKBH5 and IGF2BP2 play in ovarian cancer immune microenvironment, we used various databases to explore their relationships with immune cells, not only at tissues level, but also at single-cell level. Finally, we validated the role of ALKBH5 plays in macrophage polarization through RT-PCR. Taken together, our results could potentially represent the roles of ALKBH5 and IGF2BP2 played in macrophages in ovarian cancer, which might work as the potential immunotherapy biomarkers.

Materials and methods

Identification of differentially expressed m6a genes in macrophages.

Two independent datasets GSE35495 and GSE36537 from GEO database ( https://www.ncbi.nlm.nih.gov/gds/ ) were included to explore the differentially expressed genes (DEGs) between M0 and M2 macrophages [ 11 , 12 ]. A venn plot was constructed to explore the co-expressed genes in M2 macrophages in these two datasets. To further validate the relative expression of ALKBH5 and IGF2BP2 in M0 and M2 macrophages, two independent datasets GSE108312 and GSE35449 from GEO database were used.

Immune analysis of ALKBH5 and IGF2BP2 in ovarian cancer

To evaluate the correlation between ALKBH5 and IGF2BP2 with immune cells in ovarian cancer, TIMER2.0 was used. Online website GSCA ( http://bioinfo.life.hust.edu.cn/GSCA ) was used to investigate the correlation between mRNA expression and CNV status of ALKBH5 and IGF2BP2 with distinct immune cells in ovarian cancer [ 13 ]. Differential expression levels of immune cells in ovarian cancer and normal ovary tissues were investigated in online tool GEPIA2021 ( http://gepia2021.cancer-pku.cn ) [ 14 ]. To investigate the correlation between ALKBH5 and M2 macrophage markers IL-10 and CD163 in the TME of ovarian cancer, dataset GSE158739 was used, which contains data on tumor-associated macrophages derived from TME of ovarian cancer. To further prove the correlation between ALKBH5 and IGF2BP2 with M2 macrophages based on CIBERSORT method in ovarian cancer, two independent ovarian cancer datasets GSE44104 and GSE65986 from GEO database were used.

Prognostic value of ALKBH5 and IGF2BP2 in ovarian cancer

To evaluate the prognostic role of ALKBH5 and IGF2BP2 played in ovarian cancer, overall survival (OS) analysis and progression-free survival (PFS) analysis were conducted using the online tools K-M plotter ( https://kmplot.com/analysis ) and TIMER2.0 ( http://timer.cistrome.org ) [ 15 , 16 ]. The expressions of ALKBH5 and IGF2BP2 in cell localization were explored in online website The Human Protein Atlas (HPA) software ( https://www.proteinatlas.org ) [ 17 ]. The small molecules or drugs targeting ALKBH5 and IGF2BP2 were investigated in GSDC and CTRP databases.

Mutation analysis of ALKBH5 and IGF2BP2 in ovarian cancer

The copy-number alterations and gene mutations of ALKBH5 and IGF2BP2 in ovarian cancer were investigated in cBioPortal database. To explore the CNV status of genes and their mRNA expressions, GSCA database was used. The most correlation genes related to ALKBH5 and IGF2BP2 were investigated in cBioPortal database.

Single-cell analysis of ALKBH5 and IGF2BP2 in ovary and ovarian cancer tissues

The single-cell analysis of ALKBH5 and IGF2BP2 expression in immune cells was investigated in online sc-TIME Portal software ( http://sctime.sklehabc.com/unicellular/home ) in ovarian cancer [ 18 ]. Furthermore, we explored ALKBH5 and IGF2BP2 expressions and their correlation with various types of immune cells in ovarian tissues in HPA.

Cell culture and treatment

The human monocyte cell line THP-1 was purchased from Beijing Beina Chuanglian Biotechnology Institute. Cells were cultured in RPMI1640 with 10% FBS with 5% CO2 at 37℃. In order to induce macrophages, THP-1 was treated with 100 ng/ml PMA for 24 h. To manipulate the inhibition and overexpression of ALKBH5 in macrophages, we constructed lentivirus that could knockdown and overexpress ALKBH5 from Shanghai GenePharma Biotechnology Co., Ltd.

RNA extraction and RT-PCR

Total RNA was extracted using Trizol reagent. To reverse transcribe mRNA into cDNA, we used the PrimeScript RT reagent Kit with gDNA Eraser. SYBR Premix Ex Taq was used to perform quantitative RT-PCR through ABI 7500 Fast instrument. The sequences of the primers were shown in Supplementary Table  1 . GAPDH was used as the internal reference.

Functional analysis of ALKBH5 in ovarian cancer

Ovarian cancer patients from TCGA dataset were divided into two groups based on ALKBH5 expression level. The DEGs between these two groups were investigated through R software using “limma” package, genes were collected with p -value < 0.05 and Fold Change > 1.2. Online website STRING ( https://cn.string-db.org ) was used to construct the PPI network [ 19 ]. Cytoscape was used to identify the hub genes. Online website DAVID ( https://david.ncifcrf.gov ) was used to perform GO and KEGG analysis based on DEGs [ 20 ].

Statistical analysis

Correlations between ALKBH5 and IGF2BP2 with immune-related genes and other m6A methylation enzymes were explored based on TCGA dataset and GEO dataset using Pearson method. The correlation between ALKBH5 and IGF2BP2 with M2 macrophage markers IL-10 and MRC1 were explored in GEPIA database. All tests were evaluated with p -value < 0.05. GraphPad Prism 7 software was used to analyze all the data. Differences between two groups were tested using the Student’s t-test or Chi-square test.

ALKBH5 and IGF2BP2 were up-regulated in M2 macrophages

In Fig.  1 , we constructed a flow diagram to represent our study design. In this study, we collected two independent GEO datasets, GSE35495 and GSE36537 to demonstrate the DEGs between M0 and M2 macrophages (Supplementary Fig.  1 A-B). All the m6A methylation enzymes were analyzed to demonstrate differential expression in M0 and M2 macrophages, which showed most of the enzymes exhibited distinct expression between these two types of macrophages (Fig.  2 A). However, the m6A methylation enzymes which were up-regulated in M2 macrophages were not that much. In the venn diagram, we found that only ALKBH5 and IGF2BP2 worked as the genes that up-regulated in M2 macrophages both in GSE36537 and GSE39495 (Fig.  2 B). To further validate the relative expression of ALKBH5 and IGF2BP2 in M0 and M2 macrophages, GEO datasets GSE108312 and GSE35449 were used. The results showed that ALKBH5 and IGF2BP2 were both expressed highly in M2 macrophages (Fig.  2 C-D). In Fig.  2 E, we investigated the correlation between the m6A methylation enzymes in the two GEO datasets, which showed most of the enzymes had closely correlation. Heatmap plot was used to represent the m6A methylation enzymes in these two datasets (Supplementary Fig.  1 C). We found that the expression of ALKBH5 was relatively high in macrophages, while IGF2BP2 was expressed at low levels in macrophages. Next, we would like to investigate the correlation of ALKBH5 and IGF2BP2 with immune cells expression in ovarian cancer microenvironment. Thus, we further investigated the role of ALKBH5 and IGF2BP2 played in immune cells using TIMER2.0 database. Results showed that the expression of ALKBH5 significantly correlated with macrophage, neutrophil, Tregs and endothelial cells expression, especially in macrophages had the closest correlation with R = 0.362 (Fig.  2 F). In IGF2BP2 showed close correlation with monocytes, B cells, myeloid dendritic cells and macrophages, while the IGF2BP2 showed the closest correlation with monocytes with R = -0.353 (Fig.  2 G). These results suggested that ALKBH5 and IGF2BP2 showed closely correlation with macrophage expression in ovarian cancer, which might participate in regulating the polarization of macrophages in ovarian cancer microenvironment.

Flow diagram of the study design

ALKBH5 and IGF2BP2 were up-regulated in M2 macrophages. A  The differential expression of m6A methylation enzymes between M0 and M2 macrophages in GSE35495 and GSE36537, the left plot represented macrophage samples from GSE35495 with three M0 macrophage samples and three M2 macrophage samples, the right plot represented macrophage samples from GSE36537 with three M0 macrophage samples and three M2 macrophage samples. B  Venn diagram to analyze co-expression genes in GSE35495 and GSE36537. C  The relative expression of ALKBH5 and IGF2BP2 in M0 and M2 macrophages in GSE108312 with three M0 macrophage samples and three M2 macrophage samples. D  The relative expression of ALKBH5 and IGF2BP2 in M0 and M2 macrophages in GSE35449 with seven M0 macrophage samples and seven M2 macrophage samples. E  The correlation between m6A methylation enzymes in macrophages in GSE35495 and GSE36537. F  The correlation between expression of ALKBH5 and different immune cells in ovarian cancer using TIMER2.0. G  The correlation between expression of IGF2BP2 and different immune cells in ovarian cancer using TIMER2.0

ALKBH5 and IGF2BP2 correlated with the expression of immune cells in ovarian cancer

Further validated the roles of ALKBH5 and IGF2BP2 played in ovarian cancer, GSCA software were used. Results showed that ALKBH5 and IGF2BP2 mRNA levels correlated with CD8 naïve cells, macrophages and neutrophils expressions (Fig.  3 A & C). However, there was no significant relationship between the CNV mutation of ALKBH5 and IGF2BP2 with the expression of those immune cells in ovarian cancer (Fig.  3 B & D). Based on these analysis, we found that ALKBH5 and IGF2BP2 could regulate the immune status of ovarian cancer microenvironment mainly through its mRNA expression levels, the mutation status of ALKBH5 and IGF2BP2 might not influence the immune status of ovarian cancer. These results represented that ALKBH5 and IGF2BP2 may be involved in regulating the immune status based on their expression value in immune cells, especially in macrophages.

ALKBH5 and IGF2BP2 correlated with immune cells in ovarian cancer. A  The correlation between mRNA expression of ALKBH5 and different immune cells in ovarian cancer using GSCA. B  The correlation between ALKBH5 CNV mutation and different immune cells in ovarian cancer using GSCA. C  The correlation between mRNA expression of IGF2BP2 and different immune cells in ovarian cancer using GSCA. D  The correlation between IGF2BP2 CNV mutation and different immune cells in ovarian cancer using GSCA

Overexpression of ALKBH5 and IGF2BP2 correlated with worse prognosis in ovarian cancer

To investigate the prognostic role of ALKBH5 and IGF2BP2 played in ovarian cancer, we used the online K-M plotter database. The results showed that high expression of ALKBH5 and IGF2BP2 was associated with a poorer prognosis both in OS and PFS analysis in ovarian cancer, which might be due to its high expression in M2 macrophages in ovarian cancer microenvironment (Fig.  4 A-B). In cell localization, ALKBH5 was widely expressed in the nucleus and cytoplasm of cells, with a predominant expression in the nucleus, while IGF2BP2 was mainly expressed in cytoplasm of the cells (Fig.  4 C).

ALKBH5 and IGF2BP2 correlated with the prognosis of ovarian cancer. A  OS and PFS analysis of ALKBH5 in ovarian cancer from K-M plotter. B  OS and PFS analysis of IGF2BP2 in ovarian cancer from K-M plotter. C  The localization of ALKBH5 and IGF2BP2 in A-431 cell line. Green color represented target protein, blue color represented cell nucleus, and red color represented microtubulues. Therefore, the upper left figure represented ALKBH5 expression, the upper middle figure represented colocalization of ALKBH5 and cell nucleus, the upper right figure represented colocalization of ALKBH5, cell nucleus and microtubulues. The lower left figure represented IGF2BP2 expression, the lower middle figure represented colocalization of IGF2BP2 and cell nucleus, the lower right figure represented colocalization of IGF2BP2, cell nucleus and microtubulues

ALKBH5 correlated with M2 macrophages markers in ovarian cancer

Furthermore, we tried to investigate the role of ALKBH5 and IGF2BP2 played in macrophages in ovarian cancer. In order to investigate whether ALKBH5 and IGF2BP2 regulated the immune status of ovarian cancer by influencing the polarization of macrophages, we investigated that the correlation between ALKBH5 and IGF2BP2 with M2 macrophage polarization-related genes. In Fig.  5 A, we found that ALKBH5 positively correlated with the expression of M2 macrophages markers IL-10 ( p -value = 0.0012) and MRC1 ( p -value = 0.026), which indicated ALKBH5 might participate in promoting M2 macrophages polarization. However, there was no significant correlation between IGF2BP2 with the polarization markers IL-10 and MRC1. To further prove the relationship between ALKBH5 and M2 macrophage markers in TME of ovarian cancer, we found that ALKBH5 positively correlated with M2 macrophage markers IL-10 and CD163 through Pearson analysis in ovarian cancer related dataset GSE158739 (Fig.  5 B). In addition, to investigate the relationship between M2 macrophages with ALKBH5 and IGF2BP2 in ovarian cancer, two independent datasets from GEO database using CIBERSORT method were searched for further study. In both GSE44104 and GSE65986, the results showed that M2 macrophages positively correlated with ALKBH5 in serous ovarian cancer, while no significant correlation between M2 macrophages and IGF2BP2 was found (Fig.  5 C-D). Thus, we assumed that ALKBH5, but not IGF2BP2 might participate in regulation the macrophages in ovarian cancer, especially by promoting the M2 polarization of macrophages. Furthermore, we analyzed the prognostic value of ovarian cancer based on the expression level of ALKBH5 and IGF2BP2 with distinct phenotypes of macrophage expressions (Fig.  5 E-F). The results showed that in M1 macrophage group, patients with high expression of ALKBH5 and low expression of M1 macrophages had the worst prognosis. While in M2 macrophage group, patients with low expression of ALKBH5 and low level of M2 macrophages exhibited the best prognosis. However, no obvious survival differences were observed in IGF2BP2 combined analysis with macrophages. The small molecules or drugs targeting ALKBH5 or IGF2BP2 were investigated using GDSC and CTRP database, which might help demonstrate the potential drugs that target ALKBH5 or IGF2BP2 in ovarian cancer (Fig.  5 G-H).

ALKBH5 correlated with M2 macrophage markers in ovarian cancer. A  The correlation between ALKBH5 and IGF2BP2 with M2 polarization markers MRC1 and IL-10 in ovarian cancer. B  The correlation between ALKBH5 and M2 macrophage markers IL-10 and CD163 in macrophages derived from TME of ovarian cancer in GSE158739. C  The correlation between ALKBH5 and IGF2BP2 with M2 macrophages in serous ovarian cancer through GSE44104. D  The correlation between ALKBH5 and IGF2BP2 with M2 macrophages in serous ovarian cancer through GSE65986. E  Combined OS analysis of ALKHB5 and expression of M1 and M2 macrophages in ovarian cancer from TIMER2.0. F  Combined OS analysis of IGF2BP2 and expression of M1 and M2 macrophages in ovarian cancer from TIMER2.0. G  The small molecules or drugs targeting ALKBH5 in ovarian cancer. H  The small molecules or drugs targeting IGF2BP2 in ovarian cancer

The mutation analysis of ALKBH5 and IGF2BP2 in ovarian cancer

In cBioPortal database, we analyzed the copy number alterations of ALKBH5 and IGF2BP2 in ovarian cancer. The copy-number alterations of ALKBH5 and IGF2BP2 in ovarian cancer were shown in Fig.  6 A. The results showed that distinct copy-number alteration of ALKBH5 represented different levels of ALKBH5 mRNA. However, no obvious mRNA level of IGF2BP2 was observed in different copy-number alteration of IGF2BP2. Similarly, in GSCA database, we analyzed the correlation between CNV status of ALKBH5 and IGF2BP2 with mRNA levels. We found that ALKBH5 mRNA level showed a significant correlation with CNV status, however, IGF2BP2 didn’t show the obvious correlation (Fig.  6 B). It is worth noting that we described the correlation between ALKBH5 or IGF2BP2 CNV status and immune cells infiltration in Fig.  3 . Different from Fig.  3 , we described the correlation between ALKBH5 CNV status with its mRNA expression levels in Fig.  6 . In total, we found that mutation of ALKBH5 is only 1.5% in ovarian cancer, however, the mutation of IGF2BP2 accounts for 27% of ovarian cancer patients (Fig.  6 C). Finally, the top 15 genes correlated with ALKBH5 and IGF2BP2 in ovarian cancer were shown in Fig.  6 D.

The mutation status of ALKBH5 and IGF2BP2 in ovarian cancer. A  The copy number alteration of ALKBH5 and IGF2BP2 in ovarian cancer. B  The correlation between copy number alteration of ALKBH5 and IGF2BP2 with mRNA expression. C  The mutation status of ALKBH5 and IGF2BP2 in ovarian cancer. D  The 15 top genes correlated with ALKBH5 and IGF2BP2 in ovarian cancer. The left figure represented ALKBH5, and the right figure represented IGF2BP2

The single-cell analysis of ALKBH5 and IGF2BP2 in immune cells in ovarian cancer

To explore the role of ALKBH5 and IGF2BP2 in immune cells at single-cell level in ovarian cancer, we found that ALKBH5 was widely expressed in immune cells, but its expression was highly expressed in macrophages (Fig.  7 A). However, the expression of IGF2BP2 was very low in immune cells in ovarian cancer microenvironment. In the single-cell analysis of ovary tissues, we found that ALKBH5 was expressed highest in the blood and immune cells (Fig.  7 B). Further investigated the expression of ALKBH5 in immune cells in detail, we found ALKBH5 was expressed at the highest levels in macrophages and T cells, especially in macrophages, which showed positive correlation with the macrophages markers CD163, CD68, MARCO, MRC1 and MSR1 (Fig.  7 C). These results suggested that ALKBH5 also showed significantly correlation with immune cell, especially macrophages at the single-cell level in ovarian cancer. However, we found that the expression of IGF2BP2 was mainly expressed in granulosa cells and smooth muscle cells, its expression in the macrophages of ovarian tissues and ovarian cancer tissues in single-cell level analysis were relative very low (Fig.  7 D-E). What’s more, in Supplementary Fig.  2 A, we also found the expression of ALKBH5 was relatively high in most tissues, especially in ovarian tissues. However, the expression of IGF2BP2 was very low in most of the tissues, including ovarian tissues. The expression of ALKBH5 in distinct subtypes of ovarian cancer cells was also much higher than IGF2BP2, including differentiated, immunoreactive, mesenchymal and proliferative ovarian cancer (Supplementary Fig.  2 B). Thus, we paid more attention to investigating the role that ALKBH5 played in ovarian cancer.

Single-cell analysis of ALKBH5 and IGF2BP2 in ovary and ovarian cancer tissues. A  The expression of ALKBH5 and IGF2BP2 in distinct immune cells in ovarian cancer microenvironment using sc-TIME. The orange one represented ascites DCs, the green one represented ascites macrophages, the red one and the blue one represented the monocytes, while the pink one represented tonsil DCs. The middle one represented ALKBH5, while the right one represented IGF2BP2. B  Single-cell analysis of ALKBH5 in distinct immune cells in ovary tissues. C  Correlation between ALKBH5 and distinct immune cells markers in ovary tissues. D  Single-cell analysis of IGF2BP2 in distinct immune cells in ovary tissues. E  Correlation between IGF2BP2 and distinct immune cells markers in ovary tissues

ALKBH5 promoted the M2 polarization of macrophages in ovarian cancer

To investigate the distinct roles of ALKBH5 played in ovarian cancer and normal ovary immune microenvironment. In Fig.  8 A, we found that the immune cells expressions in these two immune microenvironments showed significant differences. Most importantly, the expression of M1 and M2 macrophages were significantly higher expressed in ovarian cancer. However, the expressions of monocytes were significantly higher expressed in normal ovary tissues. We used PMA to differentiate THP-1 cells into macrophages and then we transfected lentivirus into macrophages, which could overexpress or inhibit the expression of ALKBH5 in macrophages. In Fig.  8 B, when we overexpressed ALKBH5 in macrophages, the results showed that down-regulation of M1 macrophage marker TNF-α, up-regulation of M2 macrophage marker IL-10 and ARG-1. In Fig.  8 C, when we inhibited the expression of ALKBH5 in macrophages, the results showed that up-regulation of M1 macrophage marker CD86, down-regulation of M2 macrophage marker CD163 and CCL22. These results indicated that ALKBH5 could promote the M2 polarization of macrophages. Thus, we explored the correlation between ALKBH5 and immune inhibitors, which also showed ALKBH5 might influence the immune response in the ovarian cancer immune microenvironment (Fig.  8 D). Finally, the correlation between ALKBH5 and macrophage polarization markers in ovarian cancer was investigated using the Pearson method, as shown in Fig.  8 E. Results showed that ALKBH5 correlated with most of the macrophage markers, which meant that ALKBH5 closely correlation with macrophages polarization. Due to the expression value of ALKBH5, ovarian cancer patients were divided into two groups. The DEGs were collected to investigate the biological role of ALKBH5 played in ovarian cancer (Supplementary Table  2 ). A PPI network was constructed through STRING software and Cytoscape based on DEGs (Fig.  8 F). Top 20 hub genes were identified using cytoHubba (Suppelementary Fig.  3 A). All the DEGs were collected to investigate GO and KEGG analysis (Table  1 ). Results represented that ALKBH5 was associated with immune response and inflammatory response in ovarian cancer (Fig.  8 G-H). The pathways that ALKBH5 correlated in ovarian cancer were also immune-related pathways, such as Th17 cell differentiation, NOD-like receptor signaling pathway and NF-κB signaling pathway (Table  2 ). In Supplementary Fig.  2 B-C, we found that ALKBH5, but not IGF2BP2 correlated with the apoptosis pathways and MAPK pathways in ovarian cancer.

ALKHB5 promoted M2 macrophage polarization in ovarian cancer. A  Differential expression of ALKBH5 in normal ovary and ovarian cancer immune cells. B  Overexpression of ALKBH5 in macrophages inhibited TNF-α expression and promoted IL-10, ARG-1 expression. C  Inhibition of ALKBH5 in macrophages promoted CD86 expression and inhibited CD163, CCL22 expression. D  Correlation between ALBKH5 and immune inhibitors in ovarian cancer. E  Correlation between ALBKH5 and macrophages polarization markers in ovarian cancer. F  PPI network constructed according to the DEGs of ALKBH5 in ovarian cancer using cytoscape. G  Bubble plots showed GO and KEGG analysis of DEGs based on TCGA. H  Circos plots showed the GO and KEGG analysis of DEGs based on TCGA

Ovarian cancer is always characterized by the late stage once found, with high recurrence rate and mortality. It is known as the “silent killer” for women. Studies have shown that more than 25% of ovarian cancer patients represented chemoresistance at the first relapse [ 21 ]. So it is important to find new approaches for ovarian cancer therapy. M6A methylation is the most common nucleotide modification in mRNA, about 1/4 mRNA molecules contain at least one m6A modification site [ 22 ]. M6A modification is involved in various processes of mRNA metabolism [ 23 , 24 , 25 ]. Recent studies have shown that m6A could affect a variety of cellular biological processes and played an important role in cell fate determination, lipid metabolism and immunity [ 26 , 27 , 28 ]. ALKBH5 works as an important demethylase, while IGF2BP2 works as the m6A recognition protein. However, its role in ovarian cancer needs further study. We first found that ALKBH5 and IGF2BP2 were up-regulated in M2 macrophages, and both showed significantly correlated with immune cells in ovarian cancer, especially macrophages. Importantly, we found that the closely correlation between ALKBH5 and IGF2BP2 with immune cells due to its mRNA expression levels, rather than their CNV status. Furthermore, we investigated the prognostic role of ALKBH5 and IGF2BP2 in ovarian cancer, which both showed the overexpression of ALKBH5 and IGF2BP2 represented the worse prognosis for ovarian cancer.

The mechanisms that can regulate the macrophages polarization has been investigated for years. However, the studies focused on investigating the role that m6A methylation-related enzymes that played in cancer immune microenvironment were very limited. According to our analysis, we found that ALKBH5 and IGF2BP2 were significantly correlated with the immune response in ovarian cancer. ALKBH5 is a classical m6A demethylase that primarily functions to remove m6A modification to promote mRNA nuclear processing and export. In ovarian cancer, high expression of TLR4 could activate NF-κB signaling pathway, thus up-regulated ALKBH5 to influence the m6A methylation of NANOG, which further promoted carcinogenesis in ovarian cancer [ 29 ]. In epithelial ovarian cancer, ALKBH5-HOXA10 loop regulated the methylation of JAK2, which could activate JAK2-STAT3 signaling, thus promoting chemoresistance of cancer cells [ 8 ]. Moreover, IGF2BP2 worked as an important m6A recognition protein, which mainly acted to promote the stability and translation of mRNA. In ovarian cancer, the study showed that circITGB6 can directly interact with IGF2BP2 and FGF9, thus stabilized FGF9 and promoted M2 polarization in ovarian cancer [ 30 ]. In fact, research on whether the expression of ALKBH5 and IGF2BP2 can regulate the polarization of macrophages were very limited. Most of the studies correlating m6A methylation enzymes and macrophages function have focused on studying the role of METTL3 in macrophages. In myeloid cells, the ablation of METTL3 could promote tumor metastasis, which was due to the deficiency of METTL3 increased the M1 macrophages and regulatory T cells infiltration [ 31 ]. In breast cancer, METTL14 and ZC3H13 were down-regulated, indicating a positive correlation between the expression of METTL14 and ZC3H13 positively correlated with various kinds of immune cells, including macrophages, T cells and DCs [ 32 ]. In this study, we found that among all the immune cells, ALKBH5 and IGF2BP2 showed the closest correlation with macrophages in ovarian cancer. However, we found that the expression level of IGF2BP2 was much lower than ALKBH5 in ovarian cancer immune microenvironment.

As one of the most important immune cells in cancer, macrophages have a relatively high expression of immune cells, which can not only regulate the nonspecific immunity, but also influence the specific immunity. In nonspecific immunity, macrophages can kill and clear pathogens through phagocytosis and mediate inflammatory response. In specific immunity, macrophages mainly focus on immune regulation and antigen presentation. Studies have shown that repolarization of macrophages from M2 to M1 could enhance the macrophages’ ability to kill cancer cells, including ovarian cancer cells [ 33 , 34 , 35 ]. Thus, we investigated the correlation between ALKBH5 and IGF2BP2 with the M2 macrophage markers IL-10 and MRC1, while ALKBH5 showed positively correlation, however, no obvious correlation was observed with IGF2BP2.

Single-cell sequencing has been gaining momentum in recent years. The single-cell sequencing technology involves sequencing and analyzing the genome, transcriptome and epigenome at the single-cell level [ 36 ]. Traditional sequencing is carried out on the basis of multicellularity. In fact, what we get is the average value of signals in a cluster of cells, which eliminates the information of cell heterogeneity. Single-cell sequencing technology can detect the heterogeneity information that can’t be obtained by hybrid sample sequencing, so it effective in addressing this issue. Thus, we analyzed the ALKBH5 and IGF2BP2 expression in immune cells through single-level analysis. The results showed that ALKBH5 is widely expressed in various cells, with the highest up-regulation observed in macrophages not only in ovarian cancer, but also in ovarian tissues. However, the expression of IGF2BP2 was relatively low in macrophages in ovarian cancer microenvironment. Thus, we chose ALKBH5 for further study. Here, we chose THP-1 cell line induced by PMA as the macrophage model, which is widely acknowledged macrophage lineage in many researches. Most of the studies investigating the role of macrophages in human use THP-1 cell line and induced it into macrophage by PMA, which could imitate the status of macrophage in vivo, including in ovarian cancer [ 34 , 37 , 38 , 39 ]. To validate whether ALKBH5 could promote the M2 polarization of macrophages in vitro, macrophages transfected with ALKBH5 that could overexpress or inhibit its expression were used to evaluate the polarization markers of macrophages through RT-PCR. The results showed that overexpression of ALKBH5 could promote high expression of M2 marker IL-10, ARG-1 and low expression of M1 marker TNF-α, and inhibition of ALKBH5 could promote high expression of M1 marker CD86 with low expression of M2 marker CD163 and CCL22. In fact, many genes and proteins can regulate the polarization of macrophages. However, the function of enzymes that can regulate the m6A methylation in controlling macrophage polarization has not been widely investigated yet. Based on the GO and KEGG analysis, results showed that the biological process of ALKBH5 in ovarian cancer was mostly correlated with immune response, including T cell receptor signaling pathway, inflammatory response, immune response and antimicrobial humoral immune response mediated by antimicrobial peptide. These processes were confirmed as the main processes in immune response in cancer metabolism. What’s more, in KEGG analysis, we identified pathways that related to ALKBH5 were Th17 cell differentiation, intestinal immune network for IgA production, NOD-like receptor signaling pathway and NF-κB signaling pathway. Those pathways also showed significantly correlation with immune response. Thus, we speculated that ALKBH5 might participate in regulating the immune response in ovarian cancer microenvironment.

In conclusion, our study demonstrated that ALKBH5 and IGF2BP2 were significantly up-regulated in M2 macrophages, which not only showed closely correlation with macrophage expression in ovarian cancer, but also correlated with the prognosis of ovarian cancer. In single-cell analysis, we found that ALKBH5 was mainly expressed in macrophages in ovarian cancer. Finally, we verified that ALKBH5 could regulate M2 macrophage polarization in vitro study. Thus, targeting ALKBH5 in macrophages might be a promising target for regulating the immune microenvironment in ovarian cancer, which could further influence the prognosis of ovarian cancer patients.

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Additional file 1: supplementary figure 1..

Distinct expression of m6A methylation enzymes in M0 and M2 macrophages. Supplementary Figure 2. The expression of ALKBH5 and IGF2BP2 in distinct tissues. Supplementary Figure 3. The genes and pathways correlated with ALKBH5 in ovarian cancer. Supplementary Table 1. The primers used in the study. Supplementary Table 2. The DEGs according to the expression level of ALKBH5 in TCGA datasets

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An, Y., Duan, H. ALKBH5 modulates macrophages polarization in tumor microenvironment of ovarian cancer. J Ovarian Res 17 , 84 (2024). https://doi.org/10.1186/s13048-024-01394-4

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Researchers identify patterns that predict ovarian cancer relapse

by Cedars-Sinai Medical Center

Using spatial analysis of tissue samples, Cedars-Sinai investigators have identified patterns that could predict whether patients with the most common type of ovarian cancer will experience early relapse after treatment. These patterns, detailed in a study published in Science Advances , could point to possible therapies.

"Using spatial protein analysis, we looked not only at the types of cells within and around a tumor , but also at their relative positions and how they interact," said Alex Xu, Ph.D., a research scientist at Cedars-Sinai Cancer and the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and first author of the study.

Investigators' analysis of ovarian cancer tissue samples identified patterns consistently associated with patients whose cancer relapsed soon after treatment, Xu said.

"Spatial analysis is the next frontier in tissue biomarker development and our group has demonstrated the importance of spatial analysis in several cancer types," said Akil Merchant, MD, a senior author of the study and director of the Spatial Molecular Profiling Core facility at Cedars-Sinai Cancer.

High-grade serous ovarian carcinoma is the deadliest form of ovarian cancer, and ovarian cancers are particularly challenging because they are difficult to detect, Xu said. Frequently, patients with these tumors respond to initial treatment with surgery and chemotherapy but the cancer recurs.

In this study, investigators looked at tissue samples from 42 patients who had ovarian cancer—both primary tumors and tumors that recurred after patients' initial treatment—using a technology called imaging mass cytometry, which reveals the spatial protein content of the tissue. The investigators' main findings centered around plasma cells, a crucial part of the tumor immune response .

"Our findings suggest that plasma cells are a clinically important factor determining a patient's time to relapse," Xu said. "Previous research into their role has been contradictory, with some studies suggesting their presence predicted negative outcomes while others suggested positive outcomes ."

Here investigators found that outcomes were associated with the location of the plasma cells, and their relationship to adjacent cells types.

"Plasma cells were associated with good patient outcomes when lymphoid aggregates, which are structures that include T and B cells, were also abundant in the area immediately surrounding the tumor," Xu said. "This could be because the plasma cells were part of these organized structures that facilitated communication between these immune cells, thus improving their ability to attack the tumor."

Plasma cells were linked with poor patient outcomes when cells called cancer-associated fibroblasts, which are known to interfere with the activity of immune cells, were plentiful, which suggested that fibroblasts may be preventing plasma cells from communicating with other immune cells.

"These different microenvironments could account for sometimes differing reports about the role of plasma cells in patient prognosis," said Dan Theodorescu, MD, Ph.D., director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. "This avenue of investigation could help us identify biomarkers, or even precision therapies, that improve outcomes for patients with this particularly deadly cancer."

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Selected markers of ovarian cancer and their relation to targeted therapy (Review)

Affiliations.

• 1 Department of Perinatology and Women's Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland.
• 2 Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, 31-826 Kraków, Poland.
• 3 Medical Department, Bausch Health Poland, 02-674 Warsaw, Poland.
• 4 Gynecological Oncology Center Poznań, 60-850 Poznan, Poland.
• PMID: 38628658
• PMCID: PMC11019661
• DOI: 10.3892/etm.2024.12523

Despite advances in surgical treatment techniques and chemotherapy-including anti-angiogenic and immune poly (ADP-ribose) polymerase inhibitors, the 5-year survival rate in ovarian cancer (OC) remains low. The reasons for this are the diagnosis of cancer in advanced clinical stages, chemoresistance and cancer recurrence. New therapeutic approaches are being developed, including the search for new biomarkers that are also targets for targeted therapy. The present review describes new molecular markers with relevance to targeted therapy, which to date have been studied only in experimental research. These include the angiogenic protein angiopoietin-2, the transmembrane glycoprotein ectonucleotide pyrophosphatase/phosphodiesterase 1, the adhesion protein E-cadherin, the TIMP metallopeptidase inhibitor 1 and Kruppel-like factor 7. Drugs affecting cancer stem cells (CSCs) in OC, such as metformin and salinomycin, as well as inhibitors of CSCs markers aldehyde dehydrogenase 1 (with the drug ATRA) and the transcription factor Nanog homeobox (microRNA) are also discussed. A new approach to prevention and possible therapies under investigation such as development of vaccines containing a subpopulation of CD117(+) and CD44(+) stem cells with a promising option for use in women with OC was described.

Keywords: E-cadherin; Kruppel like factor 7; Nanog homeobox; TIMP metallopeptidase inhibitor 1; aldehyde dehydrogenase 1 family member A1; angiopoietin-2; cancer stem cells; ectonucleotide pyrophosphatase/phosphodiesterase 1; endothelial cell-specific molecule 1; markers; ovarian cancer; sodium-dependent phosphate transport protein 2B; vaccines containing CSCs.

Copyright: © 2024 Markowska et al.

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• Ovarian cancer
• Risk factors

Globally, ovarian cancer is the eighth most common cancer in women, accounting for an estimated 3.7% of cases and 4.7% of cancer deaths in 2020. Until the early 2000s, age-standardized incidence was highest in northern Europe and North America, but this trend has changed; incidence is now declining in these regions and increasing in parts of eastern Europe and Asia. Ovarian cancer is a very heterogeneous disease and, even among the most common type, namely epithelial ovarian cancer, five major clinically and genetically distinct histotypes exist. Most high-grade serous ovarian carcinomas are now recognized to originate in the fimbrial ends of the fallopian tube. This knowledge has led to more cancers being coded as fallopian tube in origin, which probably explains some of the apparent declines in ovarian cancer incidence, particularly in high-income countries; however, it also suggests that opportunistic salpingectomy offers an important opportunity for prevention. The five histotypes share several reproductive and hormonal risk factors, although differences also exist. In this Review, we summarize the epidemiology of this complex disease, comparing the different histotypes, and consider the potential for prevention. We also discuss how changes in the prevalence of risk and protective factors might have contributed to the observed changes in incidence and what this might mean for incidence in the future.

The disease we call ‘ovarian’ cancer encompasses a wide range of tumour types, including cancers that arise in the fallopian tube; changes in coding and reporting make incidence trends over the past decade difficult to interpret.

Between 1920 and 1960, successive birth cohorts had lower risk of developing ovarian cancer, although incidence might be increasing again in women born after about 1970.

With the recognition that high-grade serous cancers originate in the fallopian tube, salpingectomy (opportunistic or targeted) offers the opportunity for prevention and could delay the need for oophorectomy among women with a high genetic risk.

Hormonally related factors, including pregnancy, oral contraceptive use and breastfeeding, reduce the risk of ovarian cancer, particularly the endometrioid and clear cell histotypes; the benefits of newer contraceptive formulations are less clear.

Lifestyle exposures, including smoking, obesity and, potentially, sedentary behaviour or inactivity, all increase the risk of a woman developing the less common histotypes but do not appear to affect the risk of developing the most common high-grade serous cancers.

If current trends continue, the incidence of ovarian cancer might start to increase, although widespread uptake of salpingectomy and expanded identification and interventions targeting BRCA mutation carriers have the potential to reduce incidence.

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Penelope M. Webb

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Webb, P.M., Jordan, S.J. Global epidemiology of epithelial ovarian cancer. Nat Rev Clin Oncol 21 , 389–400 (2024). https://doi.org/10.1038/s41571-024-00881-3

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Ovarian cancer.

Taruna Arora ; Sanjana Mullangi ; Manidhar Reddy Lekkala .

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Last Update: June 18, 2023 .

• Continuing Education Activity

Ovarian cancer is one of the most common causes of cancer-related deaths in women of developed nations. They should be diagnosed early for better chances at curing it to avoid the high rates of morbidity and mortality. This article reviews the epidemiology, risk factors, pathophysiology, histopathology of ovarian cancer and also highlights the role of the interprofessional team in the management of this condition along with a discussion of few landmark trials and recent ongoing trials impacting the future treatment regimens and subsequent prognosis of patients with this disease.

• Describe the epidemiology of ovarian cancer.
• Review the evaluation of a patient with suspected ovarian cancer.
• Summarize the treatment options of ovarian cancer.
• Outline some interprofessional team strategies that can result in better care coordination for patients presenting with ovarian cancer.
• Introduction

Ovarian cancer is the leading cause of death in women diagnosed with gynecological cancers. It is also the fifth most frequent cause of death in women, in general. [1]  Most of the cases are diagnosed at an advanced stage, which leads to poor outcomes of this disease. The existing screening tests have a low predictive value contributing further to this misery. Detailed gynecological evaluation along with transvaginal ultrasound and laboratory marker like cancer antigen-125 (CA-125) assay are the key early detection strategies which have shown no significant beneficial effect in the morbidity or mortality of this cancer. [2]  

The standard line of care treatment includes surgery and platinum-based chemotherapy; however, anti-angiogenic bevacizumab and Poly(ADP-ribose) polymerase (PARP) inhibitors have gained momentum in the management of this gynecological malignancy in the past decade. [3]  

A high rate of recurrence following the initial treatment has been observed. Most of these relapsed cases are less curable and known to have an increased incidence of treatment failures. Hence, effective prevention and detection strategies and new treatment modalities based on a better understanding of molecular characterization of this cancer are the need of the hour. This article reviews the epidemiology, risk factors of ovarian cancer and also highlights the evaluation and multidisciplinary approach in the management of this condition, along with a discussion of a few of the recent ongoing trials.

There are various risk factors associated with ovarian cancer. It mostly affects postmenopausal women, where increasing age is associated with an increased incidence, advanced stage of this disease, and lower reported survival rates. Parity poses a protective role according to a few case-control studies with higher age at childbirth linked to a decreased risk of ovarian cancer. [4]  The strongest risk factor of ovarian cancer is a positive family history of breast or ovarian cancer, where a personal history of breast cancer also augments the risk. [5]  Several studies have shown an increased risk of smoking, especially the risk of mucinous epithelial tumors. [4]

• Epidemiology

In 2020, there are approximately 21,750 new ovarian cancer cases, which comprises 1.2% of all cancer cases. The estimated number of deaths related to it are 13,940. The 5-year relative survival rate is expected to be 48.6%. Around 15.7% of the ovarian cancer cases are diagnosed at the local stage, and about 58% at the metastasized stage, where the 5-year survival dips down to 30.2% instead of 92.6% if detected at an early stage of local spread. An average incidence rate per 100,000, age-adjusted to the 2000 US standard population is 11.1 in 2012-2016. The incidence is highest in non-Hispanic whites (11.6 per 100,000), followed by American Indians and Alaska Natives (10.3 per 100,000), Hispanics (10.1 per 00,000), non-Hispanic blacks, and Asian and Pacific Islanders. Ninety percent of ovarian cancers are epithelial, with the serous subtype being the most common. Age-adjusted rates of new ovarian cancer cases are on a reducing trend based on statistical models of analysis. [6]

• Histopathology

The four most common histological types of epithelial ovarian cancer are serous, endometrioid, clear cell, and mucinous tumor.  They have further subtypes based on their peculiar biology and treatment responses. The uncommon subtypes are Brenner and seromucinous.

Ovarian cancer can be further classified into two subtypes- Type I or Type II tumors, the latter being a more fatal variant, thought to be caused by continuous ovarian cycles leading to inflammation and endometriosis. Type I tumor includes low-grade serous, endometrioid, clear-cell, and mucinous carcinomas, with the rare subtypes being seromucinous and Brenner tumors. Type I tumors mostly arise from atypical proliferative (borderline) tumors. Type II tumors include high-grade serous carcinoma, carcinosarcoma, and undifferentiated carcinoma, which mainly originate from serous tubal intraepithelial carcinoma. Type I tumors usually present at an early stage and are low grade except for clear cell, which is considered high grade. Their proliferative activity is usually low. They are diagnosed early and carry a good prognosis. In comparison, Type II tumors are high-grade tumors and almost always of advanced stage. They have high proliferative activity with rapid and aggressive progression and a high degree of chromosomal instability compared to type I with the presence of p53 mutations in most of the cases. [7]

Ovarian serous carcinoma is the most common subtype of ovarian carcinoma. It presents as low-grade (10% of all the serous subtype tumors) or high-grade carcinoma (90% of all the serous subtype tumors).  The low-grade subtype (LGSC) shows minimal nuclear atypia, rare mitosis, and lesser molecular abnormalities. In contrast, the high-grade subtype (HGSC) shows significant nuclear atypia and mitosis (>12 per 10 high-power fields) with more copies of molecular abnormalities as seen by cytogenetic analysis. [8] LGSCs are usually diagnosed at a young age and carry a better prognosis than HGSCs, which tend to present at an older age with a 10-year mortality rate of 70%. [9]  Further analysis revealed that a high frequency of KRAS and BRAF mutations are found in low-grade serous carcinoma, whereas high-grade serous carcinoma shows a high frequency of p53 and BRCA 1 and 2 genes mutations with an absence of KRAS/BRAF mutation. [8]  

Ovarian endometrioid carcinomas have been postulated to be derived from endometriosis. Morphologically, their cut sections reveal cystic areas showing soft masses and bloody fluid, with less common solid areas showing extensive hemorrhage and necrosis. No major molecular markers have been studied in this subtype; however, the beta-catenin gene mutation is noted to be one of the most common molecular abnormalities. One can differentiate between the endometrioid carcinoma arising from ovaries and uterus based on the molecular studies, even though they appear quite similar morphologically. Ovarian endometrioid cancers have microsatellite instability and PTEN alterations less frequently than the ones arising from the uterine cavity. [8]  Single ovarian carcinoma is found to have a less frequency of beta-catenin mutation as compared to synchronous tumors. [10] They are usually diagnosed at an earlier stage, offering a better prognosis to women with this histological subtype of ovarian cancer.

Ovarian mucinous carcinoma (MOC) is often heterogeneous, where a mixture of elements, including benign and malignant tumors, are found in a single specimen. KRAS mutations are common in these tumors. As commonly associated with metastases from the gastrointestinal tract (GI), the intestinal subtype will show the presence of glands with architectural and cytology clinical features of adenocarcinoma; however, it may lack stromal invasion. [8] It is hard to distinguish primary ovarian mucinous carcinomas from metastatic mucinous appendix tumors due to their close association, hence many gynecologic oncologists practice routine appendectomy in all these patients with MOC. [11] Evidence of micro invasions is less commonly found in intestinal subtype borderline tumors. Invasive mucinous carcinoma is uncommon, and the prognosis is found to be favorable compared to serous subtype, considering the mostly diagnosed at stage I itself, about 80%. [8] The molecular alterations responsible for malignant conversion of the benign mucinous tumor is still unknown.

Ovarian clear cell carcinomas are less prevalent and account for <5% of ovarian carcinoma. Histopathologically they show cellular clearing, cystic growth pattern, and a characteristic hobnail growth pattern. Immunohistochemically, overexpression of BAX in stage I and stage II tumors is predominant, whereas anti-apoptotic protein BCL-2 is expressed more in metastatic lesions than in primary lesions.  A lower relative BCL-2/BAX ratio is found in early-stage ovarian clear cell carcinoma tumors as compared to the higher relative ratio found in metastatic lesions. [8] They are also commonly diagnosed in earlier stages and hence carry a good prognosis, similar to endometrioid cancers.

Cytokeratin-7 (CK7) shows diffuse and strong staining in all serous ovarian tumors. It is positive in 80% to 100% of mucinous ovarian tumors, and other ovarian epithelial tumors also show positivity for CK7. About 96% of ovarian adenocarcinomas were positive for CK7 compared to metastatic colorectal, which shows about a 25% positivity.

• History and Physical

Symptoms of ovarian cancer are non-specific, and hence they can be easily missed at an early stage as the symptoms can be attributed to other possible disease processes. The symptoms often become apparent in the late stage (stage III or stage IV). The presenting symptoms include a combination of abdominal fullness, bloating, nausea, abdominal distention, early satiety, fatigue, change in bowel movements, urinary symptoms, back pain, dyspareunia, and loss of weight. The symptoms occur vaguely months before the diagnosis of ovarian cancer. [12]

A thorough physical examination should be done, including rectovaginal examination on an empty bladder to look for pelvic and abdominal masses in clinical cases of high suspicion. In advanced cases, a palpable pelvic mass or ascites or diminished breath sounds due to the presence of pleural effusions can also be found. As a result of metastases to the umbilicus, a sister Mary Joseph nodule will rarely be seen. Sign of Lesar-Trélat, which refers to a sudden increase in the finding of seborrheic keratosis, also gives a clinical clue indicating the presence of occult cancer. [13]

Paraneoplastic syndromes can be infrequently associated with ovarian cancer. Subacute cerebellar degeneration due to tumor-induced autoimmune reactivity against cerebellar antigens can lead to symptoms like ataxia, dysarthria, nystagmus vertigo, and diplopia. This condition commonly precedes the occurrence of the primary ovarian tumor by months or years. Trousseau's syndrome has also been associated with ovarian cancer. Increased levels of circulating parathyroid hormone-releasing protein can lead to hypercalcemia, which can manifest as altered mental status, fatigue, constipation, abdominal pain, and increased thirst and urinary frequency. Such early warning signs of various paraneoplastic syndromes should be considered well in advance to avoid the diagnosis of ovarian cancer directly at an advanced stage where the patient may not be amenable to curative therapy. [14] [13]

In patients with a high degree of clinical suspicion, radiological imaging including transvaginal ultrasonography (TVUS, highly sensitive and preferred) and/or abdominal and pelvic ultrasonography is done. It gives a fair idea about the size, location, and complexity of the ovarian mass. For defining tumor extension, further imaging with chest and abdomen pelvis CT scan, pelvic MRI, and/or PET scan can be done. 

Measurement of CA-125 levels is usually done in adjunction with the imaging. CA-125 is elevated in most of the epithelial ovarian cancers overall, but only half of the early stage epithelial ovarian cancers. [15] The specificity and positive predictive value is found to be higher in postmenopausal women than in premenopausal women. Increased CA-125 levels are also observed in other physiological or benign pathological conditions such as endometriosis, pregnancy, ovarian cysts, inflammatory peritoneal diseases. Hence, other biomarkers are currently being studied to improve specificity for ovarian cancer biomarkers. Human epididymis protein 4 (HE4) is a new biomarker that is currently being evaluated. It is found to be more sensitive for ovarian cancer and found in approximately 100% of serous and endometrioid subtypes. Based on recent studies, a combination of higher CA-125 and HE4 levels are thought to be predictive of malignant ovarian tumors and may serve as a useful diagnostic tool in the future. [16] CA-125 levels can also be used to calculate the risk of malignancy index (RMI), which also utilizes TVUS findings and menopausal status. RMI above 200 is associated with a high risk of malignancy, with a greater than 96 % specificity. [13]

The malignancy algorithm (ROMA) risk utilizes a mathematical formula that incorporates HE-4 and CA 125 levels adjusted for pre and post-menopausal status to determine the risk of malignancy. [17]  The ROMA is a valuable screening test that takes advantage of the high specificity of HE4 and high-sensitivity of CA-125 to detect more patients of ovarian cancer overall, especially in the early stages. The risk of malignancy index (RMI) index is usual for the patient, where the score incorporates TVUS findings, menopausal status, and CA-125 levels. [13] Currently, multimarker longitudinal models are being worked on for the early detection of ovarian cancer. [18]

Optimal staging with exploratory laparotomy and close evaluation of abdominal and pelvic region for disease, including inspection of peritoneal surfaces with biopsy and/or pelvic washings, is done. It establishes the stage using the International Federation of Gynecology and Obstetrics (FIGO) staging of ovarian cancer. It is followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy (BSO) with para-aortic and pelvic lymph node dissection and omentum. The tissue biopsies evaluated by a pathologist help provide the final diagnosis concerning the histological type, grade, and staging. [9]

• Treatment / Management

Debulking Surgery

Treatment of ovarian cancer conventionally includes a combination of chemotherapy and surgery. In the early stage of invasive epithelial ovarian carcinoma, unilateral salpingo-oophorectomy while preserving the uterus and contralateral ovary is done, with comprehensive surgical staging where lesions show a low likelihood of progressing to malignancy. However, for advanced-stage ovarian cancer, a debulking surgery comprising hysterectomy/bilateral salpingo-oophorectomy (BSO) has shown better outcomes. It is imperative to determine whether debulking surgery would be beneficial for a patient by initially performing exploratory laparoscopic surgery. The presence of a large or residual tumor burden can block perfusion to the affected region leading to damaged tissue and increase chances of further cellular damage with multidrug chemotherapy resistance. [9]   Laparoscopic surgeries are noted to be less invasive with decreased recovery time as opposed to debulking surgeries. Patients with ovarian cancer should have genetic risk evaluation and germline, somatic (BRCA 1/2) testing done if previously not tested, as the latter guides the maintenance therapy.

Primary Debulking Surgery versus Neoadjuvant Chemotherapy

A gynecologic oncologist initially evaluates patients with suspected advanced stage IIIC or IV ovarian cancer to determine if they are appropriate surgical candidates or not. Neoadjuvant chemotherapy is recommended to decompress the tumor burden for the ones deemed poor surgical candidates with a low likelihood of optimal cytoreduction.  According to the Society of Gynecologic Oncology (SGO) and American Society of clinical oncology (ASCO), clinical practice guidelines state that women with a favorable surgical profile can receive either neoadjuvant chemotherapy or undergo cytoreduction surgery. But if they have a high likelihood of attaining cytoreduction to less than 1 cm with acceptable morbidity, primary cytoreductive surgery should be preferred. Before administering neoadjuvant chemotherapy, patients should carry a histological diagnosis of invasive ovarian cancer confirmed by biopsy preferred over specimens obtained from fine-needle aspiration of paracentesis. [19]

Various clinical trials have compared neoadjuvant chemotherapy with interval cytoreduction surgery versus primary cytoreductive surgery upfront, showing equal overall median survival. Two of the phase III trials have shown non-inferiority of neoadjuvant chemotherapy compared to cytoreductive surgery followed by chemotherapy in women with stage IV disease. This proves that neoadjuvant chemotherapy can be significantly utilized in patients with advanced-stage invasive ovarian cancer patients who are poor surgical candidates with high tumor burden. The European organization for research and treatment of cancer (EORTC), phase III trial EORTC 55971 recruited women with stage IIIC-IV epithelial ovarian cancer (n=670) and CHORUS trial had a similar recruitment profile with women of stage III A-B besides (n= 550). They showed non-inferiority of median overall survival with neoadjuvant chemotherapy when compared to primary cytoreductive surgery upfront. In a pooled analysis of individual patient data from these two trials, EORTC 55971 and CHORUS trials, women with stage IV disease had better survival outcomes with neoadjuvant chemotherapy followed by cytoreductive surgery. [20]   An exploratory analysis of the EORTC 55971 randomized trial found that patients with stage IIIC (<4.5 cm) and less invasive metastatic tumors had better survival outcomes with primary cytoreductive surgery. In contrast, patients with stage IV disease (>4.5cm) and more invasive metastatic tumors had better survival outcomes with neoadjuvant chemotherapy. [21]

Maximal Cytoreductive Surgery

One of the most powerful independent determinants of improved median survival among patients with stage III or IV ovarian carcinoma is to achieve maximal cytoreduction. Hence, irrespective of the surgery sequence, before or after neoadjuvant chemotherapy, optimal cytoreduction is strongly recommended to achieve ideally no residual disease. A meta-analysis of 6885 patients with stage III and IV ovarian cancer showed a 5.5% increase in overall median survival with a 10% increase in maximal cytoreduction in one of the studies. When the actuarial survival was being estimated comparing cohorts with less than or equal to 25% maximal cytoreduction and more than 75% maximal cytoreduction, there was an increase of 50% of mean weighted median survival time.  However, platinum dose intensity did not have a statistically significant relation to the log median survival time. [22]  If interval cytoreduction surgery is being performed after neoadjuvant chemotherapy, it is usually done after four or fewer cycles ensuring early surgical intervention in the disease course. However, if the patient has received bevacizumab as a part of their initial neoadjuvant chemotherapy regimen, there should be a gap of at least 20 days before surgical intervention due to the risk of highly compromised postoperative healing. [23]  

Primary Chemotherapy and Neoadjuvant Therapy

• Early-stage ovarian cancer:Adjuvant chemotherapy in women with early-stage ovarian cancer has been studied extensively and based on the evidence. The final clinical decision has to be individualized for every patient. Based on four randomized control trials (ACTION 2003; Bolis 1995; ICON1 2003; trope 2000) which studied platinum-based chemotherapy, women with early-stage epithelial ovarian cancer showed better overall survival (OS) (HR 0.71; 95% CI 0.53 to 0.93) and progression-free survival (PFS) (HR 0.67; 95% CI 0.53 to 0.84) with adjuvant chemotherapy than the ones who did not receive it.  However, one of those trials, ICON1 2003, showed similar evidence in high-risk patients with adjuvant chemotherapy but not among others. Based on the pooled data in a meta-analysis, which included all the patients (total of 772) in ICON1 2003 and two-thirds of patients in ACTION 2003, evidence of overall benefit in early-stage ovarian cancer women was observed after sub-optimal staging. [24]  In stage IA or 1B epithelial ovarian cancer or grade 1 endometrioid carcinomas, considering the good survival rates, surgical treatment alone is recommended over adjuvant chemotherapy with close observation. [23]  Another prospective randomized phase III trial was done. Patients were randomly assigned to either adjuvant platinum-based chemotherapy or observation followed by surgery, with endpoints being overall survival and recurrence-free survival (RFS). It provided evidence that chemotherapy improves both overall and recurrence-free survival in the non-optimally staged patients (patients with residual disease); however, these findings were not observed in optimally staged patients (patients with a slight chance of residual disease). This suggests that adjuvant chemotherapy in early-stage ovarian cancer affects the micro-metastasis that goes unnoticed at the time of surgical staging. [25]  A meta-analysis of all the randomized clinical trials that studied women of stages I-II epithelial ovarian cancer compared to adjuvant chemotherapy with observation showed no overall survival benefit of adjuvant chemotherapy (hazard ratio 0.91, 0.51 to 1.61). [23] Overall, the available evidence supports the use of adjuvant chemotherapy in patients with early-stage ovarian cancer with high-risk features like the stage IC and stage II disease and clear cell or high-grade histology. While the optimal regimen is unclear, most clinicians use carboplatin with paclitaxel extrapolating their evidence in the advanced stage of ovarian cancer.
• Advanced stage ovarian cancer:The standard approach in treating patients with advanced ovarian cancer uses platinum and a taxane. The option of intravenous (IV) and intraperitoneal (IP) chemotherapy depends on the optimal debulking of the tumor. A phase III trial, GOG111, showed improved overall survival in patients with a combination of cisplatin and paclitaxel when compared to the cohort receiving cisplatin and cyclophosphamide combination. The first line chemotherapeutic agent for epithelial ovarian cancer is platinum-based cisplatin or carboplatin along with a taxane family agent, paclitaxel or docetaxel. There have been many studies concluding that carboplatin is as effective as cisplatin and better tolerated. Also, weekly dose-dense chemotherapy with carboplatin and paclitaxel combination has not shown any additional benefit in PFS than standard three-weekly chemotherapy or an additional third agent or a longer period of the chemotherapy cycle. [23]  Chemotherapeutic agents are administered IV or IP or a combination of both. In advanced age ovarian cancer patients, IP carboplatin chemotherapy is well-tolerated. There have been four landmark trials, namely GOG 104, GOG 114, GOG 172, and GOG 252, which have shown improved survival benefit of intraperitoneal or intravenous chemotherapy, with strong evidence supporting the same, however clinically, its use has been inconsistent. [26] [27] This is mostly due to increased frequency of toxicity, especially neutropenia, thrombocytopenia, neurotoxicity, and adverse gastrointestinal symptoms affecting the quality of life of patients treated with intraperitoneal chemotherapy as well as due to the addition of bevacizumab studied in GOG 252 didn't show any advantage of IV/IP compared to IV with bevacizumab. [28]  

Chemotherapy in Elderly

Elderly patients aged over 70 years or older with comorbidities who have stage III-IV ovarian cancer were studied in a randomized control trial, which showed worse survival outcomes with carboplatin monotherapy versus carboplatin-paclitaxel three weekly/weekly. [23]  But when combination therapy is being used, a modified dose-dense regimen of weekly carboplatin plus paclitaxel has shown to be better tolerated with a lower toxicity profile than the conventional dosing (three weeks schedule). Still, it did not prolong progression-free survival, as shown in a MIT07 phase III trial, which can also be used for elderly patients with comorbidities. [29] [30] The frail elderly patients were found to have decreased high-grade neutropenia, febrile neutropenia, thrombocytopenia, and neuropathy. [23]   An ongoing prospective trial of older women of age equal to or greater than 70 on different chemotherapy regimen combinations will help us predict chemotherapy tolerance. However, preliminary results have commented on patients with higher baseline instrumental activities of the daily living score are more likely to complete four chemotherapy cycles and less likely to experience high-grade toxicity. [31]

Maintenance Therapy

Maintenance therapy is conceptualized to ensure the effective killing of residual slowly dividing cells by decelerating the cell turnover so that the dormant population of cancer cells does not progress to grow enough to be detected by either elevation of biomarkers or clinical evidence of recurrent disease. Several randomized trials have been done to compare maintenance therapy versus observation. 

• Platinum-based agent:A phase III trial, GOG 178, randomized patients to 12 months versus 3 months of maintenance therapy with paclitaxel after complete clinical response with platinum/paclitaxel therapy in patients with stage III-IV ovarian cancer. After 50% accrual interval analysis, improved PFS was seen favoring the extended therapy cohort. However, the study closed early. A follow-up study later showed no overall survival benefit compared to the same maintenance monotherapy for 22 months versus 14 months. [32]  Another trial, GOG 175, showed no significant difference in 5-year survival or recurrence-free interval (RFI) where high-risk early-stage ovarian cancer patients were randomized to observational versus weekly paclitaxel 40 mg/m²x 24 weeks after completion of 6 cycles of carboplatin and paclitaxel for 3 cycles. [33]  A three-arm phase III trial following standard chemotherapy, GOG 0212, compared observation without immediate therapy to 12 months of paclitaxel or polyglutamated paclitaxel but showed disappointing results. [34]  To conclude, the results of maintenance, chemotherapy trials have been discouraging.
• Anti-angiogenic inhibitor:Pazopanib, an oral multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/2/3, platelet-derived growth factor (PDGFR) alpha/beta and c-kit, has also been studied as maintenance therapy in a study of 940 patients with patients of ovarian cancer stage II-IV. These patients had a complete clinical response to five cycles of platinum-taxane chemotherapy and were randomized to pazopanib versus placebo for 24 months showing a median improvement in PFS in the pazopanib arm; no benefit was seen in overall survival data. BRCA1/2 carriers were noted to have an additional significant benefit. [35]  Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that has been studied in combination with chemotherapy followed by bevacizumab, single agent, maintenance therapy in two major landmark trials (ICON7 and GOG0218) of patients with advanced-stage ovarian cancer. The studies showed an improved PFS in the maintenance bevacizumab cohort when compared with surveillance only. [36]  The FDA eventually approved it. Bevacizumab has also been associated with serious side effects like hemorrhage, thrombosis, hypertension, proteinuria, bowel perforation. [23] In a subset analysis of the ICON 7 trial, patients with large volume residual disease after their primary cytoreductive surgery or stage IV disease who fall into the high-risk category showed a greater median overall survival benefit. Secondary analysis of GOG0128 revealed improved overall survival in a particular subgroup of patients with ascites, who are at high risk of recurrence and mortality from stage IV disease. [36]  This targeted therapy should be individualized in patients. However, it does show significant benefit in PFS when used as concurrent therapy followed by single-agent maintenance therapy but without any clear clinical benefit in overall survival.
• Poly(ADP)-ribose polymerase (PARP) inhibitors:PARP inhibitors have recently gained momentum for the maintenance treatment of ovarian cancer. Olaparib was the first FDA-approved drug in this subgroup indicated to treat advanced BRCA mutated ovarian cancer after platinum-based chemotherapy, based on SOLO-1, phase III randomized double-blind, placebo-controlled trial. It showed a reduction in disease progression or death by 70% (hazard ratio 0.30, 0.23 to 0.41; P<0.001). [37] PAOLA-1 trial, a phase III randomized controlled trial of 806 women with stage III-IV high-grade serous or endometrioid ovarian cancer, showed a PFS benefit of 4.5 months in the group that received olaparib and bevacizumab maintenance versus placebo and bevacizumab. [38] This combination of olaparib and bevacizumab achieved FDA approval as a first-line maintenance treatment for these patients with ovarian cancer after initial platinum-based chemotherapy with partial or complete response or tumors associated with homologous recombination deficiency (HRD) defined by the presence of deleterious BRCA mutation. Further noted clinical trials include the VELIA trial and PRIMA trial using Veliparib and Niraparib maintenance therapy, respectively, showing markedly improved PFS compared to the placebo group in patients with newly diagnosed advanced-stage ovarian cancer who initially responded to first-line platinum-based chemotherapy. [39] [40]
• Immunotherapy:It has recently shown significant benefits in solid malignant tumors. However, published data do not show any benefit in patients with ovarian cancers so far. The resulting controversial data diverted the focus on combination strategies involving immune- checkpoint inhibitors with PARPs, chemotherapy, anti-angiogenic agents, and more. A combination of such therapies shows more significant anti-tumor activity than concentrating on a single pathway. This promising data is from initial phase trials, and further results from ongoing phase II and III trials are awaited. [41]
• Vaccines:Vaccines are currently being studied for ovarian cancer, where the basis lies in activating the immune cells to destroy the cancer cells. The potential tumor-associated antigen molecules targeted in ovarian cancer in ongoing ovarian cancer vaccine researches are CA-125, p53 protein, HER-2, and more. [41] There are currently ongoing pilot and phase I or II trials for the use of therapeutic vaccines in ovarian cancer patients by employing novel techniques. Other emerging therapies being studied in clinical trials are using adoptive T-cell transfer and chimeric antigen receptor therapy (CAR-T) as a part of future strategies to ensure reduced cancer burden and improved life expectancy in this patient population.

Recurrent Ovarian Cancer

About 80% of women with advanced-stage ovarian cancer more commonly have tumor progression or recurrence. Platinum free interval (PFI) is one of the most reliable predictors indicating the response of recurrent ovarian cancer to subsequent chemotherapy. PFI refers to the interval between the completion of the last platinum-based chemotherapy and the occurrence of relapse. [42]  However, platinum sensitivity is generally used to refer to an interval of greater than 6 months between the last platinum-based chemotherapy (PBC) cycle and commencement of subsequent PBC.

The role of surgery in cases of recurrent ovarian cancer is yet quite undefined. GOG 213, a phase III multicenter randomized clinical trial enrolled patients with platinum-sensitive recurrent ovarian cancer, randomized patients to surgical cytoreductive surgery followed by adjuvant PBC or only PBC with a primary endpoint of overall survival showed no improved benefit in patients receiving secondary surgical cytoreduction followed by chemotherapy and chemotherapy alone (HR for death 1.29, 0.97 to 1.72; P=0.08). [23]   Desktop III trial, which compares surgery followed by chemotherapy versus chemotherapy only in recurrent platinum-sensitive ovarian cancer, is currently ongoing whose results are eagerly awaited.  They had announced their preliminary results in ASCO 2017 showing improvement in PFS and longer interval of the period to the start of subsequent chemotherapy in favor of surgery followed by chemotherapy. There are two other trials- Surgery for Ovarian Cancer Recurrence (SOCceR) and Surgery or Chemotherapy in Recurrent Ovarian Cancer (SOC 1) comparing surgery and chemotherapy with surgery alone in such groups of patients, with awaited results. To conclude, none of the studies have resulted in longer overall survival with second-degree surgical cytoreduction in patients with platinum-sensitive recurrent epithelial ovarian cancer diagnosed surgery. [43]

Large phase III trials have also resulted in the approval of bevacizumab, as discussed above, which was studied in combination with chemotherapy for the treatment of recurrent ovarian cancer as well as for maintenance therapy (GOG 218, or OCEANS and AURELIA trials). [42]  The studies have shown an objective improvement of PFS. However, they failed to prove a benefit in overall survival. Nevertheless, antiangiogenic agents have shown activity in these platinum-sensitive recurrent ovarian cancer however further studies are needed to define their benefit clearly. Evidence shows the use of aromatase inhibitors like letrozole for the treatment of recurrent low-grade serous and endometrioid epithelial ovarian cancer based on large retrospective cohort studies.

PARP inhibitors have been under clinical development at various stages and have shown their efficacy in patients with germline BRCA mutations. They were first approved as monotherapy in ovarian cancer patients with deleterious germline or somatic BRCA mutations who have not responded to chemotherapy. Further studies showed significant PFS benefit in patients with an initial response to be BC with maintenance PARP inhibitor therapy. An overall survival benefit is yet to be proven, which requires a longer follow-up. SOLO-2 study assessed maintenance monotherapy with olaparib in patients with platinum-sensitive recurrent ovarian cancer and BRCA mutation showing significantly improved PFS for the patients receiving olaparib with no significant detrimental effect on patient's quality of life. [44]  

PAOLA-1, a phase III trial, studied olaparib with bevacizumab in platinum-sensitive recurrent ovarian cancer showing PFS benefit in the patients receiving the combination. The results were quite consistent with those observed in the SOLO 1 trial. The safety profile of olaparib was quite consistent in the trials, with a higher incidence of serious adverse events noted in the group receiving a combination of olaparib and bevacizumab than with placebo plus bevacizumab, the most common one being anemia. [38]  Many phase III trials have shown PARP inhibitor maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer with clinical benefits.  Recently in the 2019 SGO annual meeting, an abstract was presented which described a retrospective study of a few patients who have been previously treated with PARP inhibitor for epithelial ovarian cancer, where a second PARP inhibitor treatment was used; however, the most common reason for discontinuation of treatment was toxicity. [23]  Further studies using PARP inhibitors as maintenance therapy and predicting their resistance would be areas of further research.

Platinum resistance poses a very poor prognosis, where these patients have a recurrence of the disease within 6 months of completion of cytoreductive surgery and adjuvant chemotherapy.  It is imperative to have goals of care discussion with these patients as their overall survival rates are quite grim. Focusing on newer targets like tumor vasculature, DNA repair, intracellular signaling inhibition, and other molecular targets will provide more avenues to be explored for optimizing the treatment of recurrent ovarian cancer.

To conclude, advanced-stage ovarian cancer patients are treated with primary reductive surgery, followed by platinum-based chemotherapy. But poor surgical candidates or patients who might not achieve effective cytoreductive surgery are recommended to undergo neoadjuvant chemotherapy. Optimal cytoreductive surgery is very important to achieve as it is one of the most powerful predictors of survival of these patients. There is a high rate of relapse in patients with advanced-stage whose response to subsequent platinum-based chemotherapy depends on various factors. Targeted therapies are the new emerging treatment strategies where bevacizumab and PARP inhibitors have become first-line therapies for maintenance and PARP inhibitors as the first line for recurrent cases. Genetic screening for all newly diagnosed ovarian cancer is recommended.

• Differential Diagnosis

The differential diagnosis for ovarian cancer includes:

• Colon cancer
• Embryologic remnants
• Gastric adenocarcinoma
• Metastatic gastrointestinal carcinoma
• Ovarian torsion
• Peritoneal cyst
• Retroperitoneal mass
• Uterine fibroids
• Endometriosis
• Papillary adenocarcinoma
• Serous adenocarcinomas
• Undifferentiated adenocarcinomas
• Small-cell adenocarcinomas
• Brenner tumors
• Radiation Oncology

Historically, whole abdomen radiation was practiced during early times; however, due to the increased frequency of toxicity and complications, its use became nonexistent. Currently, the role of radiation in ovarian cancer is limited to palliation, either for symptom control or to treat a localized spread of disease. Adjuvant radiotherapy has not even shown any survival benefit in the early stages of clear cell carcinoma, including a high-risk subset of patients. [45]

Due to the advent of advanced systemic therapies, radiation has taken a backseat in the management of ovarian cancer, offering limited use. Stereotactic body radiotherapy (SBRT) is one of the newer techniques for palliative radiation. There is still evidence of high rates of distant progression of lesions with its use, even when local control is achieved. [46]

Currently, with the emergence of new techniques like SBRT, intensity-modulated radiotherapy, and low dose hypofractionation, the role of radiation is strongly considered for local-regionally recurrent ovarian cancer, especially for chemotherapy-resistant lesions. [47] [48]

Ovarian cancer is staged according to the 8th edition American Joint Committee of Cancer (AJCC), International Federation of Gynecology and Obstetrics (FIGO) staging system and corresponding Tumor, Node, Metastasis (TNM) classification.

Stage I - Tumor limited to ovaries (one or both) or fallopian tube(s)

• IA - Tumor limited to one ovary (capsule intact) or fallopian tube, no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings
• IB - Tumor limited to both ovaries (capsules intact) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings
• IC - Tumor limited to one or both ovaries or fallopian tubes, with any of the following:
• IC1    Surgical spill
• IC2    Capsule rupture before surgery or tumor on the ovarian or fallopian tube surface
• IC3    Malignant cells in ascites or peritoneal washings

Stage II - Tumor involves one or both ovaries or fallopian tubes with a pelvic extension below pelvic brim or primary peritoneal cancer

• IIA - Extension and/or implants on the uterus and/or fallopian tube(s) and/or ovaries
• IIB - Extension to and/or implants on other pelvic tissues

Stage III - Tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with microscopically confirmed peritoneal metastasis outside the pelvis and/or metastasis to the retroperitoneal (pelvic and/or para-aortic) lymph nodes

• IIIA1 - Positive retroperitoneal lymph nodes only (histologically confirmed)
• IIIA1i  Metastasis up to and including 10 mm in greatest dimension
• IIIA1ii  Metastasis more than 10 mm in greatest dimension
• IIIA2   Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes
• IIIB - Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension with or without metastasis to the retroperitoneal lymph nodes
• IIIC - Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension with or without metastasis to the retroperitoneal lymph nodes (includes an extension of tumor to the capsule  of liver and spleen without parenchymal involvement of either organ)

Stage IV - Distant metastasis, including pleural effusion with positive cytology; liver or splenic parenchymal metastasis; metastasis to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity), and transmural involvement of intestine

• IVA - Pleural effusion with positive cytology
• IVB - Liver or splenic parenchymal metastases; metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); transmural involvement of intestine

The prognosis of ovarian cancer is directly dependent on the disease stage at the time of diagnosis. It is also significantly associated with baseline performance status, FIGO stage, and volume of residual disease post-primary cytoreductive surgery. The median survival of ovarian cancer is approximately around 40% to 50% at 10 years, with stage-related survival for stage I between 70% to 92% compared to stage IV being less than 6%. [49]  

In women with a disease that spread to adjacent tissues, 5-year survival rates drop down to 80% and 25% for the ones with metastatic disease. [9]  Patients with recurrent disease can be treated. However, they are usually incurable. Recurrent platinum-sensitive ovarian cancer median survival is approximately 3 years; however, it is about just 1 year for platinum-resistant patients. [49] [50]  

Most of these patients with ovarian cancer develop malignant bowel obstruction in the late-stage, which is quite difficult to manage. Palliative symptom management is the mainstay in such patients. Debulking surgery is the strongest predictor of prognosis, where the volume of residual disease post-surgery is directly correlated to overall survival and PFS. [51]

• Complications

Women who succumbed to ovarian cancer are found to have various complications in the last 6 months of life, the most common ones being:

• Fatigue or weakness (75%)
• Nausea or vomiting (71%)
• Constipation (49%)
• Pedal edema (44%)
• Anemia (34%) 

Women who could not be offered treatment are frequently found to have serious complications like ascites, bowel obstruction, pleural effusion, and bladder obstruction, apart from disorders of nutrition. [52]

• Deterrence and Patient Education

The patient should be explained and counseled about all the treatment options available along with prognosis at the time of diagnosis, depending on the stage of presentation. Counseling for genetic testing should also be done, which does have an impact on treatment at times. The palliative care team and other related consultants' involvement should be sought timely regardless of cancer stage to enable comprehensive care, anticipate the disease course, and make a great impact on the quality of life of the patients. Patients should also be explained about the recent ongoing clinical trials if pertinent to their particular case.

• Enhancing Healthcare Team Outcomes

Ovarian cancer remains one of the lethal malignancies in women despite the leading ongoing clinical trials and the introduction of new treatment lines in the past few decades. The poor clinical outcome is majorly due to the failure of effective strategies for the early detection of ovarian cancer. [53] There is also evidence regarding the deviation of care from the recommended guidelines, possibly due to clinical variation seen in ovarian cancer care. [54]

With the goal of ovarian cancer to be diagnosed at an earlier and more curable stage, we are still in need of the development of effective strategies. The volume of residual disease post cytoreduction surgery is one of the powerful determinants of patients' survival. Hence it should be done only by an experienced gynecologic oncologist who sees a high number of cases at a large busy hospital (>20 cases/year). [55]

Shared decision-making in terms of management of patients regarding newly available treatment strategies or clinical trials by going through benefits, safety profile, symptom control, and a discussion about the prognosis is one of the key elements. A close interprofessional team play with major roles played by medical oncologists and surgical oncologists helps in the smooth and effective management of the patients. Involvement of palliative care early helps fully optimize the treatment course and improve the quality of life. [56] [57]

Patients in clinical remission should be offered affordable yet effective strategies for close surveillance follow-ups where patients should also be educated about the symptoms indicating recurrence of the disease and should be encouraged for genetic risk counseling if not done previously in the early disease course.

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Disclosure: Taruna Arora declares no relevant financial relationships with ineligible companies.

Disclosure: Sanjana Mullangi declares no relevant financial relationships with ineligible companies.

Disclosure: Manidhar Reddy Lekkala declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Arora T, Mullangi S, Lekkala MR. Ovarian Cancer. [Updated 2023 Jun 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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