research articles ovarian cancer

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Research Results and Study Updates

See Advances in Ovarian Cancer Research for an overview of recent findings and progress, plus ongoing projects supported by NCI.

FDA approved mirvetuximab soravtansine-gynx (Elahere) to treat people with advanced, platinum-resistant ovarian cancer whose tumors overproduce a protein called FR-α. The full approval was based on the results of a large, randomized trial called MIRASOL, which showed Elahere improved survival for these people.

Researchers have developed tiny “drug factories” that produce an immune-boosting molecule and can be implanted near tumors. The pinhead-sized beads eliminated tumors in mice with ovarian and colorectal cancer and will soon be tested in human studies.

New results from a large study show that trametinib (Mekinist) is an effective treatment for low-grade serous ovarian cancer. The findings are the first strong evidence that this rare type of ovarian cancer should be treated differently from other forms of the disease.

For patients with recurrent ovarian cancer who meet strict criteria, additional surgery may improve survival, results from a large clinical trial show.

A microRNA—a molecule made by cells to turn genes on and off—called miR-181a may help high-grade serous ovarian cancer form, a study has found. The scientists think the microRNA could potentially help doctors detect ovarian cancer earlier.

Three recently launched NCI-supported studies could help researchers better understand the causes of racial/ethnic disparities in ovarian cancer. The ultimate goal is to eliminate disparities and improve survival for all women with the disease.

Secondary surgery for women with recurrent ovarian cancer does not improve how long those women live, findings from a large trial show. The results call into question the current standard of practice for these patients.

In three large clinical trials of women with newly diagnosed ovarian cancer, treatment with a PARP inhibitor as first-line therapy, maintenance therapy, or both, extended the length of time before participants’ cancers came back or got worse.

Many women diagnosed with ovarian and breast cancer are not undergoing tests for inherited genetic mutations that can provide important information to help guide decisions about treatment and longer-term cancer screening, a new study has found.

Surgery to remove all the lymph nodes in the area around an advanced ovarian tumor did not improve survival in a recent randomized clinical trial. The study also found systematic lymphadenectomy was associated with more frequent serious complications.

In a recent trial, the PARP inhibitor olaparib substantially delayed ovarian cancer from coming back after the first line of chemotherapy. Could the findings change the standard of care for newly diagnosed ovarian cancer with a BRCA mutation?

FDA has expanded its approval of rucaparib (Rubraca) as a maintenance therapy for women with recurrent ovarian, fallopian tube, or primary peritoneal cancer whose tumors shrank after subsequent treatment with a platinum-based chemotherapy.

Scientists have struggled to come up with a simple test to detect endometrial and ovarian cancers early, when they are most likely to respond to treatment. Can a liquid biopsy test called PapSEEK change that?

The experimental vaccine targets a protein found at elevated levels in about 90% of the most common type of ovarian cancer. If validated in human studies, researchers believe the vaccine may be particularly useful for women who carry BRCA1 and BRCA2 gene mutations.

A new study provides more evidence that the most common form of ovarian cancer may originate in the fallopian tubes, and that there is a window of nearly 7 years between development of fallopian tube lesions and the start of ovarian cancer.

A large international study suggests that the presence of certain immune cells within the tumors of some patients with ovarian cancer are associated with improved survival.

FDA has granted regular approval to olaparib tablets (Lynparza®) as maintenance treatment for patients with recurrent ovarian cancer who are having partial or complete responses to platinum-based chemotherapy.

Results from the first large prospective study of breast and ovarian cancer risk in women with inherited mutations in the BRCA 1 or BRCA2 genes confirm the high risks estimated from earlier, retrospective studies.

The FDA approved the PARP inhibitor niraparib for use as a maintenance therapy for some women with advanced ovarian cancer.

The FDA has approved rucaparib for women with BRCA-positive advanced ovarian cancer based on findings from two small clinical trials showing that it shrank tumors.

Ovarian Cancer: An Overview

• PMID: 32606233

Ovarian cancer currently is the fifth leading cause of cancer-related deaths among women in the United States, and approximately 140 000 women die globally per year of ovarian cancer. This debilitating disease presents subtly, and when it is diagnosed, treatment options often are limited. To provide care that is most favorable for the patient, health care professionals must have a basic understanding of the signs and symptoms of ovarian cancer and the imaging tools and treatment options available. This article provides a succinct overview of ovarian cancer, including diagnostic imaging.

© 2020 American Society of Radiologic Technologists.

Publication types

• Ovarian Neoplasms / diagnostic imaging*
• Ovarian Neoplasms / mortality
• Ovarian Neoplasms / therapy
• United States / epidemiology

REVIEW article

Research progress in endometriosis-associated ovarian cancer.

• Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan Province, China

Endometriosis-associated ovarian cancer (EAOC) is a unique subtype of ovarian malignant tumor originating from endometriosis (EMS) malignant transformation, which has gradually become one of the hot topics in clinical and basic research in recent years. According to clinicopathological and epidemiological findings, precancerous lesions of ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC) are considered as EMS. Given the large number of patients with endometriosis and its long time window for malignant transformation, sufficient attention should be paid to EAOC. At present, the pathogenesis of EAOC has not been clarified, no reliable biomarkers have been found in the diagnosis, and there is still a lack of basis and targets for stratified management and precise treatment in the treatment. At the same time, due to the long medical history of patients, the fast growth rate of cancer cells, and the possibility of eliminating the earliest endometriosis-associated ovarian cancer, it is difficult to find the corresponding histological evidence. As a result, few patients are finally diagnosed with EAOC, which increases the difficulty of in-depth study of EAOC. This article reviews the epidemiology, pathogenesis, risk factors, clinical diagnosis, new treatment strategies and prognosis of endometriosis-associated ovarian cancer, and prospects the future direction of basic research and clinical transformation, in order to achieve stratified management and personalized treatment of ovarian cancer patients.

1 Introduction

Endometriosis (EMS) is a prevalent condition that significantly impacts the quality of life and reproductive function in women. According to statistics, the prevalence of EMS among women of childbearing age ranges from 5% to 10% ( 1 ), while it can reach as high as 20% to 60% in women experiencing pelvic pain or infertility ( 2 ). Despite its benign nature, EMS shares biological characteristics with malignant tumors, showing invasive, adhesive, and metastatic potentials, with a risk of malignant transformation. As epidemiological and molecular genetic research continues to reveal, EMS is closely related to epithelial ovarian cancer (EOC), especially ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC). Therefore, ovarian cancers closely associated with endometriosis, which may arise malignantly from endometriosis, predominantly manifest as OCCC and OEC. Collectively, these are referred to as Endometriosis-associated ovarian cancer (EAOC). Early in 1925, Sampson ( 3 ) pioneered the demonstration of the correlation between EMS and ovarian cancer and subsequently proposed the pathological diagnostic criteria for EAOC. These criteria comprise: 1) the existence of cancerous tissue in proximity to endometriotic lesions, 2) exclusion of metastasis from other tumor sources, and 3) the presence of characteristic glandular epithelium surrounding endometriotic lesions. In 1953, Scott introduced an additional criterion ( 4 ): microscopic evidence of the transformation from endometriotic lesions to malignant tissue. Compared to non-EAOC patients, those with EAOC exhibit a younger age at diagnosis, an earlier onset of the disease, lower tumor grades, and lower recurrence rates ( 5 ), suggesting that EAOC represents a distinct subtype of solid tumors. At present, the diagnosis of EAOC mainly depends on surgery and pathological examination, but the rate of missed diagnosis is often increased due to the “burnout effect” of the tumor and the doctor’s neglect of EMS lesions when reading the film. By comprehensively reviewing the epidemiology, pathogenesis, risk factors, clinical diagnosis, treatment modalities and prognosis of EAOC, this review aims to elucidate the distinctive characteristics of EAOC, facilitate early identification by clinicians and provide a valuable reference for enhancing the prognostic outcomes associated with EAOC.

2 Epidemiology of EAOC

In the investigation, we have noted a relatively low risk of ovarian cancer in the general population, standing at merely 1.31% ( 6 ). Nevertheless, for individuals affected by EMS, the risk of ovarian cancer undergoes a significant escalation, exhibiting a relative risk of 2.51-fold ( 7 ), with a lifetime risk reaching 2.5% ( 8 ). Despite the comparatively modest overall incidence risk, the heightened attention is warranted due to the elevated mortality rate of ovarian cancer within gynecological cancers and the prevalent and chronic nature of EMS. In recent years, substantial interest has been directed towards researching whether individuals with endometriosis face an elevated risk of cancer. Consistent findings in the research field underscore that EMS significantly elevates the risk of OCCC and OEC. A study in the Netherlands involving 131,450 patients with histologically confirmed cases of endometriosis revealed incidence rate ratios for OCCC and for OEC ( 9 ) with similar incidence rates from a Chinese study ( 10 ).

3 EAOC pathogenesis

3.1 molecular biology.

Currently, high mutation frequencies are observed in the genes ARID1A, phosphatase and tensin homolog (PTEN), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3C) in EAOC ( 11 ). The ARID1A gene, encoding a crucial component of the SWI/SNF complex, is considered a tumor suppressor gene and is frequently mutated in various cancers, with the highest mutation rates found in the two ovarian cancers associated with endometriosis ( 12 ). By using gene sequencing technology, ARID1A mutations were identified in 46% of 55 cases of OCCC, 30% of 10 cases of OEC, and none of the 76 cases of high-grade serous ovarian carcinoma ( 13 ). PTEN, located on chromosome 10, is a tumor suppressor gene involved in cell regulation,inhibiting tumor cell proliferation, adhesion, metastasis, and angiogenesis ( 14 , 15 ). The PI3K/AKT/mTOR (PI3K) pathway is a classical signaling pathway that plays a crucial role in regulating cell survival, growth, and proliferation, and mutations in this pathway are common in human cancers ( 16 ).

Previous research has indicated that ARID1A gene mutations in OCCC may be associated with the abnormal activation of the PI3K-AKT pathway ( 17 ), a key player in altering tumor growth, proliferation, and metastasis. This abnormal activation enhances the invasiveness of tumors, shortening the time to cancer recurrence and death, suggesting an unfavorable prognosis ( 18 ). However, a mouse experiment revealed that the sole loss of ARID1A gene function does not induce ovarian cancer. Deleting the ARID1A gene alone does not induce ovarian cancer in mice, but when the ARID1A and PTEN genes are simultaneously knocked out, 60% of mice develop ovarian cancer with intra-abdominal dissemination, and 40% exhibit excessive proliferation of ovarian epithelium ( 19 ). Further research by Chandler et al. indicated that simultaneous deletion of the ARID1A gene and activation of the PIK3CA gene can induce OCCC in mice ( 20 ). In addition, ARID1A mutation can lead to impaired interferon (IFN) gene expression and reduce tumor response to immunotherapy ( 21 ).

A recent study involving 1,623 EAOC patients, including 1,078 cases of OEC and 545 cases of OCCC, confirmed these findings ( 22 ). Specifically, the relationship between ARID1A loss/mutation, clinical characteristics, outcomes, CD8+ tumor-infiltrating lymphocytes (CD8+TIL), and DNA mismatch repair deficiency (MMRD) revealed ARID1A gene inactivation in 42% of OCCC and 25% of OEC. However, ARID1A inactivation did not significantly impact the overall survival and progression-free survival of OCCC and OEC. Nonetheless, the continuous advancement in targeted therapeutic approaches, synthetic lethal strategies, and the investigation of the prognostic significance of ARID1A in immune modulation therapy is ongoing, indicating potential implications for prognosis ( 23 , 24 ). Additional genes associated with EMS malignancy and EAOC: tumor suppressor gene p53, hepatocyte nuclear factor 1 homeobox B (HNF-1β), β-catenin gene (CTNNB1), kirsten rat sarcoma viral oncogene (KRAS), protein kinase B (KT), MicroRNA (miRN) are detailed in Table 1 .

Table 1 Genes associated with EAOC formation.

Past studies have indicated that the tumor microenvironment, particularly cancer-associated mesenchymal stem cells (CA-MSCs), plays a crucial role in the growth of ovarian cancer. Atiya et al.research report highlighted a subset of endometriosis-associated mesenchymal stem cells (enMSCs) in endometriosis ( 36 ), characterized by the loss of CD10 expression. This subset, by increasing the expression of iron export proteins, elevated intracellular iron levels in OCCC, thereby promoting OCCC growth and enhancing resistance to chemotherapy. Significantly, CD10-enMSCs also rendered OCCC more sensitive to iron apoptosis inducers and dihydroartemisinin (DH), offering a potential intervention pathway for future OCCC treatment.

Building upon current research, Wilczyński et al. proposed the hypothesis that endometriosis stem cells might be the primary targets for the carcinogenesis of EAOC ( 37 ). They delineated the process of transformation from endometriosis stem cells to cancer stem cells and the steps involved in the evolution from endometriosis to EAOC. However, more robust evidence is needed to thoroughly elucidate the exact carcinogenic mechanisms of EAOC.

3.2 Estrogen and epigenetics

EMS, being an estrogen-dependent disease, fosters the accumulation of estrogen in the local microenvironment. Estrogen plays a crucial role in the progression of endometrial lesions to atypical hyperplasia and even malignancy ( 38 ). Understanding the changes in estrogen signaling pathway will help to reveal the mechanism of estrogen involved in the malignant transformation of EMS. Andersen et al. analyzed estrogen regulatory genes and found that inactivation of estrogen receptor ERα, decreased progesterone receptor (PR) levels, and increased estrogen receptor ERβ may be the driving factors for EMS malignant transformation ( 39 ). This transition, accompanied by the overexpression of genes induced by estrogen receptor ERα, such as nuclear receptor interacting protein 1 (NRIP1) in EAOC, and the derepression of estrogen receptor ERα target genes, like FGF18, may promote the development of lesions towards EAOC. Wang et al.found that estrogen can influence gene methylation, and the estrogen-DNMT1 signaling pathway might induce high methylation of runt-related transcription factor 3 (RUNX3) ( 40 ), thereby promoting the malignant transformation of EMS. Several studies have identified common epigenetic features between EMS and ovarian malignancies ( 2 , 41 , 42 ) with epigenetic modifications in EAOC involving non-coding miRNA and histone modifications. Future research should focus on the interaction between hormonal regulation and inflammatory responses during the transformation process to gain a more comprehensive understanding of the mechanisms underlying the development of EMS into EAOC.

3.3 Iron related oxidative stress

Elevated iron levels are considered a risk factor for cancer development, and patients with EMS often exhibit iron overload, which may be one of the factors contributing to EAOC. Iron is associated with cancer through a variety of mechanisms, including cancer metabolism, genome stability, and tumor microenvironment ( 43 ). Iron and its metabolites produce a large number of Reactive Oxygen Species (ROS) through Fenton reaction ( 44 ) and hemoglobin autooxidation ( 45 ), leading to DNA damage and acting as carcinogenic inducers in the process of EAOC. The body’s macrophage and other antioxidant defense systems are also activated, leading to the “two-step theory” of oxidative stress ( Figure 1 ): The enhanced antioxidant capacity can protect cells from death or apoptosis, but at the same time, it also leads to DNA damage, genomic instability and mutation accumulation, thereby promoting the occurrence of tumors ( 46 ). In addition, iron-related oxidative stress can lead to the destruction of peritoneal mesothelial, which is conducive to the adhesion and metastasis of ectopic endometrial cells and tumor cells. Therefore, oxidative stress is a “double-edged sword” in the occurrence of EAOC ( 47 ).

Figure 1 EMT Malignant Transformation - Iron Related Oxidative Stress. hemoglobin (HB), haptoglobin (HP), heme-binding glycoprotein (Hx), heme oxygenase-1 (OH-1), reactive oxygen species (ROS), carbon monoxide (CO), low-density lipoprotein receptor-related protein 1 (CD91), macrophage-specific protein (CD163), superoxide (O2 − ), perhydroxy (HO2 − ).

3.4 Inflammatory response and immunodysregulation

EMS as a chronic inflammatory disease, creates a microenvironment in ovarian EMS that promotes inflammation, and sustained chronic inflammation may be a driving factor in inducing EAOC. Galectin, an important regulator of inflammation, shows high expression in EMS. Studies have found correlations between galectin-1, -3, and -9 and EAOC ( 48 ). In cancer cells, galectin is associated with the regulation of oncogenic signaling pathways, apoptosis, and changes in proliferation rates, making it a potential target for future cancer therapy ( 49 ).

The high-level expression of inflammasome complex genes (NLRP3, AIM2, PYCARD and NAIP) and inflammasome-related pathway genes (TLR1, TLR7, TOLLIP, NFKBIA and TNF) demonstrated their role in the progression of EMS and EAOC ( 50 ). However, there is still a lack of detailed analysis of the relevant immune components in the malignant transformation of EMS ( 51 ), and the exact immune pathways and cellular processes are still unclear, which is worthy of further research in the future.

4 EAOC risk factors

4.1 high estrogen state.

A high estrogen state is considered a significant risk factor for the malignant transformation of EMS ( 52 ). Factors such as early menarche, infertility, or low parity keep patients in a prolonged state of endogenous high estrogen levels, increasing not only the likelihood of EMS but also the risk of EAOC. A stratified study on 66,450 women investigating 12 risk factors for epithelial ovarian cancer found that the risk of OEC gradually increases with earlier age at menarche and later age at menopause ( 53 ). Recent research exploring hormone replacement therapy (HRT) in postmenopausal women with a history of EMS found that, except for HRT using estrogen alone, other HRT regimens do not increase the risk of ovarian cancer in postmenopausal women with a history of endometriosis ( 54 ). This reflects the potential increased risk of EAOC with exogenous estrogen, highlighting different pathways in the role of endogenous and exogenous estrogen in the association between EMS and EAOC, deepening our understanding of this complex relationship.

4.2 Menopause

In a retrospective case-control study, Udomsinkul et al. identified menopause as a significant independent risk factor for EAOC ( 55 ). In postmenopausal women, ovarian function declines, leading to a significant decrease in estrogen levels. It is generally believed that postmenopausal patients may experience relief from symptoms of EMS due to the decline in estrogen levels. However, Giannella et al. reported an incidence of endometriosis in menopausal women to be 2-4% ( 56 ), highlighting the importance of special attention to this group. The decreased likelihood of physiological cysts and the increased risk of malignant transformation of ovarian masses in postmenopausal women make it a noteworthy consideration.

4.3 Age and the course of endometriosis

Current research indicates that age and the long-term development of EMS are important risk factors for EAOC patients. It is noteworthy that EAOC patients are diagnosed at a younger age, with the average diagnosis age being 48.65 years compared to 54.39 years for non-EAOC patients ( 57 ). In a study the longest duration of ovarian endometriotic cysts in EAOC patients was 23 years, with an average duration of 10 years ( 58 ). The study suggests that the long-term development of ovarian endometriotic cysts increases the risk of malignant transformation. Murakami et al.analyzed the medical history of EAOC patients and found that the median time from the diagnosis of endometriotic cysts to the diagnosis of EAOC was 36 months, with approximately 75% of patients progressing to EAOC within 60 months ( 59 ). Given the low incidence of EAOC, the phenomenon of endometriotic cysts rapidly progressing to cancer in a short period suggests that EAOC may occur in earlier, less detectable stages, highlighting the occult nature of EAOC and emphasizing the importance of identifying the risk in early-stage EAOC patients.

4.4 Hysterectomy

The relationship between hysterectomy and ovarian cancer is intricate. Previous studies suggest that hysterectomy may impede retrograde menstrual flow and the transfer of carcinogenic substances ( 60 ), thereby reducing the risk of ovarian cancer. Khoja et al. after accounting for confounding factors such as estrogen and estrogen-progestin use, as well as a history of EMS, found that the risk of ovarian cancer decreases only in women with a combination of hysterectomy and EMS ( 61 ), while there is no correlation in women without EMS. Ring et al. research also confirms that, although hysterectomy is not generally associated with the risk of ovarian epithelial cancer ( 62 ), it significantly reduces the risk of ovarian clear cell carcinoma.

In patients with endometriosis, the infrequent use of oral contraceptives, comorbid depression, or pelvic inflammation may elevate the risk of ovarian cancer ( 63 ). However, for patients with EAOC, there is currently a lack of well-designed studies providing conclusive evidence regarding these risk factors.

5 Clinical diagnosis of EAOC

5.1 clinical symptoms and signs.

Clinical symptoms and signs of EAOC are atypical, lacking specific diagnostic criteria. According to the “dualistic model of ovarian cancer”, researchers suggest that EAOC often belongs to Type I ovarian cancer, characterized by relative indolence, typically lower invasiveness, and less propensity for widespread dissemination ( 64 ). Symptoms of EAOC are often similar to those of endometriosis, mainly presenting as pelvic masses. Clinicians should be vigilant for EAOC when endometriosis patients exhibit typical cyclical pain rhythm changes, abnormal uterine bleeding, or if the mass has a maximum diameter >10 cm or shows rapid enlargement ( 65 ).

5.2 Tumor marker

Currently, there is a lack of specific and cost-effective biomarkers to identify the occurrence of EAOC. Serum carbohydrate antigen 125 (CA125) is the most commonly used ovarian tumor marker. Previous studies suggested that malignancy is likely when CA125 is >200 U/ml. However, CA125 is not highly specific, as it can be influenced by various factors such as endometriosis, inflammation, and menstruation. Its sensitivity in early-stage EAOC is also relatively low. In other study CA125 levels showed no significant statistical difference between patients with ovarian endometriotic cysts and those with EAOC ( 66 ).

Compared to CA125, carbohydrate antigen 19.9 (CA19.9) and human epididymal protein 4 (HE4) have advantages in diagnosing EAOC. CA19.9 is a potential serum marker for diagnosing EAOC; in Magalhães et al. study, a serum CA19.9 >22.31 U/ml showed a sensitivity of 82.14% in distinguishing between ovarian endometriotic cysts and EAOC ( 67 ). HE4, highly expressed in ovarian cancer and unaffected by endometriosis, exhibits high specificity. Xu et al. found that a serum HE4 >59.7 pmol/L could diagnose EAOC, with a specificity of 99.4% when HE4 >140 pmol/L ( 68 ). For epithelial ovarian cancer, the combined detection of HE4 and CA125 demonstrates higher sensitivity than CA125 alone. Multiple studies suggest that the joint examination of various tumor markers is more effective in diagnosing ovarian epithelial cancer ( 69 ). In a comprehensive review, concluded that the combination of CA125 and HE4 is currently the most effective diagnostic approach for ovarian epithelial cancer, but its discriminative ability for EAOC requires further clinical research and analysis for validation ( 70 ).

5.3 Radiology

Ultrasound plays a crucial role in the diagnosis of epithelial ovarian cancer. Typical features include cystic and solid masses, thick septa, associated solid nodules or papillary projections, and areas of necrosis. Ovarian cancer often presents with ascites and enlarged lymph nodes, with peritoneal, mesenteric, and omental metastases. In differentiating from EAOC, ultrasound examination should focus on specific characteristics of EAOC, such as a cystic lesion diameter larger than 10 cm or showing an increasing trend, having a unilocular or multilocular solid component, and rich blood flow signals ( 71 ). The disappearance of ground glass echoes is also indicative of malignancy ( 72 ). Moreover, EAOC typically manifests as a unilateral cystic lesion with papillary projections, and ascites is less commonly observed ( 73 ).

Magnetic Resonance Imaging (MRI) with its excellent soft tissue resolution and multi-planar imaging advantages offers greater accuracy in differentiating EAOC compared to Computerized Tomography (CT). A study found that Whole-Body Diffusion-Weighted Imaging/MRI (WB-DWI/MRI) achieved an accuracy of 93% in determining the benign or malignant nature of ovarian masses, significantly higher than CT’s accuracy of 82% ( 74 ). Using MRI relaxation method to measure the total iron concentration and transverse relaxation rate of cyst fluid in ovarian endometriosis cysts can predict the malignant transformation of ovarian endometriosis ( 75 ). In Zhang X et al. research, using MRI to depict the features of EAOC and non-EAOC, revealed that EAOC, especially clear cell ovarian cancer, more commonly presents as a unilocular cystic mass ( 76 ), showing statistically significant lateralization. Cystic fluid exhibits low signal intensity on T2-weighted imaging, and focal nodular growth patterns are more frequent. These findings underscore the critical role of ultrasound and MRI in the diagnosis of EAOC.

6 Progress in the management and treatment of EAOC

Most ovarian cancer patients experience recurrence within approximately three years. Advanced ovarian cancer and recurrent cases often exhibit resistance to platinum-based drugs, leading to a deterioration in clinical prognosis ( 77 ), making ovarian cancer treatment a longstanding challenge in gynecologic oncology. Compared to the common high-grade serous ovarian carcinoma, EAOC has a lower incidence rate, but it shows better early prognosis, although the late-stage survival rate is significantly lower than high-grade serous ovarian carcinoma. EAOC patients generally exhibit poorer response to platinum-based chemotherapy compared to non-EAOC cases ( 78 , 79 ). Current experience in EAOC treatment primarily stems from studies on epithelial ovarian cancer. The initial standard treatment for EAOC includes surgery followed by platinum-based chemotherapy ( 77 ). Early-stage EAOC patients should undergo comprehensive staging surgery, while for intermediate to late-stage EAOC patients, consideration should be given to primary debulking surgery (PDS) upon preoperative or intraoperative assessment of extra-ovarian metastasis. Surgery should aim to remove all macroscopically visible tumors to reduce tumor burden, enhance chemotherapy efficacy, and improve prognosis.

6.1 Lymphadenectomy

Lymph nodes serve as crucial pathways for solid tumor metastasis. Systematic lymph node dissection in early-stage ovarian cancer patients is valuable for determining tumor staging, however it is not known whether it is beneficial for prognosis. EAOC as a specific subtype of ovarian epithelial cancer, is often diagnosed in its early stages. Recent evidence from a multicenter retrospective study suggests that early-stage and low-grade endometrioid ovarian cancer patients who undergo lymph node dissection have superior 5-year disease-free survival and overall survival rates compared to those who do not undergo lymph node dissection ( 80 ), with rates of 92.0% vs. 85.6% ( p =0.016) and 97.7% vs. 92.8% ( p =0.013), respectively. Another prospective, multicenter, randomized phase III clinical trial designed by Deng et al. in 2023 is ongoing. By comparing the progression-free survival (PFS) and overall survival (OS) outcomes of patients with stage IA-IIB epithelial ovarian cancer who undergo lymph node dissection surgery versus those who do not ( 81 ), this study aims to provide more precise evidence regarding the efficacy and safety of early lymph node surgery. The benefits and drawbacks of performing lymph node dissection in advanced ovarian cancer patients have been elucidated by high-quality evidence. A multicenter, phase III randomized controlled trial published in the New England Journal of Medicine in 2019 demonstrated that systematic pelvic and para-aortic lymph node dissection did not prolong patients’ OS or PFS and was associated with a higher incidence of postoperative complications ( 82 ). Subsequently, the National Comprehensive Cancer Network (NCCN) guidelines adjusted the indications for lymph node dissection surgery.

6.2 Intraperitoneal chemotherapy

A small proportion of EAOC is diagnosed in advanced stages, where achieving complete resection through surgery is challenging. Researchers have long attempted to enhance drug efficacy through intraperitoneal chemotherapy, particularly for advanced ovarian cancer. Early clinical trials conducted by the Gynecologic Oncology Group (GOG), including GOG-104, GOG-114, GOG-172, and GOG-252, failed to establish intraperitoneal chemotherapy as a first-line treatment due to design flaws, insufficient statistical evidence, and a higher likelihood of adverse reactions. Hyperthermic intraperitoneal chemotherapy (HIPEC), which combines thermal therapy and intraperitoneal perfusion treatment with intraperitoneal chemotherapy, has become a hot topic in debulking surgery for advanced ovarian cancer in recent years. In 2018, Van Driel et al. demonstrated that adding HIPEC to stage III epithelial ovarian cancer patients led to longer recurrence-free survival and overall survival without increasing the incidence of side effects ( 83 ). The clinical trial OVHIPEC-1 reported by Aronson et al. in 2023 confirmed a 10-year survival benefit of HIPEC in primary stage III epithelial ovarian cancer patients undergoing interval cytoreduction surgery ( 84 ). The efficacy of HIPEC in patients suitable for initial cytoreduction surgery remains uncertain. The OVHIPEC-2 trial, initiated in January 2020, is expected to provide results in this regard ( 85 ). However, the statistical results of the HIPECOVA trial conducted by Villarejo Campos et al. in 2024 failed to demonstrate a significant improvement in the prognosis of ovarian cancer patients with HIPEC ( 86 ). Therefore, HIPEC treatment remains experimental rather than standard therapy.

6.3 Drug chemotherapy

Currently, the standard first-line treatment regimen for EOC and EAOC is platinum-based combination chemotherapy, specifically carboplatin plus intravenous paclitaxel administered every 3 weeks for a total of 6 cycles. The JGOG 3016 trial previously reported significant improvements in progression-free survival and overall survival with a weekly dose-dense paclitaxel regimen and a 3-weekly carboplatin regimen, whereas the ICON8 trial did not observe this benefit. These trials have different strengths and weaknesses, and the differences may be related to pharmacogenomics or other factors such as dose intensity. The findings of Clamp et al. in 2022 confirmed that weekly dose-dense first-line chemotherapy did not improve overall survival or progression-free survival compared to standard 3-weekly chemotherapy ( 87 ). Therefore, the 3-weekly regimen chemotherapy remains the first-line approach.

Late-stage EAOC carries a poor prognosis, warranting in-depth research into targeted therapy and immunotherapy. Currently, molecular targeted therapies for ovarian cancer, such as poly ADP-ribose polymerase (PARP) inhibitors and the anti-angiogenic agent bevacizumab, have shown favorable outcomes in maintenance therapy for epithelial ovarian cancer patients with BRCA mutations, thereby extending the survival of ovarian cancer patients to some extent ( 88 ). However, even with satisfactory tumor reduction achieved through surgery and standardized chemotherapy and maintenance therapy, cancer patients may still experience treatment failure due to platinum resistance or tumor recurrence, highlighting the need to enhance drug efficacy and prolong recurrence-free survival. Mirvetuximab soravtansine (MIRV), an antibody-drug conjugate targeting folate receptor (FR) alpha, has shown promising efficacy when combined with bevacizumab in platinum-resistant recurrent ovarian cancer patients. Mirvetuximab soravtansine (MIRV) is a folate receptor (FR)-targeting antibody-drug conjugate (DC). In 2020, researchers found that MIRV combined with bevacizumab demonstrated good efficacy in treating platinum-resistant recurrent ovarian cancer patients. The confirmed objective response rate (ORR) was 39%, with a particularly effective response observed in the subset of platinum-resistant ovarian cancer patients with high FRα expression, achieving an ORR of 56%. The median duration of response was 12 months, and the PFS was 9.9 months ( 89 ). Phase 2 clinical studies of MIRV in epithelial ovarian cancer patients reported in 2023 further demonstrated its anti-tumor activity, along with good tolerability and safety, providing encouraging results ( 90 ). EAOC is highly likely to originate from endometriosis-associated ovarian cysts, which are often considered complex immune-related diseases. Immunotherapy has shown great potential in the treatment of EOC and EAOC. However, previous large phase III studies exploring the addition of immunotherapy to standard first-line treatment regimens have been disappointing, including the IMagyn050/GOG 3015/ENGOT-OV39 ( 91 ) and JAVELIN Ovarian 100 ( 92 ) studies. A turning point in immunotherapy emerged in 2023 with the release of interim data from the global multicenter phase III DUO-O study, showing promising clinical efficacy, warranting continued attention.

Recently, based on the establishment of animal models of endometriosis, successful reports of establishing EAOC mouse models have also emerged ( 93 ). By simulating tumor characteristics and reproducing the biological properties of tumors, these models can provide important reference for clinical precision treatment research, which is crucial for the study and development of precision treatment for EAOC.

7 Conclusion

The intricate relationship between EMS and ovarian cancer warrants in-depth investigation. Early identification of high-risk individuals for cancer among endometriosis patients is of paramount importance, necessitating the development of early detection methods and close monitoring. Future research directions in understanding the mechanisms and molecular genetics of EAOC may involve the utilization of advanced technologies, such as next-generation sequencing and whole transcriptome sequencing, as personalized diagnostic tools. The objective is to identify and confirm the driver mutations and candidate genes associated with the malignant transformation of EMS. These efforts hold the potential to provide more precise targeted therapies and immunotherapies for ovarian cancer, thereby improving patient prognosis and survival outcomes.

Author contributions

LT: Writing – original draft. CB: Writing – review & editing.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: endometriosis, ovarian neoplasms, endometriosis-associated ovarian cancer, risk factors, diagnosis

Citation: Tang L and Bian C (2024) Research progress in endometriosis-associated ovarian cancer. Front. Oncol. 14:1381244. doi: 10.3389/fonc.2024.1381244

Received: 03 February 2024; Accepted: 15 April 2024; Published: 25 April 2024.

Reviewed by:

Copyright © 2024 Tang and Bian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Ce Bian, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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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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Journal of Ovarian Research

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• Published: 05 October 2021

Next steps in the early detection of ovarian cancer

• Robert C. Bast 1 ,
• Chae Young Han 1 ,
• Zhen Lu 1 &
• Karen H. Lu 2  

Communications Medicine volume  1 , Article number:  36 ( 2021 ) Cite this article

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• Ovarian cancer

A recent ovarian cancer screening trial found no reduction in mortality, despite increased detection of early stage disease. Here, we discuss these findings and examine next steps to develop more effective approaches for the early detection of ovarian cancer.

Ovarian cancer afflicts more than 300,000 women each year worldwide. Despite improved care with cytoreductive surgery and combination chemotherapy, the majority of patients will die from their disease. When cancer is limited to the ovaries in stage I, up to 90% of patients can be cured with currently available treatment 1 . Even when disease has spread to pelvic organs in stage II, up to 70% survive for more than 10 years. With further spread over the surface of the abdominal cavity (stage III) or outside the abdomen (stage IV), long term survival is reduced to 20% or lower. Approximately 25–30% of patients are currently diagnosed in stage I or II. It has long been assumed that increasing the fraction of women with ovarian cancer detected at an early stage could improve survival and decrease mortality.

The negative outcome of the UKCTOCS calls into question where we should go next to find an effective strategy for early detection of ovarian cancer.

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

The UKCTOCS, the largest ovarian cancer screening trial conducted to date, randomized postmenopausal women at average risk for developing ovarian cancer to a control group (101,314), annual transvaginal sonography (TVS) for 7 years (50,623), or “multi-modal screening” for 7 years (50,625) involving a “two-step process”, where changes in annual CA125 ovarian tumor biomarker blood tests were analyzed with a Bayesian Risk of Ovarian Cancer Algorithm (ROCA) prompting TVS in a small fraction of patients with a significant increase in CA125 2 . Executing a screening study of this magnitude constitutes a remarkable achievement. In the initial report in 2016, there was no significant reduction in mortality overall, but a 20% reduction was found in a pre-specified subset of women with incident disease who had been diagnosed after 7 years of screening on the multi-modal arm ( p  = 0.021). Given wide statistical bounds around the estimate, re-analysis was planned after 5 years of additional follow-up. The update confirmed a stage shift with an increase in early stage disease and a decrease in late stage disease in the screened population, but failed to confirm a reduction in mortality 1 .

Failure to sustain a mortality advantage despite an increase in early stage disease could relate to inadequate therapy. As collaborating sites were chosen for expertize in gynecologic oncology, surgery is likely to have been state-of-the-art. It would be important to know that all early stage patients received six cycles of carboplatin and paclitaxel. If the choice and duration of chemotherapy were at the discretion of collaborating oncologists, some might have chosen single agent carboplatin or used only three cycles of combination chemotherapy for early stage disease.

Early stage (I/II) disease detected in the multimodal arm of the UKCTOCS was associated with increased mortality, consistent with the possibility that rising CA125 detected additional micro-metastatic disease or identified visible tumors that resisted conventional chemotherapy. While PARP-inhibitor maintenance therapy is generally prescribed for advanced stage (III/IV) disease, patients with screen-detected homologous repair deficient early stage (I/II) ovarian cancer might also benefit. Novel agents, including SIK2 inhibitors 3 , are being developed to enhance primary treatment with carboplatin and paclitaxel potentially improving care for both early and late stage disease.

Furthermore, the magnitude of the stage shift observed in the UKCTOCS may not have been sufficient to reduce mortality. The fraction of stage I/II patients in the UKCTOCS increased from 28.4% with no screening to 38.1% with CA125 followed by TVS. The fraction of patients with stage IV disease decreased from 20.7 to 15.1%. A much greater stage shift was observed in the single arm Normal Risk Ovarian Screening Study (NROSS) that has been conducted, in parallel, over the last 19 years in post-menopausal women at average risk in the United States, using the identical two-step multi-modal screening plan with the CA125 based ROCA followed by TVS. Among the 7597 women screened, 16 epithelial ovarian cancers have been detected—2 were borderline and 14 invasive—with 11 (69%) in early stage (I or II) (updated from ref. 4 ). One of 16 cases (6%) was detected in stage IV. Both trials confirmed that adequate specificity could be attained with the two-step strategy, requiring no more than 2–4 operations to detect each case of ovarian cancer. The reason for a greater stage shift in the smaller trial is not clear. This could reflect statistical variation with the smaller size of the NROSS. Difficulties were, however, encountered with TVS imaging in the UKCTOCS. In a retrospective review of 1000 archived cases, ovaries and fallopian tubes could be identified in only 50% of cases 5 . TVS imaging could have been more reliable in the NROSS. Another difference between the trials relates to processing of blood for measurement of CA125. In the NROSS, blood was drawn in glass tubes without gel, serum was separated and frozen on the same day, while in the UKCTOCS blood was drawn in gel separation tubes, shipped at ambient temperature and separated after up to 56 h. A modest systematic reduction in CA125 levels in the UKCTOCS could have decreased the ability to detect early stage disease. In addition, particular care was taken in the NROSS to follow elevations of CA125 with repeated TVS and to minimize time to surgical intervention.

The negative outcome of the UKCTOCS calls into question, where we should go next to find an effective strategy for early detection of ovarian cancer. While some might suspend attempts to detect early stage ovarian cancer awaiting a novel and disruptive technology, the two-step screening strategy has already achieved adequate specificity and a clear stage shift, although sensitivity is not yet adequate. There are opportunities for improvement both in serum biomarkers and in imaging. Only 80% of ovarian cancers express CA125 and serum levels of CA125 are elevated in only 70% of stage I/II cancers. A recent review identified 35 biomarkers that complement CA125 and could potentially improve sensitivity of the initial step in screening 6 . A combination of CA125, HE4, and CA72.4 detects 16% of cases missed by CA125 7 . Through a collaboration sponsored by the NCI Early Detection Research Network (EDRN), CA125 detected 72% of early stage cases at 98% specificity, whereas a combination of CA125, HE4 antigen-autoantibody complexes 8 and osteopontin 9 detected 89% at 94% specificity 10 . A second-generation ROCA algorithm is being developed and can be tested prospectively for specificity in the NROSS cohort.

In addition to detecting a greater fraction of early stage patients, panels of biomarkers could improve lead time with detection of cancers at longer intervals before clinical presentation. Autoantibodies could arise in response to very small volumes of early disease, which would be particularly important for high grade serous lesions arising from the fallopian tube. Anti-p53 autoantibodies have been detected in more than 20% of patients with early and late stage ovarian cancer 11 . Assaying serum samples from the UKCTOCS, titers of anti-p53 autoantibodies increased 8 months before elevation of CA125 and 22 months prior to clinical presentation in patients who did not exhibit increases in serum CA125 12 . This is the first of >120 biomarkers tested by our group that increased lead time over CA125. Among 19 promising autoantibodies tested, anti-p53, anti-CTAG1, and anti-IL-8 detected the greatest fraction of early stage ovarian cancer patients 11 .

A variety of additional biomarkers are being developed to detect ovarian cancer including ctDNA, methylated DNA, and miRNAs. Alterations in cervical and peripheral blood ctDNA can complement CA125 in detecting early stage disease 12 . While ovarian cancer has been included in DNA-based pan-cancer screening strategies 13 , 14 , detecting stage I/II disease has proven challenging. Future research should optimize the integration of DNA and protein biomarkers.

Whatever the biomarker panel chosen, screening could be performed more frequently. In patients at high risk, largely related to germ-line BRCA1/2 mutations, screening with the ROCA every 3 months proved more effective than annual screening 15 , 16 , While it is difficult to imagine more frequent screening for ovarian cancer alone in patients at conventional risk, blood might be drawn every six months to screen for multiple cancers in women over 50. Ovarian cancer screening could be paired with DNA-based pan-cancer screening strategies or combined with site-specific blood tests that are being developed to detect colorectal adenomas, and breast and pancreatic cancers 17 .

Imaging, the second step in two-stage screening, poses perhaps the greatest unmet need. As a single modality, TVS lacks adequate sensitivity and specificity for early detection of ovarian cancer. The majority of high-grade serous cancers probably arise in the fallopian tubes. Even in expert hands, fallopian tubes could not be imaged in 23% of 549 healthy women 18 . CT, PET-CT, and MRI also have problems with sensitivity, specificity, exposure to radiation and cost for screening 7 .

One possible solution in patients with rising serum biomarkers and negative TVS is falloposcopy, where a fiberoptic scope is threaded through the uterus and fallopian tube to visualize the fimbriae and ovary. This would be particularly relevant for women with BRCA1/2 mutations who are delaying risk reducing surgery. The EDRN is currently evaluating the feasibility of this approach. Another technology that is being developed is superconducting quantum interference detection (SQUID), which is a sensitive method for detecting faint magnetic fields. Anti-CA125 antibodies have been conjugated with ferritin nanospheres. Only antibody conjugated nanospheres bound to cells are detected by magnetic relaxation. Ex vivo, 10 6 ovarian cancer cells (0.1 mm) can be detected 7 . If uptake of antibody-coated nanospheres can be optimized in xenografts, this approach might be utilized to detect recurrent ovarian cancer and then tested in healthy women with rising biomarkers and negative TVS.

Conclusions

Given the specificity of the two-step screening strategy, opportunities to improve both phases and the impressive stage shift in the CA125-based NROSS trial, further development of this approach appears worthy of pursuit. The potential benefit for ovarian cancer patients is substantial. Computer simulations suggest that an effective strategy for early detection could reduce mortality by 10–30%, a dramatic improvement over our current attempts to improve therapy 7 .

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Acknowledgements

This work was supported by funds from the NCI Early Detection Research Network (5 U01 CA200462-02, RCB), the MD Anderson Ovarian SPOREs (P50 CA83639 and P50CA217685, R.C.B.), National Cancer Institute, Department of Health and Human Services; the Cancer Prevention Research Institute of Texas (RP160145, R.C.B.); Golfer’s Against Cancer; the Tracey Joe Wilson Foundation; and generous donations from the Ann and Henry Zarrow Foundation, the Mossy Foundation, the Roberson Endowment, Stuart and Gaye Lynn Zarrow, Barry and Karen Elson, and Arthur and Sandra Williams.

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Robert C. Bast, Chae Young Han & Zhen Lu

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R.C.B. wrote the commentary. C.Y.H., Z.L., and K.H.L. contributed data and reviewed the manuscript.

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Bast, R.C., Han, C.Y., Lu, Z. et al. Next steps in the early detection of ovarian cancer. Commun Med 1 , 36 (2021). https://doi.org/10.1038/s43856-021-00037-9

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Mini-colons revolutionize colorectal cancer research

As our battle against cancer rages on, the quest for more sophisticated and realistic models to study tumor development has never been more critical. Until now, research has relied on animal models and simplified cell culture methods, which are valuable but cannot fully capture the complex interplay of factors involved in tumor development.

Even newer, more advanced models for studying cancer, such as organoids -- tiny, lab-grown versions of organs -- do not faithfully replicate the cell behaviors and tissue architectures seen in actual tumors.

This gap has significantly hindered our understanding of the intricate processes underlying cancer initiation, progression, and response to treatment, and calls for more sophisticated models to accurately mimic the disease's complexity.

In a significant leap forward for cancer modeling, scientists have combined microfabrication and tissue engineering techniques to develop miniature colon tissues that can simulate the complex process of tumorigenesis outside the body with high fidelity, giving rise to tumors that closely resemble those found in vivo .

The breakthrough, now published in Nature , was made by Luis Francisco Lorenzo Martín, Tania Hübscher and other members of the group of Matthias Lütolf at EPFL, with input from the group of Freddy Radtke (EPFL) and colleagues at Roche's Institute of Human Biology.

The mini-colons are topobiologically complex, meaning that they not only replicate the physical structure of colon tissue, including its distinctive crypt-and-lumen architecture, but they also mimic the cellular diversity present in the actual colon tissue during healthy and diseased states.

Optogenetics: Turning cancer "on"

Another important feature of the mini-colons is that they can be induced to develop tumors "at will" and in targeted areas -- a massive advantage for cancer research. The researchers were able to turn inducible oncogenic genes on using "optogenetics." This cutting-edge technique uses light to control biological processes such as gene expression.

By integrating a blue-light-responsive system into the mini-colons, the researchers made them undergo controlled oncogenic mutations, which can reveal tumor evolution with unprecedented details. This optogenetic approach allowed the scientists to induce targeted changes in specific cell populations within the mini-colons, mimicking the localized onset of colorectal cancer in the body.

"In essence, we used light to trigger tumorigenesis by turning on oncogenic driver mutations in a spatiotemporally controlled manner in healthy bioengineered colon epithelial organoids," says Matthias Lütolf, who is also the founding director of Roche's new Institute of Human Biology. "This basically allows you to watch tumor formation in real-time and do very detailed analyses of a process that's very difficult to study in a mouse."

The ability to trigger these genetic changes with light in the miniature colons not only allows more controlled and more precise activation of the oncogenes, but also provides a powerful tool to study the dynamic processes of tumor development and the cellular response to these mutations in real-time. This innovative use of optogenetics opens up new possibilities for dissecting the molecular and cellular mechanisms of cancer.

By manipulating genetic and environmental conditions, the researchers were also able to replicate and observe a range of tumor behaviors in the mini-colons, and even identified key factors influencing cancer progression -- for example, the protein GPX2, which associated with stem cell characteristics and tumor growth.

This groundbreaking research offers a potent new tool for exploring the underlying mechanisms of colorectal cancer and testing potential therapies, particularly when applied to human patient-derived tissues. The mini-colons' ability to mimic tumor dynamics can reduce our reliance on animal models, which can accelerate the discovery and development of effective treatments.

• Colon Cancer
• Brain Tumor
• Lung Cancer
• Ovarian Cancer
• Breast Cancer
• Prostate Cancer
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Story Source:

Materials provided by Ecole Polytechnique Fédérale de Lausanne . Original written by Nik Papageorgiou. The original text of this story is licensed under Creative Commons CC BY-SA 4.0 . Note: Content may be edited for style and length.

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• L. Francisco Lorenzo-Martín, Tania Hübscher, Amber D. Bowler, Nicolas Broguiere, Jakob Langer, Lucie Tillard, Mikhail Nikolaev, Freddy Radtke, Matthias P. Lutolf. Spatiotemporally resolved colorectal oncogenesis in mini-colons ex vivo . Nature , 2024; DOI: 10.1038/s41586-024-07330-2

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Ovarian cancer.

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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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