Risk factors for developing ovarian cancer include infertility, estrogen therapy, and obesity – these have been implicated in the increased prevalence of the disease in developed countries. Conversely, factors such as the use of contraceptives over long periods, breastfeeding, childbirth, early onset of menopause, and the surgical removal of fallopian tubes are associated with a reduced risk of endometrioid and clear cell ovarian carcinoma. However, conditions like endometriosis are linked with an increased risk of these cancer types. Ovarian cancers of a serous type and those with a low differentiation level are moderately related to childbearing and hormone therapy after menopause, while having a stronger association with hereditary ovarian cancer history.
Patients carrying germline mutations in BRCA1/2 genes display a significantly increased risk, between 16-65%, of developing high-grade serious types of ovarian cancer. Women with DNA repair gene mutations (mismatch repair genes associated with Lynch syndrome) face a 10%-12% lifetime risk of developing this type of cancer, as elucidated by Eleni Aravantinou-Fatorou MD, MSc, Oncologist at Metropolitan Hospital.
Unfortunately, no preventive methods for ovarian cancer detection are dependable to date. Cancer antigen 125 (CA-125) testing is not recommended for the general healthy population. An elevated CA-125 level is not diagnostic of ovarian cancer, as it can increase in other benign and malignant conditions, such as endometriosis and ovarian cysts. CA-125 is increased in approximately half of the women with stage I ovarian cancer and in about 85% of women with an advanced stage of the disease.
The majority of women are diagnosed upon the manifestation of symptoms, usually at more advanced stages. Common symptoms include abdominal pain, constipation, diarrhea, frequent urination, vaginal bleeding, abdominal bloating, and fatigue. More severe stages may present with ascites and abdominal masses, leading to nausea, anorexia, dyspepsia, and early satiety.
In terms of classification, the World Health Organization acknowledged five distinct subtypes of malignant epithelial ovarian cancer in 2020, based on histopathology, immunohistochemistry, and molecular analysis. These include high-grade serous carcinoma (70% of cases), endometrioid carcinoma (10%), clear cell carcinoma (6%-10%), low-grade serous carcinoma (5%), mucinous carcinoma (3%-4%), and some rarer types. Each subtype represents a separate disease, with distinctpathogenesis, clinical characteristics, and prognosis, underscoring the necessity of diagnosis by an experienced pathologist.
Early-stage ovarian cancer is primarily treated through surgical resection. The aim is to remove the disease and accurately stage it with the removal of pelvic and para-aortic lymph nodes in high-grade histological subtypes. Lymph node involvement risk in low-grade endometrioid carcinoma is below 1%, thus lymphadenectomy can be avoided in such cases. In young women with low-stage and low-risk disease, fertility-sparing limited surgery is a consideration. Complementary chemotherapy, often platinum-based, is given according to stage and histological type to improve overall survival and reduce relapse.
In advanced-stage ovarian cancer, the goal of surgery is complete or optimal cytoreduction. The timing of surgical cytoreduction in relation to chemotherapy is an ongoing conversation. Decisive recommendations should be made by oncological committees in specialized centers. The optimal practice for patients with stage III-IV disease is primary cytoreductive surgery if the patient is physically fit and complete resection appears possible, followed by systematic therapy.
Systematic chemotherapy is recommended for all patients with advanced disease, typically involving six cycles of paclitaxel and carboplatin. The addition of bevacizumab, an antiangiogenic monoclonal antibody, to chemotherapy and later as maintenance therapy has shown benefits in prolonging time to relapse. However, it has provided overall survival benefits only for high-risk patients. The introduction of PARP inhibitors (olaparib, niraparib, rucaparib) as maintenance therapy has markedly improved time to relapse, patient quality of life, and overall survival.
Patients with advanced ovarian cancer should undergo testing for BRCA 1/2 mutations and assessment of HRD status, which serve as prognostic indicators for the disease and predictive of treatment response. Over 50% of high-grade serous ovarian cancers are HRD positive, including 15%-20% of cases with germline mutations in BRCA 1/2 genes. Somatic BRCA 1/2 mutations, often due to epigenetic changes, are frequently involved in the remaining HRD positive ovarian cancers.
Current treatment decisions heavily rest on these specific genetic markers, guiding the choice of optimal maintenance treatment, which includes PARP inhibitors as monotherapy, bevacizumab as monotherapy, and the combination of bevacizumab with PARP inhibitors. Hormonal therapy as maintenance treatment appears to have a place in cases of low-grade serous ovarian cancer with high expression of estrogen and progesterone receptors, as suggested by retrospective studies.
Significant advances have been made in treating ovarian cancer with such innovative therapies. However, despite high response rates to first-line treatment, 70% of patients will experience a relapse within the first three years. There is an imperative to push further for improved chances of recovery. Promising initial results from the combination of chemotherapy, angiogenesis inhibitors, PARP inhibitors, and immunotherapy give hope in managing this challenging disease. Anticipation runs high for the outcomes from combinations and new drugs, including targeted therapies with more sophisticated mechanisms of action, which hopefully will change the trajectory of advanced ovarian cancer, concludes Aravantinou-Fatorou.
