Ovarian Cancer: Staging, BRCA/HRD Testing & Treatment

Ovarian cancer arises when cells in the ovary, fallopian tube, or the peritoneal lining begin to grow uncontrollably. The great majority of cases are epithelial ovarian cancers, meaning they start in the cells covering the surface of the ovary or lining the fallopian tube; within this group, high-grade serous ovarian carcinoma (HGSOC) is by far the most common and aggressive subtype, accounting for around 70% of epithelial cases. Less common epithelial subtypes include endometrioid, clear cell, mucinous, and low-grade serous carcinomas, each with somewhat different behaviour and treatment response.

Research over the past two decades has shown that many so-called "ovarian" high-grade serous cancers actually originate in the fimbrial end of the fallopian tube before spreading to the ovary and peritoneal surface, which is why the disease is now often referred to collectively as ovarian, fallopian tube, and peritoneal cancer. This shared origin explains why these three sites are staged and treated using the same system.

Beyond epithelial tumours, the ovary can also give rise to much rarer cancers, including germ cell tumours (which arise from egg-producing cells and tend to occur in younger women) and sex cord-stromal tumours (which arise from hormone-producing supportive cells). These behave very differently from epithelial ovarian cancer, often affect younger patients, and are generally treated with different protocols.

Because the ovaries sit deep within the pelvis, tumours can grow substantially and spread across the abdominal cavity before causing noticeable symptoms. This biological pattern, combined with the absence of an effective screening test for the general population, is a major reason why most ovarian cancers are found at an advanced stage.

A diagnosis of ovarian cancer, even at an advanced stage, does not mean treatment options are limited. Most patients begin with a combination of surgery and chemotherapy, and genetic and molecular testing results increasingly open the door to additional maintenance therapies that can meaningfully extend the time before the cancer returns.

Because a portion of ovarian cancers are linked to inherited mutations, receiving genetic counselling and testing is a standard and important part of your care pathway, both for your own treatment planning and for informing your family about their own potential risk and screening options.

Early ovarian cancer often causes few or no symptoms, which contributes to delayed diagnosis. When symptoms do occur, they are frequently non-specific and can be mistaken for digestive or bladder issues, including bloating, pelvic or abdominal pain, feeling full quickly when eating, and urinary urgency or frequency.

Other possible symptoms include unexplained changes in bowel habits, fatigue, unintended weight loss or gain, and abdominal swelling related to fluid build-up (ascites) in more advanced disease. Because these symptoms overlap with common, benign conditions, ovarian cancer is sometimes not suspected until symptoms are persistent, frequent, or worsening.

Any of these symptoms occurring most days for more than a few weeks, particularly in combination or in someone with risk factors such as a family history of ovarian or breast cancer, warrants prompt medical evaluation, including a pelvic examination and appropriate imaging.

Ovarian cancer develops through the accumulation of genetic changes in cells of the ovary, fallopian tube, or peritoneum that allow them to grow and divide abnormally. In high-grade serous ovarian carcinoma, nearly all tumours carry mutations in the TP53 gene, and a substantial proportion also show homologous recombination deficiency (HRD), a defect in the cell's ability to repair certain types of DNA damage.

About 15-20% of all epithelial ovarian cancers are associated with an inherited (germline) mutation, most commonly in BRCA1 or BRCA2, which normally help repair DNA damage through the homologous recombination pathway. When these genes are altered, cells accumulate DNA damage more easily, which can drive cancer development but also creates a specific vulnerability that certain drugs, such as PARP inhibitors, can exploit.

Other, less common hereditary syndromes linked to ovarian cancer include Lynch syndrome (associated with mutations in mismatch repair genes) and mutations in genes such as RAD51C, RAD51D, BRIP1, and PALB2. Most ovarian cancers, however, occur sporadically, without a known inherited cause, though acquired (somatic) mutations and HRD are still commonly found within the tumour itself.

Non-modifiable risk factors include increasing age (most cases occur after menopause), inherited mutations in BRCA1, BRCA2, or other homologous recombination and mismatch repair genes, a personal or family history of breast, ovarian, or colorectal cancer, and never having been pregnant or having had a later first pregnancy.

Factors associated with a somewhat lower risk include prior pregnancies, breastfeeding, and past use of combined oral contraceptives, likely related to a reduction in lifetime ovulation cycles. Endometriosis has been associated with an increased risk of certain ovarian cancer subtypes, particularly endometrioid and clear cell carcinoma.

Hormone replacement therapy after menopause has been linked to a modestly increased risk in some studies, and obesity may also contribute to increased risk. Importantly, most people who develop ovarian cancer do not have a strong family history, so genetic testing is now recommended for essentially everyone diagnosed with epithelial ovarian cancer rather than only those with a suggestive family history.

Evaluation typically starts with a pelvic examination and transvaginal ultrasound to assess any ovarian mass, followed by additional imaging such as CT or MRI to evaluate the extent of disease within the abdomen and pelvis. A CA-125 blood test is commonly checked alongside imaging, since elevated levels can support suspicion of ovarian cancer, although CA-125 can also be raised by many benign conditions such as endometriosis, fibroids, or menstruation, and is not accurate enough to be used as a stand-alone screening test in the general population.

A definitive diagnosis requires tissue confirmation, most often obtained during surgery when the tumour (and, if indicated, the ovaries, fallopian tubes, uterus, omentum, and nearby lymph nodes) is removed and examined by a pathologist. In some cases, particularly when the disease appears very advanced, a smaller biopsy or drainage of abdominal fluid (ascites) may be used to confirm the diagnosis before deciding on the sequence of surgery and chemotherapy.

Once cancer is confirmed, the pathology report identifies the histological subtype and grade, while imaging and surgical findings are used together to determine the stage. Genetic counselling and germline testing for BRCA1/BRCA2 and other relevant genes, along with tumour testing for HRD status, are typically arranged around the time of diagnosis to guide treatment planning.

Ovarian, fallopian tube, and peritoneal cancers are staged using the FIGO (International Federation of Gynecology and Obstetrics) system, which is closely aligned with the TNM classification and is based mainly on surgical and pathological findings.

Stage I disease is confined to one or both ovaries or fallopian tubes. Stage II involves spread to other pelvic organs, such as the uterus or nearby pelvic tissues, but remains within the pelvis. Stage III indicates spread beyond the pelvis to the peritoneal lining of the abdomen and/or to lymph nodes, and is further subdivided (IIIA, IIIB, IIIC) based on the extent and size of that spread. Stage IV represents distant metastatic disease, such as spread to the liver parenchyma, lungs, or fluid around the lungs (malignant pleural effusion), and is divided into IVA and IVB based on the specific location of spread.

Because early symptoms are subtle, roughly three out of four patients are diagnosed with stage III or IV disease. Accurate staging, which usually requires surgical exploration of the abdomen alongside imaging, is essential because it strongly influences both prognosis and the specific sequence of surgery and chemotherapy that is recommended.

Molecular and genetic testing plays a central role in modern ovarian cancer care. Germline (blood-based) testing for BRCA1 and BRCA2 mutations is recommended for essentially all patients with epithelial ovarian, fallopian tube, or peritoneal cancer, regardless of family history, since these results affect both treatment choice and family risk assessment. Many centres now also test for a broader panel of hereditary genes, including RAD51C, RAD51D, BRIP1, PALB2, and Lynch syndrome-related genes.

Separately, tumour tissue is typically tested for homologous recombination deficiency (HRD), a broader marker of impaired DNA repair that includes but is not limited to BRCA mutations; this is usually assessed through a combined genomic scar and mutation-based assay. Tumours that are HRD-positive, whether due to a BRCA mutation or another cause, are more likely to respond well to platinum-based chemotherapy and to benefit substantially from PARP inhibitor maintenance therapy.

CA-125 remains the most widely used blood biomarker for monitoring disease over the course of treatment and after completion of therapy, since rising levels can be an early sign of recurrence, sometimes preceding symptoms or visible disease on imaging. Additional tumour markers, such as HE4, are sometimes used alongside CA-125, particularly when evaluating a pelvic mass before surgery.

High-grade serous ovarian carcinoma (HGSOC) is the most common and best-studied subtype, characterised by near-universal TP53 mutations, frequent HRD, and typically presents at an advanced stage; it is usually sensitive to platinum-based chemotherapy, at least initially. Low-grade serous carcinoma is a distinct, less common entity that tends to grow more slowly, is less responsive to chemotherapy, and may involve different molecular drivers such as KRAS or BRAF mutations.

Endometrioid and clear cell carcinomas are less common subtypes that are sometimes associated with endometriosis; clear cell carcinoma in particular tends to be less responsive to standard platinum chemotherapy and is an active area of clinical trial research. Mucinous carcinoma of the ovary is uncommon and, when advanced, is often treated with chemotherapy regimens more similar to those used for gastrointestinal cancers.

Beyond epithelial cancers, germ cell tumours (such as dysgerminoma and yolk sac tumour) typically occur in adolescents and young women and are generally highly curable with surgery and chemotherapy. Sex cord-stromal tumours, such as granulosa cell tumours, tend to grow slowly, can produce hormones leading to distinctive symptoms, and are managed differently from epithelial ovarian cancer, often with a greater emphasis on surgery alone for early-stage disease.

Treatment approach depends heavily on stage, subtype, and how much disease can be surgically removed. For most patients with epithelial ovarian cancer, treatment involves a combination of surgery and platinum-based chemotherapy, with the sequence tailored to the individual: some patients have surgery first (primary debulking surgery) followed by chemotherapy, while others receive chemotherapy first (neoadjuvant chemotherapy) to shrink the tumour before an interval debulking surgery, particularly when disease is very extensive at diagnosis.

The goal of surgery is to remove as much visible tumour as possible, ideally leaving no residual disease, since the amount of tumour left behind after surgery is one of the strongest predictors of outcome. Standard chemotherapy typically combines a platinum agent (such as carboplatin) with a taxane (such as paclitaxel), usually given over about six cycles.

After completing initial chemotherapy, many patients are offered maintenance therapy to delay recurrence. Bevacizumab, a drug that blocks blood vessel growth to tumours, may be added during and after chemotherapy for higher-risk disease. PARP inhibitors (such as olaparib, niraparib, and rucaparib) are used as maintenance therapy, particularly in patients with a BRCA mutation or HRD-positive tumour, where the benefit tends to be most pronounced, though some PARP inhibitors are also used more broadly.

If the cancer recurs, treatment depends on how long it has been since the last platinum-based chemotherapy: cancers that recur more than six months after finishing platinum therapy (platinum-sensitive) are usually re-treated with platinum-based chemotherapy, sometimes with a PARP inhibitor or bevacizumab added, while cancers that recur sooner (platinum-resistant) are typically treated with non-platinum chemotherapy, sometimes combined with bevacizumab or in the context of a clinical trial. Fertility-sparing surgery, preserving the uterus and unaffected ovary, may be an option for carefully selected patients with early-stage disease who wish to preserve fertility.

Survival in ovarian cancer varies considerably by stage, subtype, and molecular features, and published statistics represent population averages rather than a prediction for any individual. According to SEER data compiled by the U.S. National Cancer Institute, the overall 5-year relative survival for ovarian cancer across all stages is approximately 50%, but this figure masks a wide range depending on stage at diagnosis.

When ovarian cancer is diagnosed and confined to the ovary (localised, roughly stage I), 5-year relative survival is around 90-93%. For disease that has spread to nearby structures or regional lymph nodes, 5-year relative survival is approximately 70-75%, while for distant metastatic disease (stage IV or widespread stage III), 5-year relative survival is roughly 30-31%.

Outcomes are also influenced by molecular features: patients with BRCA-mutated or HRD-positive HGSOC generally have better responses to platinum chemotherapy and PARP inhibitor maintenance and, on average, longer survival than those with HRD-negative disease. It is important to discuss what these statistics mean for your specific situation with your oncology team, since factors such as how completely surgery removed the tumour, response to chemotherapy, and overall health also strongly influence individual outcomes.