Ovarian cancer is the seventh most common cancer among women globally, with 46% survival five years after diagnosis.¹ In 2020 there were more than 313,000 new ovarian cancer diagnoses worldwide and more than 207,000 deaths due to the disease.² Ovarian cancer has a poor prognosis because it presents with non-specific symptoms (Table 1) and is diagnosed at an advanced stage in more than two-thirds of patients. Late-stage presentation has a five-year relative survival rate of 30%, compared to 93% for early-stage disease.³ Consequently, there is a pressing need for an effective ovarian cancer screening test that would allow earlier detection of ovarian cancer in asymptomatic women with the goal of reducing the number of deaths due to the disease. The cancer antigen-125 (CA125) blood test and transvaginal ultrasound scan (TVS) have been the most extensively studied screening tools to date but have not reduced ovarian cancer mortality in randomised controlled trials.

Table 1. Symptoms associated with ovarian cancer.

Ovarian cancer screening in the general population

The low prevalence of ovarian cancer, and relatively poor specificity and positive predictive value of CA125 and TVS used alone on a single occasion can result in false positive screening results that lead to unnecessary surgical interventions. In 2018 the US Preventive Services Task Force issued a recommendation against population-based screening for ovarian cancer, based on a review of four randomised screening trials.⁵ The two largest studies were the Prostate, Lung, Colorectal and Ovarian screening trial (PLCO) and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).^{6 7} The PLCO trial included 68,557 women undergoing yearly CA-125 and TVS compared to no screening in a US population. No reduction in ovarian cancer mortality was observed (RR 1.18 95% CI 0·82–1·71) and 3285 women experienced a false positive result with 1080 of those undergoing surgery. Improved sensitivity, specificity and positive predictive value has been achieved with two stage screening strategies where an increase in serial serum CA125 triggers a TVS.⁸ The UKCTOCS was a randomised control trial of 202,638 women receiving either no screening, TVS, or multimodal screening (MMS) comprising a proprietary algorithm – the Risk of Ovarian Cancer Algorithm (ROCA), which incorporates historical CA-125 levels and current CA-125 levels to triage women to additional investigation with TVS. UKCTOCS is the largest randomised trial of ovarian cancer screening and one of the largest randomised trials ever conducted. At a median follow up of 16.3 years (IQR 15.1 – 17.3) there was no reduction in ovarian cancer deaths in either the MMS or TVS group, with hazard ratios of 0·96 [95% CI 0·83–1·10] for MMS vs no screening and 0·94 [0·82–1·08] for TVS vs no screening. There was a ‘stage shift’ observed at diagnosis, with a 24.5% lower incidence of stage IV disease and a 47.2% higher incidence of stage I/II in the MMS arm, but although some cancers were detected earlier this did not translate to a decrease in disease-specific mortality. UKCTOCS did not include analyses by ovarian cancer histotype, which is a limitation of the study. Such analyses would likely not have been feasible for the rarer histotypes but would have been possible for high-grade serous ovarian cancer which is the most common subtype.⁹

Ovarian cancer screening in high-risk populations

Approximately 10% of patients with an epithelial ovarian malignancy, and 17% of those with high-grade serous carcinomas, will have a genetic predisposition (Table 2).¹⁰ Women with pathogenic germline variants in BRCA1/2 have a risk of developing an ovarian malignancy of 17–44%, compared to the general Australian population risk of 0.9% by age 80.^{11 12} The definitive, and currently only, evidence-based strategy for individuals at high risk of ovarian cancer due to pathogenic germline variants is a risk reducing bilateral salpingo-oophorectomy.¹³ Whilst this is highly effective in reducing ovarian cancer incidence and mortality, it carries with it the implications of surgical menopause and loss of fertility in reproductive age group women.

The Cancer Genetics Network and Gynecologic Oncology Group assessed 3818 women at elevated risk of ovarian cancer every three months with CA-125, yearly TVS, and a reflex TVS in event of rising CA-125.¹⁴ Whilst nine ovarian cancers were identified, there were 20.7 false positives for every case of cancer detected. The United Kingdom Familial Ovarian Cancer Screening Study enrolled 4531 women at high risk using a similar screening strategy.¹⁵ Whilst this study showed a shift towards a lower stage at diagnosis in screened women most of these women were diagnosed at the time of a risk reduction surgery, not as part of the screening protocol. Australian guidelines currently recommend against screening in asymptomatic high-risk individuals.¹⁶

Table 2. Lifetime risks of epithelial ovarian/fallopian tube/primary peritoneal cancer for specific pathogenic germline gene variants.

What is happening in current practice?

Despite evidence that screening for ovarian cancer does not reduce mortality, screening occurs frequently. A recent survey study of 1264 high-risk women enrolled in an Australian breast cancer cohort with more than 832 respondents (response rate 65.8%), and 531 clinicians (GPs and gynaecologists), with 252 respondents (response rate 47.4%), found that 15% of women had been screened for ovarian cancer in the preceding two years despite national guidelines that recommend against it.¹⁸ Although most clinicians agreed there was no reliable way to detect ovarian cancer at an early stage, and that screening can lead to unnecessary investigations and surgery, about half agreed that they would usually order a CA125 and TVS upon patient request. Inappropriate screening is performed for a variety of reasons including patient expectations, medicolegal concerns, and a belief that screening reduces mortality. Many patients believed that screening would improve survival and overestimated their personal risk of ovarian cancer. Previous studies have found that up to 50% of clinicians in the US request ovarian cancer screening for average risk women.^{19 20} Interventions to reduce inappropriate screening are likely to require complex individual and system-based approaches that incorporate patient and clinician education, behavioural change strategies, decision support tools and regulatory processes.

Future prospects

In recent years there has been a paradigm shift in our understanding of the aetiology of high-grade serous carcinoma, the most common and lethal ‘ovarian cancer’ histotype. The advent of next generation sequencing technology enabled genomic analyses of omental metastases and fallopian tubes in patients with advanced disease and showed that in situ lesions in the tubal epithelium – serous tubal in situ carcinomas (STICs) – are the precursors to high-grade serous carcinoma.²¹ It is now accepted that most high-grade serous ‘ovarian’ cancers originate in the distal fallopian tube.²² Thus, in high-grade serous cancer, malignant cells on the ovarian surface are in fact metastatic deposits of fallopian tube origin, which challenges the concept of stage I ‘ovarian cancer’. Given the tubal origin of high-grade serous carcinoma, efforts have been focussed on early identification of small fallopian tube cancers such as cytologic sampling of the fallopian tubes using hysteroscopic brush cytology.²³ Further, opportunistic salpingectomy, which is the removal of fallopian tubes during hysterectomy or instead of tubal ligation without removal of ovaries, reduced ovarian cancer risk in a population-based cohort study in British Columbia.²⁴

RANZCOG now recommends consideration be given to opportunistic bilateral salpingectomy at the time of hysterectomy for benign gynaecological disease and that the risks and benefits be discussed with the patient on a case-by-case basis and that consideration should be given to bilateral salpingectomy instead of tubal occlusive procedures for female sterilisation.²⁵ In high-risk individuals, such as carriers of pathogenic germline variants in BRCA1/2, current Australian guidelines do not recommend bilateral salpingectomy as a risk reducing strategy due to lack of evidence of safety.²⁶ Clinical trials of risk reducing bilateral salpingectomy and delayed bilateral oophorectomy performed closer to the age of natural menopause in high-risk individuals have recently opened to recruitment in Europe and the US.²⁷

There is potential for additional protein biomarkers as screening tools to be used in combination with CA125 such as human epididymis protein-4 (HE4) as well as biomarkers such as TP53 autoantibodies, circulating tumour DNA, microRNAs, and DNA methylation, but these require further development, validation, and testing in randomised controlled trials.^{28 29} Novel imaging technology such as radiomics and radiogenomics may improve detection and form part of a multimodal screening approach.³⁰ Resources from the UKCTOCS trial will likely play a key role in future biomarker research and validation as many longitudinal serum samples were obtained during the trial with linked clinical data.

Conclusion

Currently evidence does not support ovarian cancer screening in healthy asymptomatic women regardless of their level of risk. Novel technologies offer considerable promise, and ongoing research for a cost-effective screening test that reduces ovarian cancer mortality is an imperative. In the meantime, strategies such as opportunistic salpingectomy in low-risk populations, and identification of genetic risk with counselling and appropriately timed risk-reducing salpingo-oophorectomy, are integral public health measures to reduce ovarian cancer incidence and mortality.

Our feature articles represent the views of our authors and do not necessarily represent the views of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG), who publish O&G Magazine. While we make every effort to ensure that the information we share is accurate, we welcome any comments, suggestions or correction of errors in our comments section below, or by emailing the editor at [email protected].

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