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New Strategies in Detecting Early-Stage Ovarian Cancer

M3 Global Newsdesk Mar 20, 2024

Unlocking the mysteries of ovarian cancer detection. Dive into the latest breakthroughs in screening technologies, promising a future of early detection and improved outcomes.

Key takeaways

  1. Ovarian cancer often presents after metastasis, so early detection remains an unmet need.
  2. Screening of serum biomarkers like CA-125 or the use of transvaginal ultrasound to pick up the disease lacks outcomes benefits, and false positives carry risk.
  3. Emerging screening technologies focus on proteomics and imaging.

Ovarian cancer usually presents with vague symptoms, often after the disease has metastasised. According to authors publishing in the Journal of Clinical Oncology, overall, 70%–75% of cases are detected at stage III or IV when the cure rate is <30%.[1] Currently, only 25%–30% of patients are diagnosed at stage I or II.

Algorithms predict that mortality could drop by 10%–30% if ovarian cancer was detected at an earlier stage. 

Nonetheless, neither serum biomarkers nor transvaginal ultrasonography (TVU) alone is specific or sensitive enough to detect the disease, according to the National Cancer Institute (NCI).[2] Manual pelvic examination also lacks sensitivity for the detection of early-stage disease, with no evidence of decreased mortality. 

"Several biomarkers with potential application to ovarian cancer screening are under development but have not yet been validated or evaluated for efficacy in early detection and mortality reduction."

National Cancer Institute

For these reasons, it’s worthwhile for physicians to evaluate the shortcomings of current screening methods and to take note of some research into multimodal tests, per the NCI.

CA-125 serum testing

This biomarker is used to monitor patients with epithelial ovarian carcinomas, and testing of it has been proposed as an indicator of early ovarian cancer either alone (using a threshold cutpoint) or in algorithms assessing changing levels over time. 

The most commonly reported CA-125 reference threshold that indicates a positive screening test is 35 U/mL. Notably, this threshold was used in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial (CA-125 levels were measured along with TVU).

Elevated CA-125 levels are not specific to ovarian cancer, as they are also present in non-gynecological cancers, liver disease, endometriosis, congestive heart failure, and pleural/peritoneal fluid accumulation, during the first trimester of pregnancy. According to the results of two nested case-control studies using serum banks, the sensitivity for CA-125 levels of at least 35 U/mL was 20%–57% for cases occurring within the first 3 years of follow-up, and the specificity was 95%.

Multimodal screening


In The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), researchers compared screening outcomes in three groups of postmenopausal women aged 50 to 74 years who received 7 to 11 rounds of annual screening: TVU alone (n=50,623), multimodal screening with CA-125 testing plus TVU (n=50,625), and no screening (control; n=101,299). 

Longitudinal CA-125 measurements were assessed using the Risk of Ovarian Cancer Algorithm (ROCA), which defines a positive test as one where there is a statistically significant increase in a woman’s serial CA-125 measurements. The aim of this approach is to use subtle in-person changes to detect cancer earlier. In the trial, ROCA was the primary screen, and TVU was the secondary screen.

The results showed a 39.2% increased incidence of stage I or II disease and a 10.2% lower incidence of stage III or IV disease in the multimodality screening arm vs. no screening. Regardless of this stage shift, however, at a median follow-up of 16.3 years, there was no significant difference in mortality, with 0.6% of patients dying in both the multimodality screening arm and the control arm.

PLCO (nested analysis)

The PLCO trial previously mentioned also reflected multimodal screening, utilising six annual tests for serum CA-125 (threshold: 35 U/mL) and four annual screens with TVU (n=39,105 for screening; n=39,111 for standard care). 

A nested analysis found that, although ovarian volume increases were detected 1 to 2 years before diagnosis, this difference did not translate to clinical practice.

Moreover, of the 3,285 women with false-positive results, 1,080 received surgical follow-up, with 15% experiencing at least one serious complication.


The article in the Journal of Clinical Oncology provided an update on the Normal Risk Ovarian Screening Study (NROSS). This study evaluated the use of a two-stage screening approach in a population of 7,856 postmenopausal women at conventional hereditary risk for ovarian cancer. ROCA was used to evaluate CA-125 each year, and patients were followed up with TVU if directed by ROCA. 

The authors observed that the two-stage screening strategy with CA-125 followed by TVU had adequate specificity to achieve a positive predictive value of 50%. Only two operations were required to detect each case of ovarian cancer, a finding that was consistent with the three to four operations required in the UKCTOCS, using a similar strategy. 

"Remarkably, 70% of ovarian cancers detected by the ROCA in the NROSS were in early stage (I-II)."

NROSS investigators, Journal of Clinical Oncology

The authors commented on the implications of their results for the detection of cancers originating in the fallopian tubes. A fraction of high-grade serous ovarian cancers can arise from the fallopian tubes, where there are no anatomic barriers to prevent transperitoneal spread. It may thus be particularly difficult to detect small, early-stage tubal cancers.

Although the fraction of cancers arising from the fallopian tube in women at conventional genetic risk is not known, the investigators expressed the potential of their approach: “Our data suggest that the majority of ovarian cancers can be detected in early stage regardless of their site of origin.” 

They concluded that although the NROSS trial was not sufficiently powered to determine mortality, the high specificity, positive predictive value, and marked stage shift bolster further research for this approach.

Current guidance

In 2016, the FDA issued a Safety Communication that recommended against the use of current screening tests like TVU and CA-125 for ovarian cancer in any population of women. 

Asymptomatic high-risk women who have a false-negative screening test are at risk of delaying preventive treatments.

Similarly, the USPSTF concluded with moderate certainty that the harms of screening using TVU or CA-125, or both, outweighed any potential benefits. There is no reduction in mortality from ovarian cancer. Harms, judged moderate to substantial, include false-positive results, which can result in unnecessary diagnostic surgery.[3]

Multi-marker blood assays

Proteins are the functional end products of genes and play a role in establishing the cancer phenotype. Consequently, proteomics may prove useful in understanding the molecular mechanisms linked to cancer. Single and multi-marker blood assays have been forwarded as potential diagnostic tools for detecting ovarian malignancies. 

Authors of a review article on screening and diagnostics tools for ovarian cancer acknowledged that CA-125 is the most important ovarian cancer biomarker discovered to date.[4] "However, there remains an ongoing search for alternative protein biomarkers for use in coordination or in comparison with CA-125," they said. "The majority of these tests have exhibited increased accuracy for the detection of ovarian cancer over CA-125 alone while maintaining high specificity."

They cite the work by Yale researchers, who identified a six-marker panel consisting of CA-125, leptin, prolactin, osteopontinin, insulin-like growth factor 2, and macrophage inhibitory factor. 

This six-marker panel demonstrated a 95% sensitivity at 98% specificity for all ovarian cancer stages. In a follow-up study, 95% sensitivity and 95% specificity for early-stage (I-II) disease was attained with the panel.

Other protein techniques

Traditional methods used for quantification of serum proteins such as CA-125 or others include radiolabeled immunoassays or enzyme-based immunoassays (ELISAs). In addition, fluorescently labelled antibody-conjugated beads plus flow cytometry methods have been used in recent studies to identify ovarian cancer-specific protein levels in serum.

Departing from these traditional methods is the investigation of platelets, which have been used to identify and diagnose ovarian cancer. Thrombocytosis is observed in 23%–56% of ovarian cancer cases and is related to advanced disease stages and increased mortality. Paraneoplastic thrombocytosis is also correlated with an increase in hepatic thrombopoietin in response to tumour-derived IL-6 production.

Researchers used a proximity extension assay combined with next-generation sequencing and multivariate modelling to identify an 11-plasma protein panel (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2). Testing showed that this panel was capable of distinguishing early- from late-stage high-grade serous carcinoma with an AUC of 0.81. It also discriminated ovarian cancer patients (stage I–IV) from healthy individuals with a sensitivity of 75% and a specificity of 100%.

In commenting on these investigations, the review authors wrote: “So-called ‘perception-based’ approaches offer an additional new tool for classifying disease states, whereby an array of non-specific responses can be combined and processed with machine learning to produce a singular response that is highly specific and accurate.”

One example they cite is the development of a nano-sensing array consisting of modified semiconducting single-walled carbon nanotubes. This type of array detected high-grade serous carcinoma with higher sensitivity and specificity vs. traditional serum and TVU-based approaches.

Another area of active research involves the glycosylation of CA-125. Such tests hone in on specific abnormalities in N-terminal glycosylation patterns that are unique to ovarian cancer.

Emerging imaging techniques

The review article also addresses imaging diagnostics. Two major areas of research include the enhancement of current TVU imaging methods to improve accuracy, and the development of new imaging modalities that can accurately detect malignant ovarian masses. 

Screening with improved imaging techniques shows promise. For instance, Doppler with microbubble enhancement may improve conventional TVU. Microbubbles, which are microspheres consisting of a protein or lipid shell encasing a gas core, are used as contrast agents for ultrasound. 

TVU can also be paired with photo-acoustic imaging (PAI) to enhance diagnostic accuracy. PAI collects real-time functional and molecular information from tissues without using radiation or exogenous contrast. PAI allows for the high-resolution detection of angiogenesis and might detect neovascularisation in early-stage ovarian cancer. Current PAI methods, however, can only penetrate tissues up to 5 cm, and resolution declines with increased depth. Consequently, TVU co-registration is still required.

Imaging modalities other than TVU that may be able to pick up pathologic changes that are characteristic of early ovarian tumours include MRI augmented with AI and PET combined with CT. 

Hysteroscopy and laparoscopy approaches may also be useful to screen for early ovarian cancer, with diagnosis made from a sampling of endoluminal cells. Cytuity is an FDA-cleared hysteroscopic catheter with a balloon-like mechanism on the distal end of the catheter that collects tubal epithelial cells at the level of the ostium of the fallopian tube.

What this means for you

Patients should be advised that no screening test is recommended for ovarian cancer. Current screening with CA-125 or TVU lacks outcomes benefits and is potentially harmful due to diagnostic surgery resulting from false-positive results. Multimodality screening continues to be examined, and other emerging technologies, including proteomics, multi-marker blood assays, and TVU alternatives, are at the forefront of screening research.


Disclaimer: This story is contributed by Naveed Saleh and is a part of our Global Content Initiative, where we feature selected stories from our Global network which we believe would be most useful and informative to our doctor members.

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