Among women in the UK, ovarian cancer (OC) is the sixth most common cause of cancer-related death. Late-stage diagnoses making up approximately half of OC cases,1 which is particularly significant considering that the survival at one year is 93.5% at stage II, 71% at stage III and just 51.4% at stage IV.1  There are several reasons why OC is so life threatening – the first being the methods of testing. NICE states in their guidelines that serum levels of Carcinoma Antigen 125 (CA125) should be measured for women with symptoms suggestive of OC. Should the CA125 levels be over 35IU/ml, the patient subsequently has an ultrasound scan of the abdomen and pelvis.2 Whilst CA125 is sensitive for advanced OC, it lacks sensitivity for early staged disease even with Trans-Vaginal Ultrasound Scanning (TVUSS).3 Furthermore, the test lacks specificity with levels becoming elevated in endometriosis, menstruation, cysts, benign tumours, infection, and pregnancy. The symptoms of OC also contribute to its lethality, being notoriously insidious and of late onset with bloating, pelvic or abdominal pain, early satiety and urinary urgency/frequency,2 often only become noticeable after peritoneal spread has occurred. Even after their onset, the vague nature of the symptoms may cause patients and doctors to at first attribute them to more common causes such as IBS and UTIs. This means that early-stage OC, despite the guidelines, is often missed,1 demonstrating the need for a sensitive and specific diagnostic test for asymptomatic women. Discussions regarding the feasibility of this aim shall be explored, including examples of the development and implementation of early diagnostic testing for other cancers, as well as current OC diagnostic test research and specific challenges hindering progress.

 

Past Successes:

Much like OC, bowel cancer patients often present with relatively advanced disease. A bowel cancer screening programme was introduced in 2006 to rectify this. A drastic improvement in prognosis followed where mortality fell by 21% between 2005 to 2016.4 Likewise, the introduction of mammographic testing for early stage breast cancer has been associated with a 21% reduction in mortality.5 Whilst clinically very effective, these programmes have proven cost-effective.6 These examples demonstrate that the NHS is capable of developing and implementing effective diagnostic strategies that target early stage cancers or even pre-cancerous changes. Whether currently available tests for OC could be used in such a programme has been explored in several longitudinal cohort studies, with one being the United Kingdom Collaborative Trial of Ovarian Cancer Screening trial. Using a cohort of 202,638 participants and after a median follow-up interval of 16 years, it was found that there were no differences in mortality between groups tested annually with both CA125 and TVUSS, TVUSS only and no screening.3 This statistically powerful study strongly suggests that these tests are appropriate for the detection of OC in the early, asymptomatic stages. 

 

Tests in the Pipeline: 

The lack of promising evidence concerning CA125 and TVUSS, has prompted a search for novel biomarkers, an example being Human Epididymis-4 (HE4). HE4 is a glycoprotein overexpressed by OC tissue shown to have a higher specificity compared to CA125, yet have a similar or even poorer sensitivity.7 To address this, it has been suggested that the combination of the two in a single test could be used.7 This concept has been of major interest, with studies demonstrating that this improves efficiency; however, there are also studies that have found the contrary.7 Opposing evidence is possibly due to discrepancies between studies in the techniques used for measuring CA125 and HE4 and the use of differing thresholds. Further research and standardisation amongst the scientific community is needed to ascertain the value of this dual test. 

 

In recent decades, Extracellular Vesicles (EVs) have also been studied extensively. EVs are released from cells into biofluids and are produced in large quantities and with altered contents by cancer cells. Carollo et al. (2019) published a review on the existing EV literature, concluding that EVs have realistic diagnostic potential for OC.8 EV miRNAs extracted from urine or blood are feasible options, which not only demonstrates the promise of EVs, but also that the required samples can be as quick and as non-invasive as a simple urine or blood test. As well as miRNAs, EV CA125 has been shown to be elevated in Stage I and Stage II of OC and crucially, more so than free circulating CA125.8 Carollo et al. (2019) suggest that EV CA125 and EV claudin 4 could be measured together as a dual biomarker test, as claudin 4 has a low sensitivity but high specificity for OC. This dual method could be a focus for future research. Despite the promising nature of EVs, the debate continues concerning which technique is most effective for their extraction, purification and detection. Nevertheless, progress is being made leading the scientific community to hope that an early diagnostic test for OC involving EVs could be developed in the near future. 8

 

The quantification of circulating cell-free DNA (cfDNA), which is degraded DNA, showed diagnostic promise. Studies have produced varying results that were not systematically evaluated until 2016, when Zhou et al. (2016) performed a meta-analysis of nine studies (totalling 462 OC patients and 407 healthy controls).9 Whilst it was concluded that the sensitivity of cfDNA is unsatisfactory at 74%, specificity was acceptable at 90%. This, again, suggests promise for cfDNA when used as part of an integrated test with more sensitive biomarkers, such as HE-4, although there is a current lack of research into this suggestion.9 Obstacles remain in developing cfDNA as a diagnostic test as some studies only use OC patients in the advanced stages,9 calling into question the generalisability of the findings to those with early stage disease. There is also uncertainty concerning the best source for cfDNA detection with plasma-based assay and serum-based assay comparisons remaining inconclusive on the available evidence.9 Therefore, further investigation should include cfDNA measurements at an early OC stage, using different specimen types and the combination of cfDNA with other biomarkers. 

 

The aforementioned biomarkers present numerous possibilities for OC diagnosis. A key theme in the literature is that the use of a combined biomarker test could strengthen specificity and sensitivity. Indeed, several studies have demonstrated that multi-biomarker testing is advantageous over individual testing with Pal et al. (2015) finding a sensitivity of 94% and specificity of 98% with the combination of three biomarkers.10 Unfortunately, the balance of OC stage tends to be uneven amongst OC groups in these studies, with fewer women with stage I or II compared to with stages III or IV, meaning conclusions are often not specific to early OC detection. Combination studies are also lacking for biomarkers such as cfDNA and EV markers. However, this approach is encouraging and suggests that with more specific evidence a combined test could be the solution to the current poor rates of early OC diagnosis.

 

Conclusion

Overall, the rates of early-stage OC detection within the NHS is proportionally low, demonstrating how a cheap, non-invasive test that is specific and sensitive is needed. The NHS has a history of introducing effective diagnostic tests for early stage, asymptomatic cancers. The current issue lies with identifying an appropriate test. It has been demonstrated in longitudinal cohort studies that the individual and combined use of CA125 and TVUSS offers little promise. Nevertheless, there are several emerging fluid-biopsy tests. EV testing provides exciting prospects with EV miRNA, CA125 and claudin 4 having potential. Less encouraging evidence has been produced for other biomarkers, however, the possibility of dual testing of HE4 with CA125; EV CA125 with EV claudin 4; and cfDNA with HE4 could be targets for future research. A combined test such as these may overcome the disadvantages of each stand-alone test. Obstacles include reaching a consensus within the scientific community on how best to process samples including patients with early-stage disease in studies and the lack of evidence for combined biomarker tests. Longitudinal cohorts could be the solution for some of these issues as done in the past when assessing CA125 and TVUSS to strengthen the generalisability and statistical power of the findings. OC diagnosis remains an achievable goal. Previous successes within the NHS and emerging testing targets have made this possible. It is this possibility that the medical community hopes to channel towards our patients in the foreseeable future.

References

1. Cancer survival by stage at diagnosis, experimental statistics: 2012 to 2014 – Office for National Statistics [Internet]. Ons.gov.uk. 2021 [cited 12 June 2021]. Available from: https://www.ons.gov.uk/releases/cancersurvivalbystageatdiagnosisexperimentalstatistics2012to2014

2. Ovarian cancer: recognition and initial management Guidance [Internet]. Nice.org.uk. 2021 [cited 12 June 2021]. Available from: https://www.nice.org.uk/guidance/cg122

3. Menon U, Gentry-Maharaj A, Burnell M, Singh N, Ryan A, Karpinskyj C et al. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. The Lancet. 2021;397(10290):2182-2193. 

4. Morling J, Chapman C, Logan R. Impact of GFOBT screening in england on colorectal cancer mortality. Gut. 2018;67:A183-A184.

5. Johns L, Coleman D, Swerdlow A, Moss S. Effect of population breast screening on breast cancer mortality up to 2005 in England and Wales: an individual-level cohort study. British Journal of Cancer. 2016;116(2):246-252. 

6. Murphy J, Halloran S, Gray A. Cost-effectiveness of the faecal immunochemical test at a range of positivity thresholds compared with the guaiac faecal occult blood test in the NHS Bowel Cancer Screening Programme in England. BMJ Open. 2017;7(10):e017186.

7. Dochez V, Caillon H, Vaucel E, Dimet J, Winer N, Ducarme G. Biomarkers and algorithms for diagnosis of ovarian cancer: CA125, HE4, RMI and ROMA, a review. Journal of Ovarian Research. 2019;12(1).

8. Carollo E, Paris B, Samuel P, Pantazi P, Bartelli T, Dias-Neto E et al. Detecting ovarian cancer using extracellular vesicles: progress and possibilities. Biochemical Society Transactions. 2019;47(1):295-304.

9. Zhou Q, Li W, Leng B, Zheng W, He Z, Zuo M et al. Circulating Cell Free DNA as the Diagnostic Marker for Ovarian Cancer: A Systematic Review and Meta-Analysis. PLOS ONE. 2016;11(6):e0155495.

10. Pal M, Rashid M, Bisht M. Multiplexed magnetic nanoparticle-antibody conjugates (MNPs-ABS) based prognostic detection of ovarian cancer biomarkers, CA-125, β-2M and ApoA1 using fluorescence spectroscopy with comparison of surface plasmon resonance (SPR) analysis. Biosensors and Bioelectronics. 2015;73:146-152.

 Published 03-09-2022

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