An effective screening method for detection of early-stage ovarian cancer requires a specificity of at least 99.6%, sensitivity of at least 75% and a positive predictive value of at least 10% (Clarke-Pearson DL, 2009). Because of the requirement to have high specificity in order to be considered as a screening tool in the general population, this Is a great challenge. Rising
CA125 values are associated with progressive growth of ovarian cancer, whereas stable CA125 values, even when elevated, are associated with benign conditions(Lu et al, 2013). CA 125 is the marker for late stage of the ovarian cancer. It is less sensitive In early stage and in premenopausal women.
Because survival rates, which are subject to lead-time bias, were reported rather than mortality, these results do not, however, prove that screening reduced deaths from the disease and the perceived survival benefit may instead be attributed to an earlier diagnosis of disease with no impact on lifespan.
In Ueland, et al. 2011 and Coleman et al. 2016, significance of using a combination panel was effectively reported. These studies validate multivariate index assay, which is a combination of multiple markers along with CA125. These studies were intended to replace the use of CA125 alone with multivariate index assay in detecting ovarian cancer. OVA1 (Ueland et al.2011) and second generation OVA1(Coleman et al.2016) showed improvement in sensitivity and negative predictive value compared to CA125 alone. The sensitivity in early stage disease is 94% compared to 61% of CA125. Ueland et al report identified 76% of the malignancies missed by CA125. This is consistent with the study by Longoria et al. 2014, which suggested that OVA1 correctly predicted 78% of the malignancies missed by CA125.
They both decreased specificity and positive predictive value to a great amount, which would potentially cause more false positive results. Strengths of these studies are the large cohort, prospective multi-institutional data collection, which helped to have a diverse population. The studies also included both pre-menopausal and post-menopausal women, which further helped in the implementation of multivariate index assay in the pre-menopausal group, where CA125 is less sensitive by its own.
But these assays are only recommended for women presenting with adnexal masses, who are scheduled for the removal of the mass. Therefore, multivariate index assay can only appropriately predict malignancy in the early stages of the disease at the time of surgery, by complementing physician’s preoperative assessment. Because prevalence is high among the patients with current adnexal mass, this cohort increases PPV and decreases NPV
In Hamed et al. 2013, adding an additional marker to CA125 showed an improved sensitivity, but decreased specificity (96.7% sensitive & 80% specific versus 83.3% & 85%). This data is consistent with another study by Moore et al, 2008 in terms of overall trend, which reported a sensitivity of 94.3% and specificity of 75%, when HE4 and CA-125 are combined to detect malignancy. HE4 has a greater advantage over CA125, as it is not elevated in any other benign gynecological diseases. It was also able to differentiate healthy patients from benign diseases. It is also worth noting that HE4 can also be elevated in other non -gynecological cancer. Since it is not clear in the study that the researchers excluded women with non-gynecological disease symptoms or signs, the potential of using HE4 must be validated with more research. The study excluded any women with any underlying pathology, and was matched for all characteristics to the control group. The comparison of both benign and control group helped to identify major changes in the elevation of markers that can be distinguished from the ovarian cancer group. This lead to the conclusion that HE4 was superior to CA-125 in separating benign, borderline ovarian tumors, and cancers of the fallopian tubes as well This study does not distinguish the effectiveness of HE4 based on the menopausal status. This may play a factor in the wide range of HE4 serum levels (60 pmol/Lto 150 pmol/L).The study also had a cut off value for HE4 as 150 pmol/l, which could be varied in different ages of women. Thus if the study instead looked at the changes in the baseline values of the women, like ROCA, the data would have held more power. In a study nested within PLCO, HE4 was the second best marker after CA125 with a sensitivity of 73% compared to 86% for CA125 .
Data from Bluyss et al. 2015 was in favor of adding HE4 and Glycodelin (a novel marker) to CA125, even though there were not much difference between the values of CA125 and in combination with others. Sensitivity was increased from 0.894 to 0.915 and area under the curve increased from 0.957 to 0.967, after adding glycodelin and HE4 to CA125. The researchers attributed this lack of difference to the inclusion of more than 15% false negatives to the cohort that were not identified in the source sample of UKCTOCS. MMP-7 & CYFRA 21-1 were considered to be non-significant markers as they had p>0.05 and the lowest area under the curve value respectively. Not a lot of research has been done to prove the effectiveness in a biomarker panel, which therefore calls for further research. Strengths of this study were large sample size, randomization of each case matched on age, exclusion of women with a previous diagnosis of cancer.
Będkowska et al. 2017, also reported an improved early detection of ovarian cancer using the combination of CA125 with other markers than alone. A combined panel of MMP-7, HE4 and CA125 was suggested for utilization in all stages of the disease, especially in stage I & II. Sensitivity of MMP-7 was superior to CA125 in the early stages. Diagnostic power is indicated by the ROC curve, with a higher area under the curve value for the combination panel. Unfortunately, effectiveness of TIMP-1, another marker that was compared, was not able to be proved. It could not differentiate between benign and malignant ovarian tumors. A limitation to this study is the inability of the data to be compared to other researches since there is no. strength of this study is exclusion of participants with other gynecological disease and endometriosis, as CA125 and HE4 are shown to be elevated in these conditions as well. But the study failed to mention if there had been any history of other types of cancer in these women, nor if they were excluded. The study only includes patients from one institution and therefore should be mindful of selection bias.
Simmons et al. 2017 described the potential of a panel of markers which increased sensitivity by detecting cases missed by CA125 alone. The panel consisted of top 4 biomarkers from eight markers that were tested. CA125, HE4, CA72-4 and MMP-7 became the combination panel with a sensitivity of 83.2% at 98% specificity, improving on CA125 alone. A unique characteristic of this study is the use of baseline values for each of the markers and comparing variation in the levels pertaining to cancer types and menopausal status. This longitudinal analysis of the markers helped in the improved sensitivity, reduced mortality, and improved lead time. This fact was akin first established in a randomized UKTOCS and in the establishment of ROCA with CA125.
A data regarding CA125 and HE4 combination in this study was not in accordance with the value reported by Hamed et al, 2013.In this study, the CA125 and HE4 combination achieved a sensitivity of 79.7% at 98% specificity, whereas Hamed et al, 2013 showed a decreased specificity and increased sensitivity. The study used samples from UKTOCS trial, which had the benefit of a large, multi-institutional blinded study.
H.Y et al, 2017 conducted a study using GOLPH3, CA19.9, and CA125 to observe the usefulness of combination marker panel. This panel indeed showed a statistically significant result (p Results from Horala et al. 2016 showed a three-marker panel consisting of osteopontin, CA125 and HE4 with better area under the curve value of 0.958 than CA125 alone (area under the curve of 0.932). This helped in differentiating between benign and malignant ovarian cancer. Strength of this study is appropriate use of benign and healthy control groups to search for a screening marker. But this marker cannot be used as a marker for general population, but could possibly be useful in high risk population(BRCA1 or BRCA2).
This is the first study with serum angiognenesis factors, and therefore further stidies must be conducted in a large cohort to investigate the usefulness. and as with other markers osteopontine levels are also significantly elevated in other malignancies.