Revolutionary four-biomarker panel offers hope for early ovarian cancer detection

A recent British Journal of Cancer study evaluated multiple autoantibodies (AAb), antigens, and antigen-autoantibody (Ag-AAb) complexes for their capacity to complement the biomarker CA125 for early detection of ovarian cancer.

Study: Autoantibodies, antigen-autoantibody complexes and antigens complement CA125 for early detection of ovarian cancer. Image Credit: mi_viri/Shutterstock.com

Background

Ovarian cancer causes a significant number of deaths worldwide. In the US, a total of 19,880 women were diagnosed with ovarian cancer this year.

Recent advances in cytoreductive surgery and chemotherapy have improved survival rates in epithelial ovarian cancer patients. However, the survival chances significantly depend on the stage of the disease when detected. 

If ovarian cancer is detected at stage 1 of the disease, the patient has a five-year survival rate of over 90%. In contrast, when the disease is detected at stage II, i.e., cancer is limited to the pelvis, the chances of five-year survival rates dip to 70%.

This percentage further lowers in stage III, and the cure rate ultimately reduces to 20% if the disease is detected at stage IV. Computational studies estimated that detection of ovarian cancer at an early stage, i.e., I or II, can improve the cure rate by 10–30%.

Two US-based clinical trials, namely, the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and the Normal Risk Ovarian Cancer Screening Study (NROSS), investigated the association between rising CA125 levels and the Risk of Ovarian Cancer Algorithm (ROCA). 

It must be noted that NROSS screening decreased late-stage (III-IV) disease detection by 34% when compared to UKCTOCS controls. Therefore, early diagnosis of ovarian cancer is crucial to improve the cure rate.

Increased CA125 levels have been found in sera of 60–70% of patients who were at an early stage of epithelial ovarian cancer.

A greater sensitivity or higher detection rate could be achieved in the presence of additional biomarkers that complement CA125. More than 120 biomarkers, including antigens, AAb, and Ag-AAb, have been identified in this context.

AAb against antigens linked to ovarian cancer could be a promising candidate to enhance the sensitivity of CA125. These could be easily produced in response to very small amounts of tumor-associated antigens.

This strategy could play a crucial role in the early detection of ovarian cancer because AAb could be detected months or years before the elevation of CA125.

About the study

The current study compared panels of autoantibodies, Ag-AAb complexes, and ovarian cancer-associated antigens to determine the best complement of CA125, which is crucial for the early detection of ovarian cancer.

The present study was conducted with the National Cancer Institute Early Detection Research Network (EDRN).

A total of 26 different biomarkers were assessed in a single panel of sera samples in this study. Furthermore, the efficacy of five other assays for anti-TP53 AAb was investigated using serum samples from healthy controls and patients with early and late-stage ovarian cancer. 

The sera samples were used to identify the most promising classifier containing the biomarkers in the panel of CA125, human epididymis protein 4 (HE4), and HE4 Ag-AAb complexes. The sensitivity of CA125 alone validated this performance.

Study findings

In the current study, elevated CA 125 levels were found in 66% of early-stage (I-II) ovarian cancer patients at 98% specificity in the EDRN Validation panel. This finding indicates the need for further improvement in the sensitivity of this panel.

HE4 is a protein produced by epithelial ovarian cancer cells. In the current study, HE4 detected 11% of ovarian cancer cases that CA125 missed in the entire EDRN set. Here, around 19% of early-stage cases exhibited elevated HE4 Ag-AAb complexes.

The EDRN validation set demonstrated an elevated osteopontin (OPN) in 13% of early-stage ovarian cancers. OPN is a glycophosphoprotein synthesized into body fluids by arterial smooth muscle cells, osteoblasts, different epithelial cells, macrophages, and activated T cells.

This protein is also overexpressed by cancers that develop in different regions, such as the ovary.

CA125 alone could only detect 62% of early-stage cases, whereas the panel detected 75%. In addition, a significant improvement in sensitivity was achieved for the EDRN validation set.

The current study observed an elevated level of anti-p53 AAb in 20 to 25% of sera of patients with ovarian cancer. The RAPID assay was more sensitive in detecting TP53 AAb in 22% of all cases.

In the early ovarian cancer stage, elevation in only anti-CTAG1 AAb and anti-IL8 AAb was found.

CTAG1A detected 8% of early-stage and 19% of late-stage cases at 98% specificity. Anti-IL-8 AAb exhibited higher sensitivity in detecting early ovarian cancer stages.

The classifier comprising all three autoantibodies and complexes was trained in the EDRN training set, anti-CTAG1, anti-IL-8, and anti-TP53, and could detect 22% of early-stage cases at 95% specificity.

It must be noted that the sensitivity of three AAb failed to supersede CA125 alone. However, AAb produced a lead time over CA125.

Conclusions

The current study identified three biomarkers, HE4, HE4 Ag-AAb complexes, and OPN, that complement CA125. This strategy could increase early detection of ovarian cancer at 98% specificity.

It could provide a potential lead time of over 18 months in some cases, which could be crucial for treatment efficacy.