Human epididymis protein 4 antigen‐autoantibody complexes complement cancer antigen 125 for detecting early‐stage ovarian cancer

Abstract

BACKGROUND: Early detection of ovarian cancer could significantly improve patient outcomes. Cancer antigen 125 (CA 125) is elevated in sera from approximately 60% of patients with early-stage (I/II) disease. Sensitivity might be improved through the combination of CA 125 with other biomarkers. Among potential biomarkers, antigen-autoantibody (Ag-AAb) complexes have received relatively little attention. METHODS: Luminex-based immunoassays were used to measure human epididymis protein 4 (HE4), anti-HE4 autoantibody, and HE4 Ag-AAb complexes in sera from patients with early-(n = 73) and late-stage ovarian cancers (n = 49) at the time of diagnosis and from asymptomatic women with (n = 15) or without ovarian cancer (n = 212) enrolled in the Normal Risk Ovarian Cancer Screening Study. RESULTS: At 98% specificity for healthy, asymptomatic women, 7% of patients with early-stage (I/II) ovarian cancer and 4% of patients with late-stage (III/IV) disease had elevated levels of HE4 autoantibody, whereas elevated levels of HE4 Ag-AAb complexes were detected in sera from 38% of early-stage cases and 31% of late-stage cases. Complementarity was observed in receiver operating characteristic (ROC) curves between HE4 Ag-AAb complexes and CA 125 levels in early-stage ovarian cancer (P < .001). CA 125 detected 63% of cases, and a combination of CA 125 and HE4 Ag-AAb complexes detected 81%. Complementarity was also observed in ROC curves for an independent validation set with 69 early-stage patients (P = .039). HE4 Ag-AAb complexes were detected in serial preclinical serum samples from women destined to develop ovarian cancer: they correlated with CA 125 but did not provide a lead time. CONCLUSIONS: HE4 Ag-AAb complexes could complement CA 125 in detecting a higher fraction of early-stage ovarian cancers. Cancer 2020;126:725-736.

Serum Anti-PDLIM1 Autoantibody as Diagnostic Marker in Ovarian Cancer

“…Due to the heterogeneous attribute, most of ovarian cancer (OC) is insidious and painless in the early stage. Thus, there are only less than 25% of patients with OC detected at the early stage (I+II), and more than 75% of patients with OC are found at the late stage (II+IV) ( 23 ). Although the 5-year survival of OC patients has improved owing to advanced treatments, the overall cure rate still remains lower than 30% ( 24 ).…”

Proteome Profiling Uncovers an Autoimmune Response Signature That Reflects Ovarian Cancer Pathogenesis

“…There is increasing evidence for circulating immune complexes during tumor development that may serve as cancer biomarkers. We recently reported that human epididymis protein 4 (HE4) antigen-autoantibody complexes could significantly improve diagnostic performance in combination with CA125 compared with CA125 alone based on analysis of early stage ovarian cancer samples [7]. Other complexes notably involving cofilin 1 were found to be associated with pancreatic cancer [44].…”

“…There remains a need for identification of additional markers for ovarian cancer early detection. Tumor associated autoantibodies may improve on the performance of CA125 alone as we recently described for the human epididymis protein 4 (HE4) antigen-autoantibody complexes as complementing CA125 for detecting early-stage ovarian cancer [7].…”

Biomarkers and Strategies for Early Detection of Ovarian Cancer

“…While free autoantibodies were observed in less than 5% of cases, antigen-autoantibody complexes were found in 38% of early stage cases at 98% specificity. 57 Use of CA125 and HE4 antigenautoantibody complexes in combination, increase the fraction of cases detected from 63% with CA125 alone to 81% with both biomarkers. The levels of HE4 antigen-autoantibody complexes did not, however, rise earlier than did levels of CA125.…”