Abstract
Objective Human epididymis protein 4 (HE4) is a validated, complementary biomarker to cancer antigen 125 (CA125) for high grade serous ovarian carcinoma (HGSC). Currently, there are insufficient data on the utility of longitudinal HE4 measurement during HGSC treatment and follow up. We set to provide a comprehensive analysis on the kinetics and prognostic performance of HE4 with serial measurements during HGSC treatment and follow up. Methods This prospective study included 143 patients with advanced HGSC (ClinicalTrials.gov identifier: NCT01276574). Serum CA125 and HE4 were measured at baseline, before each cycle of chemotherapy and during follow up until first progression. Baseline biomarker values were compared to the tumor load assessed during surgery and to residual disease. Biomarker nadir values and concentrations at progression were correlated to survival. Results The baseline HE4 concentration distinguished patients with a high tumor load from patients with a low tumor load assessed during surgery (p<.0001). The baseline CA125 level was not associated with tumor load to a similar extent (p=.067). At progression, the HE4 level was an independent predictor of worse survival in the multivariate analysis (p=.002). All patients that were alive 3 years post-progression had a serum HE4 concentration below 199.20 pmol/l at the 1st recurrence. Conclusion HE4 is a feasible biomarker in the treatment monitoring and prognostic stratification of patients with HGSC. Specifically, the serum level of HE4 at first relapse was associated with the survival of patients and it may be a useful complementary tool in the selection of second line treatments. This is to the best of our knowledge the first time this finding has been reported.
Highlights
Epithelial ovarian cancer is an umbrella term that includes a heterogeneous group of malignancies, of which high grade serous ovarian carcinoma (HGSC) is the most common and aggressive [1]
The longitudinal kinetics of serum cancer antigen 125 (CA125) and Human epididymis protein 4 (HE4) were similar during primary treatment in both treatment arms (PDS and neoadjuvant chemotherapy (NACT)) (Tables S2 and S3)
The baseline HE4 concentration was associated with the tumor burden stated during surgery as the serum HE4 was significantly higher in patients with substantial tumor burden than in patients with less extensive tumor growth (p
Summary
Epithelial ovarian cancer is an umbrella term that includes a heterogeneous group of malignancies, of which high grade serous ovarian carcinoma (HGSC) is the most common and aggressive [1]. The survival rate of patients diagnosed with HGSC is poor (43% 5-year survival), mostly due to diagnosis at a late stage [1]. Cancer antigen 125 (CA125) is currently the only biomarker widely used in the diagnosis and treatment monitoring of HGSC [6]. The limitations of CA125 are well-known, and include insufficient detection of early stage disease, the presence of small amounts of tumor regardless of CA125 normalization, and the increase of serum CA125 in other cancers and benign conditions [7]. The shortcomings of CA125 and the insidious nature of HGSC have sprouted comprehensive research on more satisfactory biomarkers in the diagnosis, treatment monitoring, and follow up of the disease [12]. Human epididymis protein 4 (HE4) was first described by Kirchhoff et al [13], and it has since been proposed as a complement to CA125 in the diagnosis of HGSC [14]
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