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Ovarian Cancer (OC) diagnosis is entrusted to CA125 and HE4. Since the latter has been found increased in COVID-19 patients, in this study, we aimed to evaluate the influence of SARS-CoV-2 infection on OC biomarkers. HE4 values above the cut-off were observed in 65% of OC patients and in 48% of SARS-CoV-2-positive patients (not oncologic patients), whereas CA125 values above the cut-off were observed in 71% of OC patients and in 11% of SARS-CoV-2 patients. Hence, by dividing the HE4 levels into quartiles, we can state that altered levels of HE4 in COVID-19 patients were mostly detectable in quartile I (151–300 pmol/L), while altered levels in OC patients were mostly clustered in quartile III (>600, pmol/L). In light of these observations, in order to better discriminate women with ovarian cancer versus those with COVID-19, we established a possible HE4 cut-off of 328 pmol/L by means of a ROC curve. These results demonstrate that the reliability of HE4 as a biomarker in ovarian cancer remains unchanged, despite COVID-19 interference; moreover, it is important for a proper diagnosis that whether the patient has a recent history of SARS-CoV-2 infection is determined.

Currently, ovarian cancer (OC) is a target of intense biomarkers research because of its frequent late diagnosis and poor prognosis. Serum determination of Human epididymis protein 4 (HE4) is a very important early detection test. Most interestingly, HE4 plays a unique role in OC as it has been implicated not only in OC diagnosis but also in the prognosis and recurrence of this lethal neoplasm, actually acting as a clinical biomarker. There are several evidence about the predictive power of HE4 clinically, conversely less has been described concerning its role in OC oncogenesis. Based on these considerations, the main goal of this review is to clarify the role of HE4 in OC proliferation, angiogenesis, metastatization, immune response and also in the development of targeted therapy. Through a deeper understanding of its functions as a key molecule in the oncogenetic processes underlying OC, HE4 could be possibly considered as an essential resource not only for diagnosis but also for prognosis and therapy choice.