Human epididymis protein 4: the start of a post-ROMAn era?

As the result of advances in the understanding of molecular bases of cancer and introduction of targeted therapy, laboratory medicine currently plays an indispensable role in the management of cancer patients (1) . Traditionally, the measurement of tumor markers has been a topic of major interest for both medical oncology and clinical chemistry/laboratory medicine. With time the well-established paradigm of utilizing tumor marker determination for the diagnosis of cancer or tumor recurrence has evolved into a more diversifi ed concept that also encompasses the prediction of patient prognosis or response to therapy (2) . Moreover, peripheral blood is no longer the exclusive sample matrix used for assessment of tumor markers, and other sample sources including urine, breath, malignant effusions, secretions or tumor tissue are being used with increasing frequency. The term biomarker has been coined to refl ect the increasing diversity of this concept. Epithelial ovarian carcinoma (EOC) is the leading cause of death for gynecological cancer. The high mortality rate of EOC is due to the fact that the tumor is usually diagnosed at a late stage, when the chance of a defi nitive cure is quite low. However, the survival of patients affected with EOC has improved substantially over the recent decades with the introduction of multimodality treatment approach that includes radical surgery and systemic or regional (intraperitoneal) chemo therapy. Consequently, rather than a rapidly fatal malignant disorder, EOC now often takes a chronic course characterized by episodes of recurrent disease that may be repeatedly controlled by systemic chemotherapy (3) . For the past several decades, the determination of tumor markers has played an important role in the management of patients affected with EOC. The utilization of tumor markers is best documented in establishing the diagnosis of EOC. As a general rule histological confi rmation is required for diagnosis of cancer across the spectrum of different primary tumors. Unlike other tumors, e.g., breast cancer, endometrial cancer or most gastrointestinal tumors, EOC is not easily accessible to endoscopic or percutaneous biopsy. The biopsy in patients presenting with suspected EOC can usually be performed only during surgical procedure using laparoscopic approach or even laparotomy. However, the quality of the primary surgery represents the principal factor determining the prognosis in EOC patients, and poorly planned procedure with unexpected or even surprising diagnosis of EOC that ends up only as diagnostic operation will jeopardize the patient prognosis. It has been demonstrated that the patient outcome is substantially improved if the patient is operated in a high-volume center by an experienced surgeon (4) . Thus, it is critically important that the diagnosis of EOC be established before the surgery and the patient could be referred for the procedure to a center that can deliver multidisciplinary care (5) . Different algorithms have been proposed over time for noninvasive preoperative diagnosis of EOC. The introduction of human epididymis protein 4 (HE4) has provided another biomarker that could improve the preoperative diagnosis of epithelial ovarian carcinoma (6 – 9) . The simultaneous determination of carbohydrate antigen (CA) 125, imaging fi ndings or HE4 represents a relatively reliable estimate indicating the probability of the presence of epithelial ovarian carcinoma (7, 8, 10, 11) . The Risk of Malignancy Index (RMI) is an algorithm combining ultrasound fi ndings of the pelvic mass, CA125 concentrations and menopausal status, while the Risk of Ovarian Malignancy Algorithm (ROMA) combines menopausal status with the serum concentrations of CA125 and HE4 (10, 11) . It has been demonstrated that the sensitivity of ROMA is better than the sensitivity of RMI is detection of EOC (11) . However, it has been also demonstrated that in premenopausal women the diagnostic performance of ROMA was not better than HE4 alone (7) . Although most studies examining the role of HE4 in diagnosis EOC were performed in the Western world, the utility of the determination of serum HE4 in the diagnosis of EOC is not limited to Western countries as indicated by a recent study demonstrating increased HE4 concentration in Korean patients affected with EOC (6) . The utilization of biomarkers in the management of patients with EOC is not limited to establishing the diagnosis. As outlined above, the course of EOC now resembles more or less a chronic disorder. This course is often characterized by repeated recurrences of the disease that are controlled by chemotherapy before recurring again (3) . The problems associated with the diagnosis of recurrence, estimation of prognosis and prediction of response are of obvious importance. In patients with EOC, the peritoneal cavity represents the most common site of tumor spread, and the disease is frequently limited to the peritoneum. However, the marked prolongation of survival resulting from the multimodality treatment appears to be changing (or rather revealing) the natural history of EOC, and more patients live long enough to develop distant metastases. Among sites of distant relapse, central nervous system metastases, once considered extremely rare, are now being diagnosed with an increasing frequency (12) . As with other chronic disorders, chronic complications are becoming manifest in cancer patients that result from the