Current clinical application of serum biomarkers to detect and monitor ovarian cancer - update.

Approximately 20% of women are expected to suffer from an adnexal mass at least once in their lifetime [ 1 ]. About half of them undergo surgery for this reason [ 2 ]. The population risk of ovarian cancer is about 1–1.5%, which means that the majority of adnexal tumours are benign and can be operated by general gynaecologists [ 3 ]. However, many benefits have been proven for patients with ovarian cancer operated by oncological gynaecologists compared with general gynaecologists and surgeons (more accurate staging, more precise cytoreductive surgery, fewer complications, higher percentage of 5-year survival) [ 4 – 6 ]. Therefore, women with suspected ovarian tumours should be directed to centres specialized in oncological gynaecology. On that basis, new methods of selecting patients at a high risk of ovarian malignancy are investigated. Nowadays, physical bimanual examination, gynaecological ultrasound imaging, and serum biomarkers are used to assess adnexal masses. Some authors question the utility of ultrasound because of its subjectivity and dependence on sonographer’s experience [ 7 ]. Consequently, the importance of serum markers in the diagnosis of ovarian cancer is growing as they become more objective and comparable. In recent years, a wide spectrum of cytokines, growth factors, adhesion molecules, proteases, hormones, coagulation factors, acute phase reactants, and apoptosis factors have been investigated as potential single serum biomarkers and in multimarker panels in diagnosing ovarian cancer, but only cancer antigen (CA125) and HE4 have been applied to everyday clinical practice.

According to the ESMO-ESGO recommendations published in 2019, serum CA125 is useful in clinical practice but only in combination with clinical and radiological assessment. It is important to emphasize that the CA125 value is well studied in high-grade serous carcinoma, but in patients with low-grade serous, endometrioid, mucinous, or clear cell ovarian cancer surveillance should not be based on CA125 as an equally reliable marker [ 51 ]. Moreover, we do not have enough data to support CA125 values in patients treated with targeted therapies, such as bevacizumab or olaparib. The prognostic or predictive for relapse meaning of HE-4 changes was studied in combination with CA125, and radiological and clinical, assessment but the studies led to conflicting results, and finally HE-4 was not recommended in routine practice in response or progression evaluation. Recently published study by Potenza et al . aimed to assess the ability of CA125 and HE-4 to identify patients at higher risk of non-optimal response and of recurrence of disease during systemic therapy of 78 epithelial ovarian cancer patients after debulking surgery or interval debulking surgery after neoadjuvant systemic therapy. Both CA125 and HE-4 were measured at baseline and at each chemotherapy cycle. Computed tomographies were performed to confirm objective response. The authors found that in all cases of good response to chemotherapy, CA125 and HE-4 decreased to normal values after the fourth chemotherapy cycle. HE-4 had a more rapid decrease rate during chemotherapy than CA125, which had a delay of 21 days. Moreover HE-4 was re-detected faster than CA125 in patients who did not have a good chemotherapy response [ 52 ]. A study published in 2021 assessed the HE-4 and CA125 early clearance prognostic value for platinum sensitivity, 2-year progression-free survival (PFS), PFS, and overall survival (OS) in 89 patients with epithelial ovarian cancer after initial staging surgery or optimal cytoreduction, who received 6–8 cycles of adjuvant chemotherapy (16 platinum-resistant and 73 platinum-sensitive). Human epididymis protein 4 and CA125 clearance was defined as a 90% decrease from baseline value or reduction to normal. The study demonstrated that PFS and OS were associated with HE-4 clearance after the 3rd course of chemotherapy ( p < 0.0001 for both), and CA125 clearance after the 1st chemotherapy cycle ( p < 0.0001 for both), confirmed in a multivariate Cox regression analysis as independent prognostic factors. Thus, the study confirms that HE-4 and CA125 monitoring during first-line chemotherapy is useful for prognosis in terms of platinum sensitivity, PFS, and OS in epithelial ovarian cancer patients [ 53 ]. Japanese researchers conducted a study that aimed to evaluate droplet digital PCR as a method of detection of relapse in 11 ovarian cancer patients [ 54 ]. They analysed the relationship of the onset of recurrence, recurrent tumour size, and the duration of PFS with CA125 and circulating tumour DNA (ctDNA) analysis for individual mutations detected in high-grade serous and clear-cell ovarian carcinoma patients who were at high risk of relapse. As a result, mutated ctDNA fragments in plasma were detected in all 6 patients with recurrence during follow-up, earlier than CA125 changes (49 days and 7 days before imaging showed relapse, respectively: p < 0.05). No ctDNA was detected in recurrence-free patients. Thus, the method is highly sensitive and specific, but probably not useful in clinical practice as individual molecular diagnosis and repeated detection of patient-specific mutation pattern is difficult and expensive. Moreover, the ESMO-ESGO recommendations clearly indicate that ctDNA is not a tool to assess response or relapse [ 51 ].

Taken together, clinical examination, ultrasonography, and serum markers (ROMA) accurately select patients with ovarian tumours of a high risk of malignancy, which facilitates their referral to centres specializing in oncological gynaecology. Serum CA125 plays an established role in monitoring the treatment (except targeted therapies) and relapse setting in ovarian cancer patients, with a more limited role in subtypes other than high-grade serous carcinoma, and always in correlation with imaging and clinical assessment. HE-4 and ctDNA are not recommended for monitoring at that timepoint, although encouraging newly published studies might influence their role in the future.