Combined score of pretreatment platelet count and CA125 level (PLT-CA125) stratified prognosis in patients with FIGO stage IV epithelial ovarian cancer

Epithelial ovarian cancer (EOC), a lethal gynecologic cancer, accounts for 90% of ovarian malignancies [1, 2]. However, EOC has a high case-fatality ratio among gynecologic cancers [3]. EOC is larruping for distinct tumor biology of different histological types and the absence of anatomic barriers. [4] High grade serous carcinoma (HGSC) is the most common histological type with higher malignancy in EOC [3, 4]. The established treatment strategy for advanced EOC includes cytoreductive surgery and chemotherapy. Approximately 70% of EOC patients are diagnosed with advanced Federation of Gynecology and Obstetrics (FIGO) stage III or even higher stage [5]. Although overall survival (OS) has increased over the last decades in stage III EOC, survival of patients with FIGO stage IV has not changed [6]. The prognostic factors of EOC including FIGO stage, age, histological type, performance status, and location of metastases, that predict survival indicate different tumor biology and pave the way for individualization of therapy [7]. However, most prognostic factors were not studied specifically in stage IV EOC patients. There is an urgent need for stratifying prognosis in patients with stage IV EOC.

Thrombocytosis [platelet (PLT) count > 400,000/μL] is associated with various cancers. The rate of thrombocytosis ranges from 31 to 42% in EOC [8]. Thrombocytosis is identified as a prognostic factor in many retrospective studies of EOC [9]. The increase of platelet count is due to tumor-secreted cytokines, such as interleukin (IL-6), which plays a role in stimulating the growth of megakaryocytes and thrombocytosis [10]. IL-6 is overproduced in a variety of malignancies and is related to inflammation and immune suppression [11]. However, it is still unclear whether the poor survival of patients with thrombocytosis is caused by IL-6 itself or is a result of IL-6-induced thrombocytosis [12].

CA125 is an extensively studied tumor marker in EOC. The level of CA125 is used in screening test, diagnosis, monitoring of efficacy during chemotherapy, and management of follow up [13, 14]. The dynamic changes of CA125 levels at diagnosis and during chemotherapy were associated with chemosensitivity of drugs and new agents, tumor burden, and time of relapse [15, 16]. In addition, researchers found that glycogen CA125 of tumor cells binds to natural killer (NK) cells and is conducive to immune evasion [17]. As CA125 has been studied in EOC for decades, there are still many puzzles.

Stage IV EOC is a systemic disease presenting with parenchymal metastases and metastases of extra-abdominal organs [5]. The poor survival of patients with thrombocytosis was considered to be a result of IL-6-induced thrombocytosis [12]. Currently, the relevance of PLT count and CA125 level was found in EOC [18]. However, the prognostic values of both markers were not comparatively studied. Hence, we combined these markers into a PLT-CA125 score and assessed the prognostic value of this new marker in FIGO stage IV EOC.

In our study, the PLT-CA125 score was an independent prognostic factor for both OS and PFS in stage IV EOC. However, neither thrombocytosis nor elevated CA125 level was significantly associated with short PFS. The survival for stage IV patients can be more specifically stratified using combined PLT-CA125 scoring model compared with using PLT or CA125 alone. These findings imply that both thrombocytosis and an elevated CA125 level may equally contribute to the poor survival of patients with stage IV EOC.

Currently, there are evidences from retrospective studies that suggest a potential relationship between platelet count and CA125 level [19]. Platelet is an important modulator in many physiological functions of cancer, and thrombocytosis is identified as a prognostic factor in many studies of EOC [20]. IL-6, which is commonly elevated in patients with EOC and is known to be an important cytokine of inflammation and immune suppression, can stimulate megakaryocyte growth and thrombopoiesis [8]. Platelets take part in the process of haematogenous metastasis by parcelling tumor cell in the vasculature system [21]. On the other hand, platelets can promote tumor cell metastasis by breaking the membrane of vessels through the release of enzymes [22]. In addition, tumor cells expressing glycogen can aggregate platelets and induce tumor-platelet aggregation, which help tumor cells survive from immune clearance [21]. Recently, the dual role of platelets in immune functions and inflammation has gained more and more attention in infectious disease and cancer [23].

Inflammation plays an important role of tumorgenesis and tumor progression in EOC, especially in advanced disease [24, 25]. At the same time, inflammatory cytokine, IL-6, can stimulate megakaryocyte growth and induce thrombocytosis [8]. Although EOC is considered unresponsive to immune therapy, there are increasing evidences suggesting that EOC is, in fact, an immunogenic tumor with highly heterogeneous subtypes [26]. Diverse clinical and epidemiological data have shown that a natural antitumor immune response of tumor infiltrating lymphocytes and NK cells in EOC [27]. Emerging evidence about inflammation and tumor immune suppression mechanisms may pave the way for immune therapy.

Over the last decades, CA125 is extensively investigated and widely used in the diagnosis and follow-up of EOC [18]. In addition, elevated CA125 is noted in inflammatory diseases and several benign diseases. Expression of CA125 in EOC plays important roles in cell growth, transformation, and invasion of tumor cells [28]. As a large glycoprotein, the CA125 glycogen is an important molecule contacting with other cells, including NK cells and fibroblasts [17]. The immune evasion mechanism of NK cell suppression through binding to CA125 has been reported in EOC [29]. Both CA125 and platelets are related to inflammation and play important roles in the pathological status of immune surveillance in EOC. In our study, we combined these markers as a novel scoring model to stratify OS and PFS in stage IV EOC, which were shown to be better than using PLT or CA125 alone. This result implies that the PLT-CA125 score, reflecting inflammation and immune suppression, could be used to predict survival and determine potential therapeutic strategies targeting inflammatory and immune surveillance in advanced EOC.

In addition to the prognostic significance of the PLT-CA125 score, the high accessibility makes it practical in clinical use. Platelets count and CA125 level can be easily obtained in all patients suspected with ovarian cancer.

Stage IV EOC is a systemic disease and is often diagnosed with parenchymal metastases and metastases of extra-abdominal organs [5]. Our study demonstrated that the combined score of systemic inflammatory marker, PLT, and EOC tumor marker CA125 was a reliable prognostic factor for stage IV EOC. In addition, other prognostic factors of stage IV EOC, including histological type and satisfaction of surgery, were demonstrated in our study.

As a retrospective study, there are several limitations. Firstly, the sample size of the study was relatively small. Thus, confirmation of results in other cohorts and centers is necessary for further research. Secondly, the cut-off value for CA125 may vary in different study cohorts. Although the cut-off value of CA125 has been confirmed in our study cohort, the value may vary in different cohorts and centers. Finally, the performance statuses of the patients were not included in our study, which may affect the daily life abilities of the patients, and help determine treatment strategies, as well as prognosis. However, this is an inevitable defect of retrospective study.

In conclusion, the PLT-CA125 score is an independent prognostic factor in patients with stage IV EOC. It is a useful and highly accessible marker for predicting clinical outcomes and suggesting for potential therapeutic strategies in patients with stage IV EOC.