What is new about ovarian malignancies?

Risk factors

Having a family history of breast and ovarian cancer, mutations of breast cancer type 1 susceptibility protein (BRCA 1), breast cancer type 2 susceptibility protein (BRCA 2), and DNA mismatch repair genes, uninterrupted ovulation cycles (early onset of menses, childlessness, late menopause), endometriosis, ethnicity, smoking, hormonal replacement therapy, and diet are well-known risk factors of the occurrence of EOC [8]. Although these endangering agents are well-known and widely studied, many studies about them and newly discovered factors are reported each year.

The latest studies have revealed that the gender of the offspring might also present an impact on EOC risk. Bearing a male offspring was associated with an 8% lower risk of EOC. Compared to bearing all-female offspring, having all-male offspring was associated with a 14% decrease in EOC risk. The protective effect seems to be enhanced by the increasing number of male children. The biological explanations for this phenomenon might be associated with different maternal hormone concentrations [13]. Despite the fact that the study failed to reach statistical significance, previous studies – in eastern Pennsylvania [14] and Sweden [15] – reported similar findings. Slightly different results were reported in a recent pooled analysis among participants from 12 case-control studies, which included 6872 EOC patients. It was found that each additional offspring was associated with an 8% decrease regardless of whether the child was male or female. The sex of the offspring was not linked with EOC risk for serous, clear cell, and endometrioid histotypes. However, bearing male offspring was associated with lower protection against mucinous histotype, but the male sex appeared to have no significant relation to this kind of EOC [16].

Modugno et al. showed in their research that breastfeeding for at least 3 months provides significant protection from EOC. This protection is increased by an earlier age at first breastfeeding and a larger number and longer duration of breastfeeding episodes. Although this protection decreases over time, it can last for more than 30 years [17]. Another study dealt with the protective value of breastfeeding among patients with BRCA mutations. It showed that breastfeeding history was associated with a decrease of 23% in ovarian cancer risk among BRCA carriers. From 1 to 7 months of breastfeeding increased the protective effect, and after that period the association was relatively stable. The use of oral contraceptives was reported to be a significant independent protective factor, which enhanced the positive effect of breastfeeding [18].

Other research dealt with the link between benign ovarian tumours and the risk of EOC. The cohort group consisted of over 150,000 women with a primary or secondary diagnosis of benign ovarian tumours (e.g. serous cystadenoma, mucinous cystadenoma, clear cell adenofibroma, benign Brenner tumour, thecoma, and fibroma) between 1978 and 2016. The occurrence of benign ovarian tumours doubly increased the risk of mucinous ovarian cancer. The risk was independent of the age and was accelerated up to 20 years after diagnosing benign ovarian tumours. No link was found between other histological types of EOC and previous benign ovarian tumours [19].

In the Ovarian Cancer Cohort Consortium study, a connection between tumour dominance and different reproductive and hormonal risk factors of EOC was observed. Women with a dominant tumour mass were less likely to be parous (among those who have fewer children), have ever smoked, have ever taken oral contraception (OC), have had a hysterectomy, tubal ligation, or unilateral oophorectomy, in comparison to women with a non-dominant tumour mass. Additionally, patients with a right-dominant tumour mass were more likely to be parous or to have ever used OC than those with a left-dominant tumour mass. The body mass index is related to a meaningly increased risk of left- dominant ovarian cancer. The linkage between the histological type of a tumour and dominance was also observed. There were more clear cell subtype masses in left-dominant cases and more serous subtypes of tumour in the right-dominant ones [20] (Table 1).

There are also some recent studies claiming that viral infections with Papillomavirus (HPV), Cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [21], as well as an exposition to different types of asbestos fibres in occupational and environmental settings, may contribute to the development of ovarian cancers [22, 23].

Treatment

The primary treatment for early EOC is surgery. It is used for both staging and debulking (cytoreduction). It can be an exclusive and curative treatment in a disease confined to the ovaries. For later stages of the disease (IC and II), postsurgical chemotherapy is recommended. It usually consists of platinum and paclitaxel [41]. Platinum-based chemotherapy has been the primary management of ovarian cancer since the 1980s [3]. Neoadjuvant chemotherapy is also used in some nonoperative cases. Apart from intravenous chemotherapy, intraperitoneal can be ordered after suboptimal cytoreductive surgery in the FIGO III stage. Bevacizumab – a humanized monoclonal antibody targeting vascular VEGF – can be added to the conventional chemotherapy for patients after suboptimal cytoreductive (FIGO III stage) as well as for patients with disseminated carcinoma [42, 43]. Additionally, Olaparib – an oral poly (ADP-ribose) polymerase (PARP) inhibitor – can be ordered for patients with serous ovarian cancer and the presence of BRCA 1/2 mutations. Olaparib serves as a maintenance treatment for patients after relapse, who responded to platinum-based chemotherapy [44].

Epithelial ovarian cancer therapy has barely changed in the last 40 years, and it still seems to lack effective therapeutic targets. Although EOC was supposed to be scarcely immunogenic, immunotherapy appears to have more therapeutic potential than was previously thought. A lot of emphases is placed on improving the management of ovarian cancer and making it more personalized [43]. So, what is new about the treatment of ovarian cancer?

The primary goal of surgical treatment is to accomplish a complete resection with clear margins. Score R0 or R1 in the residual tumour (R) classification implicates better survival rates [45]. Ceppi et al. proved that targeted molecule-based fluorescence imaging helps achieve complete tumour resection on the microscopic scale. They used a fluorescence imaging system with an orthotopic mouse model to assess tumour detectability and to evaluate the effect of fluorescence imaging-guided surgery. The contrast agent used in this study was an intra-peritoneal nanomolecular probe, composed of single-walled carbon nanotubes, coupled to an M13 bacteriophage carrying a modified peptide binding to the secreted protein acidic and rich in cysteine overexpressed in studied mice. High microscopic tumour detection was observed with a pixel-limited resolution of 200 µm. Additionally, the researchers observed an elevated survival in animals treated with fluorescence image-guided surgical resection compared to the typical surgery [46].

The pleiotropy of transforming growth factor-beta (TGF-β) signalling in tumour tissues covers cancer initiation, development, metastasis, and reaction between stroma and cancer cells [47]. TGF-β plays a crucial role in the metastasizing by providing epithelial-mesenchymal transition (EMT). TGF-β signalling may be activated by overexpression of domain-containing ion transport regulator 5 (FXYD5) in cancer cells. The TGF-β activates the SMAD3/SMAD4 complex, which initiates the transcription of further effectors and promotes FXYD5 transcription. The FXYD5 creates a positive loop with TGF-β to drive EMT and, therefore, metastasis. It makes TGF-β a potential target in the treatment of ovarian cancer [48]. It is claimed that the debulking signature is centred around the hyperactivation of the TGF-β pathway, which drives the overexpression of genes located in the tumour and its microenvironment. Using the TGF-β inhibitors with chemotherapy, for patients after suboptimal debulking surgery or in the neoadjuvant treatment, may improve the interval debulking surgery. TGF-β inhibitors decrease migration and invasion of the tumour cells and increase response to the treatment [49]. Zhang et al. reported that inhibiting the TGF-β pathway with LY2157299 monohydrate (TGF-R1 inhibitor) in animal models reduced tumour cell proliferation, migration, and invasion. Additionally, it was found that LY2157299 is involved in slowing down cancer growth and ascites formation. These effects are correlated with reduced expression of vital stroma proteins COL11A1 and VCAN [50].

In 2020, a study assessing the impact of prolonged preoperative cycles on survival, accounting for surgical outcomes, was published. The study compared the results of treatment of 199 women with newly diagnosed ovarian cancer. Women who received 3 or 4 neoadjuvant cycles were compared with women who received 5 or more cycles. Apart from the number of cycles between the groups of women, there were no other differences in clinical factors. The rates of complete resection were similar, regardless of the number of chemotherapy cycles received. Unfortunately, more cycles of chemotherapy (5 or more) were associated with poorer progression-free survival. The analysis showed that patients taking 3–4 cycles of chemotherapy had a better prognosis than patients receiving 5 or more cycles [51].

Some recent studies reported spontaneous tumour regressions [52, 53], occasional persistent responses to immune checkpoints-inhibitors [54], and longer progression-free time and overall survival in patients with tumours with a high rate of T-cells [55]. These revelations suggest that EOC patients would potentially benefit from immunotherapy.

Zamarin et al. showed that the combination of nivolumab and ipilimumab in platinum-resistant EOC resulted in better response and longer progression-free survival. However, more studies should be conducted [56].

Combining anti-angiogenic agents and immunotherapy might occur beneficially. The single usage of anti-angiogenic agents resulting in a reduced number of blood vessels and increased tumour hypoxia seems inadequate. However, immunotherapy might be supported by additional effects of drugs targeting VEGF, angiopoietin 2, or hepatocyte growth factor pathways. A few clinical trials evaluating immune-checkpoint inhibitors in combination with anti-angiogenic agents in patients with EOC are currently in progress [57] (Table 2).

PARP inhibitors (PARPis) have been used in EOC treatment since 2014, when the Food and Drug Administration and the European Medicines Agency approved them. Olaparib, Niraparib, Rucaparib, Talazoparib, and Veliparib are the most relevant PARPis. The last 2 of them are currently under investigation. PARPis are used in patients with recurrent ovarian cancer and BRCA mutation [58]. It seems that combined treatment with PARPis and immune checkpoint blockade might be beneficial for patients with BRCA mutation. A phase I study, in which olaparib and tremelimumab [cytotoxic T-cell antigen 4 (CTLA4) immune checkpoint antibody] were used, was conducted to assess this regimen’s tolerability. No dose-limiting toxicities were identified [59]. Two more studies are currently exploring these treatment strategies. The first one is the combined therapy with niraparib and pembrolizumab [programmed death 1 (PD-1) checkpoint inhibitor] in patients with triple-negative breast cancer or recurrent ovarian cancer. The phase 1/2 study results are promising, with an overall response rate (ORR) of 25% in platinum-resistant ovarian cancer and an ORR of 45% in patients with BRCA mutations. The most common reported side effects were anaemia and thrombocytopaenia [60]. Another study suggested a synergistic therapeutic effect of the combination of olaparib and durvalumab [anti-programmed cell death ligand-1 (PD-L1)] in patients with relapsed gastric cancer [61].

Several new cell cycle checkpoint inhibitors are currently under investigation. A recent study reported the efficacy of prexasertib – a second-generation checkpoint first and second kinase (CHK1/2) inhibitor for patients who are diagnosed with BRCA wild-type high grade serous ovarian cancer and who have undergone intensive treatment. Prexasertib seems to be a useful tool in treating patients with platinum-resistant or platinum-refractory disease [62]. The studies reported that the combination of PARPi with Ataxia Telangiectasia and Rad3-related (ATR) and its downstream Checkpoint Kinase 1 (CHK1) inhibitor is more effective in reducing tumour burden in BRCA mutation models, in comparison to monotherapy [63].

Folate receptor-α (FOLR-1), which is highly expressed in tumour tissue in HGSC patients and usually undetectable in normal tissue, is another potential therapeutic target [64]. FOLR-1 is a glycosylphosphatidylinositol-connected membrane glycoprotein, which is exposed to the extracellular molecules [65]. It is involved in DNA replication and damage repair in cells by mediating cellular responses to foliate, including proliferation, cell division, and tissue growth [66]. Some trials focused on monoclonal antibodies binding to the FOLR-1 – farletuzumab [67] and mirvetuximab soravtansine [68]. Moreover, the adoptive cell transfer (ACT) therapy, in which tumour-specific cytotoxic T-cells are expanded in vivo and then infused after lymphodepleting chemotherapy [69], might be used in EOC patients. Westergaard et al. expanded tumour-infiltrating lymphocytes (TILs) from 34 tumour specimens of ovarian cancer and showed the recognition of autologous tumour cells in > 50% of the patients. Moreover, antigen-specific TILs were isolated and further expanded in vivo. These findings supported the hypothesis that patients with OC could benefit from ACT [70] and were followed by the pilot study [71].

Cancer stem cells (CSCs) are a population of tumour cells with self-renewal abilities responsible for both tumour development and resistance to the applied treatment [72]. The drug resistance in CSCs leads to relapses during treatment [73]. Signalling pathways such as Wnt/β-catenin and NOTCH are, among others, in charge of chemoresistance in CSCs [74, 75]. Therefore, inhibition of the Wnt pathway might become an efficient management in EOC treatment. Ipafricept (OMP-54F28), a first-in-class recombinant fusion protein with the extracellular part of human Frizzled-8 receptors fused to a human IgG1 Fc fragment that binds Wnt ligands, is undergoing phase I study in pancreatic and ovarian cancers [76]. Additionally, some trials concentrate on Notch pathway silencing in EOC treatment. Delta-like ligand 4 (Dll4), one of the Notch ligands, has been proven to be overexpressed in ovarian cancer. Dll4 is claimed, among others, to be responsible for tumour resistance to the anti-VEGF therapy [77]. The study by Huang et al. showed that combining Dll4 inhibitors (murine REGN1035 and human REGN421) with anti-VEGF treatment (aflibercept) significantly reduces ovarian tumour growth. Dll4 blockade (REGN1035) combined with aflibercept has more significant therapeutic effects. This success may result from the increased apoptosis in tumour cells and increased transcription factor-GATA3 expression under hypoxia conditions [78].