According to the Global Cancer Observatory (GLOBOCAN), in 2018, cervical cancer was the fourth most common type of cancer worldwide in women of all ages. The overall number of cases was 569 847, while this type of cancer was the cause of death in the 311 365 women (1). The interesting fact is that the incidence of cervical carcinoma is two to four times higher in low- and middle-income countries (2, 3), which is the consequence of the lack of adequate and more efficient therapies and vaccines, as well as novel training opportunities for medical personnel.
Types of Human Papillomavirus (HPV)
In the majority of cases, cervical carcinoma is due to infection with double-stranded DNA (dsDNA) human papillomavirus (HPV) from the Papovaviridae family. HPV types are divided into two groups according to the carcinogenic features, low-risk and high-risk types of virus. High-risk types are present in 99.7% (4) of cases of cervical carcinoma, with the two most virulent genotypes, HPV16 and 18 (5). The use of HPV vaccines is the most important way of preventing the disease caused by infection with certain high-risk types of HPV.
Prevention of Cervical Cancer
Commercially available HPV vaccines are Cervarix, a bivalent vaccine (HPV16 and HPV18), Gardasil, a tetravalent vaccine (HPV 6, HPV11, HPV16, and HPV18), and Gardasil 9, a nonavalent vaccine (HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) (6). Besides vaccines, organizing and developing cervical cancer prevention screening programs is equally important. Prevention strategies vary between countries and also depend on socioeconomic status. High-income countries have well-developed screening programs which include cytological smear screening. The establishment of the Pap smear cytology tests has led to a reduction in cervical cancer incidence and mortality in the United States of 83% (6, 7).
The standard procedure which is being done during the radical hysterectomy in early-stage cervical carcinoma is pelvic lymph node dissection (PLND) (10). This procedure is used for determining the status of pelvic lymph nodes to check if metastasis exists. The main disadvantage and adverse effects of PLND is the potential occurrence of lymphedema in the lower abdomen and lower extremities (11). Besides, those women who experience lymphedema may develop emotional problems such as depression and anxiety (10, 12). Therefore, PLND is increasingly being replaced with less-radical sentinel lymph node biopsy (SLN) to decrease the risk of lymphoedema as the severe lifelong morbidity (9).
SLN biopsy is recommended by the new European Society of Gynecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and European Society of Pathology (ESP) guidelines, as well as by the National Comprehensive Cancer Network (NCCN) guidelines as an alternative method for lymph node staging (13, 14). Detecting the SLN involves injecting a dye with a radioactive tracer into the region around the tumor. Blue dye and tracer will be drained through the sentinel or primary lymph node. This ensures identifying and surgical removing the sentinel node or group of nodes for further pathological examination (8). In the case of negative SLN, there is no need for removing the rest of the lymph nodes (15). Numerous studies and papers indicate that this procedure should become part of the standard management of early-stage cervical carcinoma.
Treatment of Patients with Advanced Cervical Cancer
The standard protocol for the treatment of patients with advanced cervical carcinoma includes cisplatin-based chemotherapy with paclitaxel (16). Unfortunately, most of them experience resistance to cisplatin and disease relapse. The new approach in the treatment of advanced cervical carcinoma is using immune checkpoint inhibitors which block inhibitory receptors of immune system elements resulting in the activation of the anti-tumor response of immune cells (18). Few monoclonal antibodies are under observation for the targeted treatment of cervical carcinoma. Pembrolizumab (Keytruda) is a humanized monoclonal antibody against PD-1 (programmed cell death protein 1) allowed for treating recurrent and metastatic cervical cancer and is given intravenously every three weeks (19, 20). Other potential PD-1 or PD-L1 targeted monoclonal antibodies that are in clinical trials are nivolumab (21, 22), atezolizumab (23), and durvalumab (24).
Additionally, molecular targeted therapy with anti-VEGF humanized antibody, bevacizumab, is being used in the treatment of the group of patients with advanced or recurrent cervical carcinoma (17). Binding to VEGF, bevacizumab inhibits vessel differentiation and endothelial cell proliferation (29). Angiogenesis, the process of the formation of a vascular network, seems to be very important for cervical cancer progression. HPV infection and hypoxia are associated with increased levels of VEGF, and the influence of the process of angiogenesis on tumor development is even higher in cervical carcinoma than in most solid tumors (25). Overexpression of VEGF is associated with progression and poor prognosis of cervical cancer (26), while the cytosol level of VEGF protein has been increased in tumor tissue in comparison to normal cervical tissue (25, 27, 28). Besides bevacizumab, other targeted drugs such as pazopanib, gefitinib, temsirolimus, cediranib, and nintedanib that block growth factors are under consideration for the treatment of advanced cervical cancer (25; 15).
Molecular Diagnostic and Laboratory Testing for HPV
Molecular diagnostic and laboratory testing have a key role in guiding the treatment of HPV-associated cancers. Infection with HPV leads to the accumulation of mutations and therefore to the silencing of the innate and adaptive antiviral immune response. In addition, the cells with incorporated viral genome lacking expression of target proteins that would be recognized by the host immune system are favored by selection (31). Since the HPV positive cervical cancer share a similar mutation pattern, laboratory tests for detecting the mutations, epigenetic changes, and dysregulated HPV gene expression, would be of great importance for the prediction of the behavior of premalignant lesions. Also, liquid biopsy can be used for early detection or monitoring of cancer burden during treatment (30). Mutational analyses have the potential to identify mutations that can predict treatment response or give us important prognostic information (32). Therefore, next-generation sequencing has the potential to become a routine clinical laboratory test at the diagnosis in order to identify patient-specific mutations for monitoring tumor burden and predict risk. Additionally, sequencing can be very useful for predicting the aggressiveness of cervical precursor lesions (30). Besides diagnostic tests, HPV laboratory tests for the prevention of cervical carcinoma are developed. There are six molecular tests approved by FDA for screening programs: Qiagen Digene HC2 High-Risk HPV DNA assay, Hologic Cervista HPV HR assay, Hologic Cervista HPV 16/18, Roche Cobas HPV test, Hologic Aptima HPV, Hologic Aptima HPV 16 18/45 (33). Detecting HPV or its gene products in paraffin-embedded tissue is possible using the test such as HPV E6/E7 mRNA in situ hybridization, HPV DNA in situ hybridization, E6/E7 immunohistochemistry, HPV E6/E7 RT- PCR, or HPV DNA Q-PCR (34).
Molecular analyses and detection of the virus have great importance in the stratification of HPV positive patients at higher risk of disease progression. New diagnostic approaches must be considered for further improvements in guiding therapeutic interventions and preventing the progression of the disease.
- GLOBOCAN 2018, https:// gco.iarc.fr
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- A phase II evaluation of nivolumab, a fully human antibody against PD-1, in the treatment of persistent or recurrent cervical cancer, NCT02257528; 2017
- Phase 1b to assess the safety and tolerability of carboplatin-cyclophosphamide combined with atezolizumab, an antibody that targets programmed death-ligand 1 (PD-L1), in patients with advanced breast cancer and gynecologic cancer, NCT02914470; 2017
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