Role of PD-L1 as a biomarker in Non-Small Cell Lung Cancer diagnosis, prognosis and targeted therapy.
Non-Small Cell Lung Cancer
Non-small cell lung cancer (NSCLC) is a type of lung cancer which occurs when healthy cells become abnormal and rapidly grow and spread in the tissues of the lung (Cherney, 2017).This uncontrolled cell growth is caused by oncogenic driver mutations such as EGFR, KRAS and ALK (Zhou et al., 2013). NSCLC is known to cause about 80% to 85% of all lung cancers with small cell lung cancers causing the rest (American Cancer Society, 2016).There are three main sub-types of NSCLC 1) adenocarcinoma 2) squamous cell carcinoma and 3) large cell carcinoma. Adenocarcinomas begin in the mucus secreting cells and are found on the outer parts of the lung. It usually occurs in former smokers, but it is also the most common type of lung cancer seen in non- smokers and younger people and is known to be more common in females than males. Squamous cell carcinomas begin in the squamous cell which are inside the airways of the lungs typically near the central part, this type is also common in smokers. Large cell carcinomas can appear in any part of the lung and are hard to treat due to their tendency to grow and spread rapidly throughout the lung. (American Cancer Society, 2019c)
Surgery to remove the cancer is the most successful route in the aim of curing NSCLC. Most patients with stages I to II NSCLC benefit from this, although patients with more advanced disease may benefit more from nonsurgical treatment such as chemotherapy. Other treatment options include targeted therapy and radiation. The five year survival rate of NSCLC is 15% (Molina et al., 2008). Immunotherapy is one of the newest ways to treat NSCLC, this involves the use of medicine to target the patient’s immune response to recognise and destroy cancer cells. T cells in the immune system cannot attack cancer cells as they express a protein called PD-L1 (also known as CD274 ornB7-H1) which stops their action. PD-L1 works by attaching to PD-1 and B7.1 receptor’s on T cells causing T cells to become inactivated. Immunotherapy aims to fight cancer by blocking PD-L1 interactions , which may prevent cancer cells from inactivating T cells through PD-1 and B7.1. (Genentech, 2016)
The role PDL-1 plays in diagnosis of NSCLC
There are many different methods used to diagnose patients with NSCLC some of these include chest x-ray/CT which help visualize cancer nodules in the lungs, a PPET scan which is also used for diagnosis but also for staging of a tumour , sputum cytology which can identify cancer cells especially with tumours as squamous cell carcinomas lie near the larger airways, bronchoscopy where a flexible tube with a camera is inserted down into the bronchi used to visualize cancer and take a biopsy, a blood test may also be done for diagnosis of NSCLC as some tumours may lead to elevated levels of calcium in the blood for example, a biopsy is also used and is necessary to make a definitive diagnosis of NSCLC and determine subtype, this can be done in many ways such as fine needle aspiration biopsy or open lung biopsy, gene testing is also used in diagnosis of NSCLC and is also helpful in choosing the most appropriate therapy for treatment, examples of these include sequential testing, gene panel testing and next generation sequencing(NGS). NGS is also used to determine the PD-L1 level and tumour mutation burden( TMB)(Eldridge, 2019). Testing for PD-L1 is now routine for newly diagnosed NSCLC patients. Some cancers express high levels of PD-L1 especially as they become more malignant and so it is beneficial to test the levels to help diagnosis a patient with the cancer and determine what stage they are at. PD-L1 expression levels are also used to determine what kind of treatment a patient will benefit from , for example a patients with 50% or greater expression of PD-L1 are recommended to be treated with pembrolizumab(Urciuoli, 2016). Tumours that express high levels of PD-L1 may be more susceptible to checkpoint inhibitors than those that express less PD-L1 and so it is necessary to check which test is appropriate to be performed on the patient depending on their stage of cancer etc. in order to find what medicine will be most beneficial to them (Ott, 2017). There are several assays available for the detection of PD-L1 in NSCLC tissue. These tests are performed by sending a biopsy of the tumour to the lab to be analysed.
There are four different immunohistochemistry (IHC) assays are approved by the FDA as diagnostic tests for NSCLC, these include Dako PD-L1 IHC 22C3 pharmDx (pembrolizumab), Dako PD-L1 IHC 28-8 pharmDx (nivolumab), VENTANA PD-L1 (SP142) (atezolizumab) VENTANA PD-L1 (SP263) assay (durvalumab). Other methods used to test for PD-L1 include quantitative immunofluorescence, flow cytometry, ELISA and real-time PCR (Brody et al., 2017). Therefore, it is beneficial to test for PD-L1 expression levels in the diagnosis of NSCLC as stages and treatment options can be better and more quickly assessed and so a better understanding of the condition is known, and the best diagnosis and treatment can be given to the patient.
The role of PD-L1 in Prognosis of NSCLC
Non-small cell lung cancer is known to have a poor prognosis and is one of the leading causes of cancer deaths worldwide, this is majorly due to the majority of patients being diagnosed when their disease has become too advanced to be treated effectively. One of the main factors that determine a patient’s five-year survival rate is the stage of the cancer they have. The stages of NSCLC include : stage 1- tumour is present in one lung, stage 2- cancer cells move to the lymph nodes surrounding the lung, stage 3- cancer cells invade the lymph nodes in the lung near the tumour and also invade the breathing tubes, chest wall and the diaphragm and stage 4- cancer cells begin to invade and spread throughout the rest of the body (Learning Lung Cancer, 2018). Staging of NSCLC is also done by the TNM system, T-describes the size of the tumour , N- indicates if the cancer is present in the lymph nodes or not and M- indicates if the cancer has spread to other parts of the body such as the brain and bone for example (American Cancer Society, 2019b). The American Cancer Society breaks down estimated survival rates of the four stages as: 1A-49%, 1B-45%, 2A-30%, 2B-31%, 3A-14%, 3B-5% AND 4-1%(American Cancer Society, 2019a). The National Cancer Institute also provides a survival statistics database for NSCLC, but it does not group them by TNM stages but into three categories: localised, regional and distant. Localised means that the cancer has not spread yet outside the lung, there is a 60% five-year survival rate for this. Regional means the cancers has spread to nearby structures or lymph nodes and this had a 33% five-year survival rate. Distant means the cancer has spread to distant parts of the body such as the brain or bones and has a 6% five-year survival rate according the database(American Cancer Society, 2019a). This highlights that the more advanced stage your cancer is the shorter fiver year survival rate you will have. Gender and race are also used as prognostic markers fir NSCLC. Men (particularly black males) are more commonly affected with NSCLC compared to women, they are also more likely to die from the condition compared to women (Lung Cancer Answers, 2019).The biomarker PD-L1 is used in the prognosis of NSCLC as many studies have shown that using different PD-L1 detection antibodies in conjunction with immunohistochemistry assays have shown high levels of PD-L1 in tumour cells in later stages of NSCLS and so lead to poor prognosis (Sorensen et al., 2016). Studies suggest that high levels of PD-L1 are associated with shorter survival rates than lower levels, also patients with high PD-L1 levels are also more likely to benefit from treatments with anti PD-1/PD-L1 therapies(Brody et al., 2017). Although there is substantial evidence from multiple studies that high levels of PD-L1 lead to a poor prognosis for NSCLC a lot more research is needed on the utility of PD-L1 as a prognostic biomarker in the disease.
The role of PD-L1 in Therapy of NSCLC
The main therapy used to treat NSCLC involving PD-L1 is immunotherapy which is a method used to eliminate the cancer by enhancing the patients’ immune system. This involves the blocking of PD-1 and its ligands PD-L1 and PD-L2 which helps enhance T cell immune responses in the body to help fight tumour cells. This blockage can be achieve by three methods 1) antibody blockage, 2) gene silencing and 3) small-molecule pathway inhibition (Wu et al., 2019). Antibody blockage refers to the blocking of the interactions between PD-1 and PD-L1 with humanized antibodies or human IgG which are used to bind either PD-1 or PD-L1, thereby blocking the ligation of PD-1 and PD-L1 and the downstream inhibitory signalling events(Zheng and Zhou, 2015). Approved drugs for humanized monoclonal IgG4 antibodies that target PD-L1 include Atezolizumab (MPDL3280A), Avelumab, BMS-936559 and Durvalumab (MEDI4736) (Zhong et al., 2019). Atezolizumab is used to block PD-L1 to boost the immune response against cancer cells, it is used to avoid ADCC of activated T-cells (Yoon, 2014) it also had shown to be a great tumour shrinker in many different cancers that had gotten worse after treatment including lung, melanoma, kidney, colorectal and gastric cancers (Anti-PD-L1 Drug Shows Promising Anti-Cancer Effects | Physician’s Weekly, 2013).Durvalumab is commonly used in patients with stage III NSCLC when their cancer cannot be removed with surgery and has not gotten worse after they have received chemotherapy with radiation, its aim is to keep the cancer from getting worse for as long as possible(American Cancer society, 2019). Avelumab is an IgG1 monoclonal antibody that has an unmodified Fc region, it blocks the interaction between PD-1 and PD-L1 in turn reactivating T-cells(Marciscano and Gulley, 2017). BMS-936559 is a humanised IgG4 monoclonal antibodies to PD-L1 and it works by blocking the binding of PD-L1 to both PD-1 and CD80 (Brahmer et al., 2012). Silencing refers to the “interruption or suppression of the expression of a gene at transcriptional or translational levels”(NCBI, 2017). Suppression of PD-L1 via gene silencing is usually more efficient than antibody blocking as a single interfering gene fragment can “switch off” the protein synthesis (Wu et al., 2019).The development of small molecules to block the pathway is generally slow with only a few being reported but they do have an advantage over monoclonal antibodies as they have “more controllable pharmacokinetic and pharmacological profiles” CA-170 is an example of a small molecule inhibitor (Zhong et al., 2019) .
PDL-1 role as biomarker in other cancers
PD-L1 is highly expressed in many different types of cancers. These include melanoma, nasopharyngeal cancer, glioblastoma, colon adenocarcinoma, hepatocellular carcinoma, urothelial cancer, multiple myeloma, ovarian cancer, gastric carcinoma, oesophageal cancer, pancreatic cancer, breast cancer , lymphomas and leukaemia’s. (Chen, Irving and Hodi, 2012).
The immune system performs several steps on cancer cells under normal conditions which leads to cancer cell death, this is known as the cancer immunity cycle. These steps include 1)firstly tumour cells produce mutated antigens which will be captured by dendritic cells (which act as messengers between the innate and adaptive immune systems ) , 2) The dendritic cell prime T cells with tumour antigen and activate cytotoxic T cells, 3) activated T cells travel to the site of the tumour and surround it, 4) they recognise and bind to cancer cells , 5) bound effector T cells release cytotoxins which kill the cancer cells. The PD-1/PD-L1 interaction represents an adaptive immune resistance mechanism, PD-L1 is commonly overexpressed in tumour cells , it binds to PD-1 receptors on activated T cells which inhibits cytotoxic T cells and so they cannot kill the cancerous cells (abcam, 2019).Many cancer immunotherapies involve the blocking of the interactions between PD-1 and PD-L1 with antibodies which allows T-cells to fight tumour cells. Some of these include Nivolumab and Permbrolizumab which block the interaction between PD-1 and PD-L2 and are used in the treatment of metastatic melanoma for example (abcam, 2019). Atezolizumab also blocks this interaction and is a drug used to treat some types of breast cancers, bladder and urinary tract cancers and is also used for non-small cell lung cancer. It is usually used when cancer can no longer be treated by surgery and has spread to other parts of the body. (Cerner Multum, 2019)
PD-L1 is used as a prognostic marker in different types of cancer. In Gastric Cancer PD-L1 had a negative prediction value, may studies have shown that expression of PD-L1 correlates with poor prognosis. It was also noticed in two studies by Wu et al and Qing et al that expression of PD-L1 was highly associated with lymph node metastasis and invasion of the cancer into the parts of the body, concluding that PD-L1 expression in gastric cancer leads to a lower survival rate for patients (Wang et al., 2016). The predictive value of PD-L1 in patients with colorectal cancer (CRC) has been known to be quite controversial showing both positive and negative prognosis for patients. Once particular study by Shi et al showed that PD-L1 expression is relatively high in Colorectal carcinomas with it leading to cell differentiation and Tumour Node Metastasis and so leading to a shorter survival time for patients (Shi et al., 2013). Whereas another study by Droeser et al seen that PD-L1 expression was associated with improved survival in MMR-proficient CRCs. There is also a positive coloration between PD-L1 expression and poor prognosis in Oesophageal cancer with one study by Chen et al suggesting that only membrane nit nuclear PD-1 expression was associated with a poor survival for patients with oesophageal cancer. Studies of PD-L1 expression in pancreatic cancer have overall seen a poor prognosis for patients. Studies have shown that expression of PD-L1 can have a role in tumour progression and invasiveness which leads to poor survival rates for patients with pancreatic cancers (Wang et al., 2016). Overall PD-L1 expression had shown to be quite a poor prognosis marker for most cancers leading to poor overall survival rates for patents although some studies in particular cancers can contradict this and so the use of PD-L1 as a prognosis marker still needs to be explored further.
PD-L1 is also known to be used as a predictive biomarker in some cancers, it can be used to help identify patients that will benefit from immunotherapy and those who may not. Some studies suggest patients with tumours that overexpress PD-L1 by Immunohistochemistry have improved clinical outcomes and overall survival with anti-PD-1-directed therapy (Patel and Kurzrock, 2015).
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