PD-L1 biomarker testing offers hope for the challenges of precision testing in bladder cancer

Bladder cancer is in an advanced stage by the time it is detected in approximately a quarter of patients at presentation. The initial symptoms of this disease (e.g. blood in the urine) often go unnoticed or are mistaken for other conditions such as a bladder infection.  

As with any cancer, the earlier bladder cancer is detected, the better the health outcomes in patients. Treatment approaches to bladder cancer heavily depend on the stage of cancer detected, as well as other factors. Treatment options may include relatively simple  intravesical therapy but also radical surgery or chemoradiation. In the case of metastatic disease, options may include chemotherapy, immunotherapy, or targeted therapy drugs. 

Early diagnosis of bladder cancer requires a vigilant eye for early, often easy-to-miss symptoms and appropriate testing. Diagnostic tests for bladder cancer include many non-invasive procedures that examine a urine sample (e.g. urinalysis, urine cytology, urine culture, urine tumor marker tests). However, these tests do not give a definitive diagnosis and many physicians prefer to rely on other tests that are invasive. The first of these is called a cystoscopy, in which cancer tissue can be detected. If cancer is detected, this test is followed by a procedure called transurethral resection of bladder tumor (TURBT), in which abnormal tissue seen during the cystoscopy is biopsied or resected to be further investigated. These tissue samples are studied under a microscope and may be run through various lab tests. 

An important new biomarker offering hope to some patients with bladder cancer is called PD-L1 (programmed cell death-ligand 1). This biomarker is already being used in many other cancers in which it is overexpressed.^1,2 PD-L1 is a protein that plays a role in our natural immune response to disease by interacting with a type of white blood cell called the T cell.³  Infections and diseases turn on T cells and start the immune response. Activated T cells, therefore, help our bodies fight off disease.⁴ However, cancer cells have a way of deactivating T cells so cancer can spread.⁵ Cancer cells do this with the help of PD-L1, a protein on cancer cells that attaches to receptors on T cells called PD-1 and deactivates the T cells.^5,6 PD-L1 helps tumors develop. 

Blocking PD-L1, however, can prevent cancer cells from inactivating T cells. This is why anti-PD-L1 inhibitors are used to treat many cancers, including bladder cancer in several stages of the disease. Examples of anti-PD-L1 include pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab—all of which are forms of immunotherapy that target PD-L1 in order to help the immune system fight cancerous tumors. These anti-PD-L1 inhibitors are indicated in people with advanced stage bladder cancer that reappears post-chemotherapy and in people for whom chemotherapy is not appropriate.^7,8 Trials investigating these drugs in earlier stages of disease are underway. 

Since PD-L1 is expressed in large quantities in some cancer cells, it is a useful biomarker to test. Those people who are positive for PD-L1 will likely benefit from treatment with anti-PD-L1 inhibitors.^1,2 Those patients with a negative PD-L1 test are not necessarily unresponsive to these drugs. Currently, in the case of metastatic bladder cancer, it makes sense to discuss your PD-L1 status with your doctor. 

References 

1. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847─856.
2. Wang X, Teng F, Kong L, Yu J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023-5039.
3. Immune checkpoint inhibitors to treat cancer. American Cancer Society website. October 1, 2018. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html. Accessed May 25, 2019.
4. NM, Nirschl CJ, Jackson CM, et al. Lymphocyte activation gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS One. 2014 Nov 5;9(11):e109080.    
5. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587.  
6. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligand in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704.  
7. Witjes JA, Bruins M, Cathomas R, et al. Muscle-invasive and metastatic bladder cancer. European Association of Urology website. https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/#11. Accessed May 28, 2019.
8. Flaig TW, Spiess PE, Agarwal N, et al. NCCN Guidelines insights: bladder cancer, version 5.2018. J Natl Compr Canc Netw. 2018 Sep;16(9):1041-1053.