- Classic serum tumor markers—α-fetoprotein, the beta subunit of human chorionic gonadotropin and lactate dehydrogenase—are cornerstones of the diagnosis, prognostication, and surveillance of patients with testicular germ cell tumors
- The sensitivity of these markers is limited, however, and they are often negative in low-stage disease, teratoma, and pure seminoma
- microRNA, especially miR-371a-3p, show promise to help refine the management of testicular cancer across the disease spectrum, although even miR-371a-3p is insensitive to teratoma
- Other emerging biomarkers are circulating tumor DNA and circulating tumor cells, which require further study to determine their role in the diagnosis and surveillance of testicular germ cell tumors
- Most existing data are retrospective and must be prospectively validated before newer biomarkers can be adopted for clinical use
For decades, biomarkers have played a key role in the management of testicular germ cell tumors (TGCT). α-fetoprotein, the beta subunit of human chorionic gonadotropin and lactate dehydrogenase, have been used to guide diagnosis and risk stratification before treatment, to monitor disease response throughout treatment, and as a crucial component of surveillance.
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Unfortunately, the overall sensitivity of these classic serum tumor markers is low, and they are often negative in patients presenting with low-stage disease or certain histologic subtypes of TGCT, such as seminoma and teratoma. For these reasons, the classic markers are often insufficient to establish a diagnosis or reliably monitor disease status.
Jillian Egan, MD, urologic oncology fellow in the Massachusetts General Hospital Department of Urology, and Keyan Salari, MD, PhD, urologic surgeon in the Department and urologic oncologist at the Mass General Cancer Center, recently reviewed biomarkers for TGCT in Urologic Clinics of North America. This summary focuses on emerging markers: microRNA, circulating tumor DNA, and circulating tumor cells.
miRNA emerged as promising biomarkers for TGCT in 2011 and are now known to be detectable in serum and other extracellular fluids as well as tumor tissue. They regulate the expression of about one-third of human genes that influence cell cycle, development, proliferation, apoptosis and differentiation, and their profiles differ in benign versus malignant disease.
Serum levels of miR-367-3p, miR-373-3p, and especially miR371a-3p have been found to be increased in TGCT patients compared with both healthy men and those with nonmalignant testicular disorders. miRNA expression correlates with primary tumor size and disease stage and decreases rapidly in response to therapy. In addition, patients with relapsed TGCT have increased levels of this biomarker.
miR-371a-3p is the most sensitive and specific for TGCT, but like most miRNA, it is not significantly differentially expressed in teratoma. A recent study published in Cancers (Basel) demonstrated the combination of miR-371a-3p and hypermethylated RASSF1A improved the detection of teratoma compared with classic markers, but as with most research into emerging biomarkers for TGCT, prospective validation is needed.
The inability to detect teratoma limits the utility of miRNA in the post-chemotherapy setting, as up to 40%–50% of patients with residual masses harbor teratoma. Still, miRNA could be helpful in situations where treatment decisions are uncertain. For example, in patients with low-stage TGCT, they might predict the presence of microscopic metastatic disease and guide decisions about adjuvant therapy versus surveillance.
Circulating Tumor DNA (ctDNA)
A study published in The Journal of Urology in 2009 showed that ctDNA levels differentiated TGCT patients from healthy controls with sensitivity and specificity of 88% and 97%, respectively. The cohort included patients for whom classic serum tumor markers for TGCT were negative. Levels of ctDNA were proportional to disease stage, increased with progression, and decreased in response to treatment. However, ctDNA is still in the early stages of investigation as a possible biomarker for TGCT.
Circulating mitochondrial DNA (mDNA) has also been shown to be elevated in patients with TGCT. It may be more useful than ctDNA because there are hundreds of copies in each cell. In a 2009 study published in BJU International, levels of mDNA levels were higher in patients with TGCT than in controls, with a sensitivity of 60% and specificity of 94%. Similar to ctDNA, investigation of circulating mDNA as a potential biomarker is in its infancy.
Circulating Tumor Cells (CTCs)
CTCs have the potential to seed metastatic sites of disease. In a study in which patients with TGCT were stratified by disease burden, 41% of those with metastatic disease had detectable CTCs. More strikingly, CTCs were detectable in all patients with cisplatin-resistant or relapsed disease.
CTCs have been more commonly detected in non-seminomatous germ cell tumors, including teratoma, which could help fill the biomarker gap in the detection of that subtype. However, to date, it's technically challenging to isolate CTCs, so opportunities for clinical studies have been limited.
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