MicroRNAs Have Promise as Biomarker in Testicular and Other Germ-Cell Tumors

MicroRNAs have all the characteristics to be a potential game changer as a biomarker in germ-cell tumors (originating in the testes, ovaries, and a few other sites), with high sensitivity, specificity, and clinical validity in pilot studies, said Lucia Nappi, MD, PhD, Medical Oncologist, British Columbia Cancer, Vancouver Centre, Canada, at the 2020 Genitourinary Cancers Symposium.

Although standard chemotherapy has resulted in a cure for some patients with germ-cell tumors, survival has not improved much over the past 40 years. Consequently, a shift has occurred in this setting from finding a cure to the optimization of treatment, Dr Nappi said.

The sensitivity of the current biomarkers (ie, alpha fetoprotein, b-HCG, and lactate dehydrogenase) in germ-cell tumors is histology-dependent and is higher in seminoma versus nonseminoma tumors, but the specificity of these biomarkers is also suboptimal, said Dr Nappi.

“There are a lot of false-negative results, and diseases that can produce these tumor markers may not at all be related to germ-cell tumors,” she said.

A similar scenario exists with the use of computed tomography (CT) scans: when the threshold for sensitivity is increased, the specificity decreases.

Seminoma and Nonseminoma Germ-Cell Tumors

MicroRNAs are small (approximately 20-23 nucleotides) noncoding RNAs that regulate oncogenes and tumor suppressor gene expression. There are 2 clusters of microRNAs that have been identified in seminoma (ie, testicular) and nonseminoma germ-cell tumors, of which the most sensitive and specific is microRNA371a-3p; the other cluster is microRNA302/367. These microRNAs are extremely specific for germ-cell tumors, and they are expressed in more than 90% of tumors.

“There are no other tumors, no other diseases or conditions other than physiologic pregnancy, where we can detect these microRNAs,” Dr Nappi noted.

One limitation is that microRNAs are not expressed by teratoma but rather by viable germ-cell tumors. “They are abundantly secreted in the blood. We can use 200 µL of serum or plasma to detect these micro­RNAs,” she said. Serum and plasma levels are correlated with clinical stage. The level of microRNAs is decreased rapidly and disappears after successful treatment.

Studies of MicroRNAs

The high performance of micro RNAs in germ-cell tumors has been confirmed across several studies in patients with metastatic or very early-stage disease. The accuracy of these tests is “extraordinarily high,” with an area under the receiver operating characteristic curve (AUC) of approximately 0.96.

In a recent study of 111 men with a history of germ-cell tumor, 132 samples from patients with metastatic or early-­stage disease were analyzed using microRNAs. Patients were divided into 3 groups according to the expected risk for harboring viable germ-cell tumors (ie, low, moderate, or high).

MicroRNA371 outperformed CT scans and the other tumor markers, with only 2 false-negatives among the 132 samples analyzed and no false-positives, for a specificity and positive predictive value of 100%, a negative predictive value of 98%, a sensitivity of 96%, and an AUC of 0.96 during a median follow-up of 15 months. Specificity and sensitivity were similar across the risk groups.

“It seems that microRNA has most of the characteristics of an ideal biomarker. It is highly sensitive and specific. It’s very easy to detect and it’s noninvasive. The results have been consistently repeated and reproduced, and it’s…about $60 per sample,” Dr Nappi said.

She pointed out that despite these favorable features, micro­RNA317 is not ready to inform clinical decisions until its clinical use has been validated in a large prospective study. The S1823 trial will assess the clinical use of micro­RNA371 in patients with newly diagnosed germ-cell tumors. The study will attempt to answer whether micro­RNA371 can be used to detect tumor relapse in this patient population. A correlative pediatric study is currently accruing patients.

In addition, a phase 2 clinical trial will assess the use of micro­RNA371 in select patients for specific treatment.

“I think that we have a potential biomarker that can help us to solve most of the equivocal situations that we face in clinical practice. If validated, microRNA371 will help us to define who are the patients with stage I [disease] who actually need adjuvant therapy [and] patients with stage IIA who actually have germ-cell tumors and need treatment,” she said.

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