MicroRNA emerges as potential germ cell tumor biomarker
In stage I disease, miRNAs show promise for detecting relapse.
The current generation of biomarkers for germ cell tumors is underwhelming. As few as 60% of stage I patients have elevated biomarkers and about 5% of patients receive an orchiectomy for benign disease.
“Testis cancer is shrouded in uncertainty,” said Aditya Bagrodia, MD, professor of urology at the University of California, San Diego School of Medicine. “Sensitive and specific biomarkers could allow for precise, individualized treatment recommendations. Circulating microRNA 371-1-3p holds the promise to be such a biomarker.”
Dr. Bagrodia opened the first Plenary session on Saturday morning with a State-of-the Art lecture on “The State of Biomarkers in Germ Cell Tumors.” MicroRNAs (miRNAs) are short, noncoding RNA sequences involved in epigenetic gene regulation. After release from cell nuclei, they modulate intracellular communication and are dysregulated in a variety of malignancies.
The first family of germ cell tumor-specific miRNAs not present in normal gonadal tissue were identified about 15 years ago, Dr. Bagrodia said. A continuing series of trials identified miRNAs in both seminoma and non-seminoma germ cell tumors. The largest trial to date, 874 patients, identified miRNA 371 in the pre-orchiectomy setting with an area under the curve of 96.6% for all comers.
“MicroRNA 371 has excellent performance and outperforms current conventional tumor markers to predict pathology in stage I disease, where there is the most ambiguity,” Dr. Bagrodia reported. “Our current risk stratification is really insufficient for individualized patient counseling.”
The data are less convincing for predicting the relapse of stage I disease. Longitudinal studies have not shown that early miRNA testing is reliably predictive of relapse following orchiectomy. But all patients who relapsed showed detectable miRNA levels about two months before clinical evidence of relapse.
“I conclude in stage I disease, miRNAs are promising to detect relapse,” Dr. Bagrodia said. “However, early post-surgery miRNAs may not predict relapse, and this is likely a sensitivity issue that can be technically overcome.”
Clinical trials indicate utility for state II disease as well, he said, as miRNAs show sensitivity and specificity of 92% with an area under the curve of 93.4%. Positive predictive value, negative predictive value and accuracy all showed 92%.
More advanced disease remains problematic. About half of patients show evidence of disease following post-treatment retroperitoneal lymph node dissection. Of these cancers, 5% are viable germ cell tumors and 45% are teratomas, and miRNA cannot detect teratomas.
“The pre-orchiectomy setting is very promising with some sensitivity issues in stage I disease,” Dr. Bagrodia said. “In stage II disease, miRNAs perform quite well. And in the post-therapy setting, we likely can pick up viable germ cell tumor, but the detection of teratoma remains outstanding. Further work regarding standardization, optimization and validation is required.”
