Detection of Early Relapse Using Circulating miR371a-3p in Patients with Early-Stage Testicular Germ Cell Tumors

Testicular germ cell tumors (GCT) are the most frequent solid tumors in adolescent and young men and therefore are very common among the young military personnel. Most patients with GCT are diagnosed when the tumor is confined to the testis (Clinical Stage I [CSI]). Most of these patients are managed with active surveillance to detect and treat the tumor relapse at an earlier higher curable stage. About 15%-50% of the CSI patients will experience a recurrence of the tumor and no markers are available to reliably estimate the risk of relapse. Chemotherapy, radiation therapy, and surgery can cure almost all of the relapsed GCT patients. However, these treatments are associated with short- and long-term side effects that can negatively impair the quality and the life span of the GCT survivors. The current methods to diagnose GCT rely on CT scan and blood work for tumor markers (B-HCG, AFP, and LDH) which have limited power to detect the GCT and are non-specific for GCT. This means that there are patients who are treated with chemo, radiation, or surgery without having clear evidence of GCT and, on the contrary, patients with recurrent low tumor burden can be missed by CT scans and lab work.

Certain small RNAs, called microRNAs, are produced only by GCT cells and are secreted in the bloodstream where they can be measured. Our group has demonstrated that one of these micro- RNAs (miR371) is more accurate than CT scan and classic serum tumor markers in detecting GCT in patients with advanced tumor.

Therefore, we propose to study miR371 in patients with non-evident GCT but who will have a relapse of the tumor (CSI after the orchiectomy). The blood of the relapser CSI GCT patients collected at the time of the confirmed relapse and prior to the relapse immediately after the orchiectomy will be used to assess if miR371 expression is better than the CT scan and serum tumor markers to diagnose low volume GCT or to predict tumor recurrence.

Moreover, two methodologies (real time polymerase chain reaction [RT-PCR] and nucleic acid sequence-based amplification [NASBA]) will be compared and the one with higher accuracy in patients with low volume GCT will be selected for future studies.

Dr. Nappi is the Principal Investigator of this project. She has been focusing on biomarkers discovery in GCT and she is leading a large clinical trial to validate miR371 by RT-PCR in GCT patients. Her goal is to change the clinical management of GCT and integrate miR371 in the decision making and treatment selection of GCT patients. This career development award will help to support Dr. Nappi research program in GCT protecting her time for research.

If miR371 will be confirmed to be highly accurate to detect early GCT relapse, the diagnosis, follow-up and treatment decisions will be made based on the miR371 status. If the new method (NASBA) proposed by Dr. Nappi proves highly sensitive in detecting few copies of miR371 in the blood, GCT practice will change profoundly. MiR371 will significantly reduce the utilization of unnecessary chemotherapy, radiation therapy, and surgery, with proportionate reduction in unnecessary long-term toxicities, which is a priority considering the young age and the long-life expectancy of these patients. These advantages will be particularly beneficial to the military personnel. Early assessment for the presence or absence of GCT could assist in deployment decisions where a negative assessment for GCT would allow immediate return to service or deployment with the ability to safe, remote follow-up through long interval miR371 blood draw. Moreover, the long-term consequences associated to radiation and chemotherapy will significantly decrease, as only patients with biological evidence of GCT (miR371 positive) will receive these treatments. In the military (and non-military) environment, this will improve the quality of life of the survivors and will extend the life expectation of these patients.