New Biomarkers for Decision Making in Advanced Testis Cancer

Abstract and Introduction

Abstract

Management of testicular germ cell tumor (GCT) patients is based on clinical determinants, mainly CT scan and serum tumor markers (alpha-fetoprotein, beta subunit of HCG and LDH). Treatment decisions are usually straightforward for patients with clear evidence of metastatic disease, confirmed either by imaging tests or by unequivocal elevated tumor markers. However, there are several clinical scenarios where the assessment of metastatic disease is complicated by the limited specificity of the current imaging tests and serum tumor markers. These include patients with clinical stage IIA GCT with negative tumor markers and patients with post-chemotherapy residual disease where, in absence of clear indicators of GCT, decision making and patient treatment allocation become challenging. Therefore, more accurate biomarkers are critical to reduce the risk of under-or over-treatment and to always deliver the most optimal therapy. The objectives of this narrative review are to review the available publications about micro-RNAs in GCT s and their potential clinical applications. Two clusters of micro-RNAs, miR-371a-3p and miR-302/367, specifically expressed by both seminoma and non-seminoma GCT and easily detectable in the peripheral blood, have demonstrated to be promising in this endeavor. Large prospective trials are ongoing to define the operating characteristics of these biomarkers and their clinical utility to improve GCT patient management and reduce the error rate deriving from clinical uncertainty, therefore reducing the risk of sub-optimal treatments.

Introduction

Testicular germ cell tumors (GCT) are highly curable malignancies and represent one of the few successful stories in the history of medical oncology.^[1,2] The characteristics of the patients population and the high cure rate achieved with chemotherapy treatment make this tumor unique.^[3] First, the goal of care is always cure and the chances for cure are highest if the appropriate treatments are delivered correctly and in a very standardized way.^[4,5] Second, cure should be achieved with as much reduction of short and particularly long-term toxicity as possible.^[6,7] This is important due to the young age of the GCT patients and the long-life expectancy following curative therapy. Chemotherapy and radiation therapy are associated with acute and long-term toxicity that affect the lifespan but also the quality of life of the GCT survivors.^[8–12]

Although adjuvant chemotherapy is an option in patients with CSI, the risks of treatment related long-term toxicity mandate a more cautious utilization of chemotherapy in cases with unequivocal evidence of GCT and when there is a clear benefit.^[13] Suboptimal management, either over- or under-treatment, jeopardize the excellent outcomes of GCT patients and are equally harmful.

Diagnosis of Metastatic GCT

Clinically, the majority of newly diagnosed GCT patients have clinical stage I (CSI) disease, which is defined by the absence of tumor outside the testis.^[14] Because of the lack of sensitive and specific biomarkers for relapse,^[15,16] most of the CSI patients are managed with active surveillance.^[17] However, 15–20% of patients with CSI seminoma and 15–50% of patient with CSI non-seminoma will relapse and require active therapy.^[18] The diagnosis of metastatic GCT, either de novo or relapsed, is usually made by integration of clinical, imaging, and serologic tests.

Imaging Tests. GCT have the advantage of demonstrating a very predictable pattern of metastases with the ipsilateral retroperitoneal lymph nodes being the first site of the metastatic spread in about 95% of the cases. Usually, nodules measuring >1 cm are considered suspicious for metastatic disease.^[19] The sensitivity and specificity of the computer tomography (CT) scan is around 70% and is therefore purely based on morphologic criteria and limited by size criteria.^[20] Decreasing the cut off for significance increases the sensitivity but decreases the specificity, making this strategy not suitable for GCT patients where overtreatment is concerning because of the risk of long-term toxicity. Functional imaging tests (i.e., FDG-PET scan) have a very limited role in GCT; there are no data supporting their use in non-seminoma because of the known low FDG uptake of teratoma that results in a high rate of false negative results. In seminoma, FDG-PET has a relatively small utility in the post-chemotherapy setting for lesions >3 cm. As demonstrated by retrospective and prospective studies, in this setting FDG-PET scan has a high negative predictive value; however, the high false positive rate (around 70%) limits the utilization of PET scan in this context for treatment decision, even if the results are positive.^[21,22]

Although FDG-PET scan has been recently proposed to de-escalate metastatic seminoma patients treatment,^[23] the data are still controversial and insufficient to recommend the use of interim FDG-PET scan for treatment de-escalation in seminoma patients.

Serum Tumor Markers. Although tumor markers (TM) alpha-fetoprotein (AFP), beta subunit of HCG (B-HCG) and LDH have a crucial role in GCT, their operating characteristics are also suboptimal in a number of clinical scenarios, contributing to a high degree of uncertainty.^[24] The detection of tumor markers in patients with GCT depends on the histology (higher sensitivity in non-seminoma than in seminoma) and tumor burden. Specifically, B-HCG is expressed by <30% of seminoma patients while B-CG and AFP are expressed by 50–60% of non-seminoma patients.^[25]

Moreover, the half-life of AFP is around 7 days and it is 24–48 hours for B-HCG. This long half-life has to be considered when the patients are assessed for tumor response or residual disease on the base of the TM only since sometimes, especially when the initial levels were very high, they can be misinterpreted as falsely positive. Several non GCT related conditions are related to false positive TM elevation. Liver disease, liver toxicity, certain drugs, and some genetic conditions (hereditary persistence of AFP) lead to non GCT related increase of AFP. For B-HCG, false positive high levels have been described with use of marijuana, heterophile antibodies and high levels of LH hormones. LDH is the less specific of the GCT TM and can be increased for a variety of reasons including hemolysis or in case of G-CSF use.^[26] TM have diagnostic but also prognostic value and in fact they are part of the IGCCCG classification.^[27] Moreover, their levels are usually assessed during chemotherapy to monitor the response to the treatment. The TM decline rate identifies poor risk patients with better outcomes.^[28] The kinetics of TM after the first cycle of chemotherapy has been proposed to select the poor risk patients to treatment escalation in the GETUG 13 study.^[29] The updated results of the trial conducted in 263 patients, after a median follow-up of 5.6 years demonstrated that the patients with unfavorable TM decline treated with dose-dense chemotherapy had a better 5-year PFS [60% vs. 47%; HR: 0.65 (0.43–0.97); P=0.037] while the 5-year OS rate was not statistically significant [70.4% vs. 60.8%; HR: 0.69 (0.43–1.11); P=0.12].^[30] This study confirmed the importance of TM decline in poor risk patients although it did not provide clear definition of the best regimens for chemotherapy intensification.

Objectives

The objectives of this narrative review are: (I) to review the most relevant publications about micro-RNAs in GCTs; (II) to discuss the micro-RNAs potential clinical applications in patients with advanced GCTs. We present the following article in accordance with the Narrative Review reporting checklist (available at https://dx.doi.org/10.21037/tau-20-1246).

Methods

Literature review of the available publications was conducted searching "micro-RNA AND/IN germ cell tumors", "miR371a-3p in germ cell tumors" in PubMed.