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Craig Nichols, MD, on MicroRNA-371 for Guiding Testicular Tumor Treatment

– Experimental biomarker has many ideal qualities, including high specificity


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Researchers believe they have found a near-ideal biomarker to guide treatment for patients with early-stage testicular germ cell tumors (GCTs).

Current predictive models based on clinicopathologic characteristics have been of limited use, said Craig Nichols, MD, of the University of British Columbia in Vancouver, and colleagues, in a "Comments and Controversies" article in the .

"Although such models have augmented standard evaluations, at best, they are only modestly predictive with the highest-risk groups having only approximately 50% recurrence rate. Consequently, these models have underperformed in the clinical setting and have not been widely adopted to guide treatment decisions," the authors wrote.

However, circulating plasma and serum microRNA-371 (miR371) has qualities suggesting it could be an "ideal" biomarker.

Nichols, who is also co-director of the Testicular Cancer Program at Virginia Mason Medical Center in Seattle and founder of Testicular Cancer Commons, which aggregates and shares information about the disease, explains why.

How would a better predictive tool benefit patients with early-stage testicular germ cell tumors?

Nichols: Localized or regional presentations of testicular germ cell tumors constitute 80-85% of all incident cases in North America. The challenge in these common earlier-stage settings is not curing the disease -- ultimate cure rates are very close to 100% in current practice -- but curing the disease with as little short- and long-term patient burden as possible.

The challenge is identifying 15-25% of CSI [clinical stage I] seminoma or nonseminoma who will recur with active germ cell malignancy after the diagnostic orchiectomy (false negative clinical assessments), and identifying the 20% or so of patients who have suspected clinical relapse by imaging (1-3 cm retroperitoneal adenopathy) who, in fact, do not have a relapse of germ cell malignancy (false positive clinical assessments) and do not require chemotherapy or radiation therapy (for seminoma).

An easily obtained, cost-effective, and easily analyzed biomarker that had greater specificity and greater sensitivity than current imaging and classic HCG [human chorionic gonadotropin], AFP [alpha-fetoprotein], and LDH [lactate dehydrogenase] would allow highly accurate assessments as to the presence or absence of active germ cell malignancy. As a consequence, over- and under-treatment in the most common clinical settings for testicular germ cell tumors would be reduced.

What makes miR371 a good biomarker?

Nichols: In a word or two, high specificity. MiR371 is now felt to be a pathognomonic feature of germ cell malignancy. MiR371 is a very small microRNA (22 base pairs) that is expressed in all germ cell malignancy tissue and is found in abundance in the circulation of patients with active germ cell malignancy. The only other human condition that is known to have circulating miR371 overexpression is normal pregnancy.

In circulation, miR371 is stable and can be measured with standard RT-PCR [reverse transcription-polymerase chain reaction] methods. Current research costs are approximately USD $60/sample. Very high specificity and positive predictive value has been reported by a number of investigators (95-100%). Sensitivity with current methodologies is of some concern, but sensitivity at the lower end of our current ability to detect disease (approximately 1 cm disease) appears to exceed current imaging or classic tumor markers.

Are there any limitations to miR371 as a biomarker?

Nichols: The aforementioned sensitivity and negative predictive value, particularly at low clinical or subclinical volumes of disease, is a current limitation but is not of great practical concern since high negative predictive value will not likely translate into high patient benefit. In contrast, high positive predictive value has great potential to lessen overtreatment, simplify active surveillance, and simplify post-treatment follow up.

One of the most clinically relevant studies of miR371 was conducted by , on which you are a co-author. What were the key findings of this study?

Nichols: In contrast to the important study, which also appeared in JCO in 2019, Nappi and colleagues addressed the entire spectrum of presentations of germ cell tumor with less emphasis on the pre- and peri-orchiectomy timeframe. In the Nappi study and Dieckmann study, the suspected high specificity for active germ cell tumors was confirmed, the rapid clearance of the biomarker with effective treatment was demonstrated, and both studies demonstrated that teratoma does not express miR371.

In addition, the Nappi study demonstrated very high sensitivity and high negative predictive value in the setting of high disease volumes. Nappi and colleagues were the first group to use plasma-based methodologies and the first to utilize Streck tube capture and centralized processing approaches -- approaches that make scaling of these methods over large geographies highly feasible.

Can you tell us about one or two of the clinical investigations currently evaluating miR371?

Nichols: The two largest studies currently underway are the North American investigations (Nichols, Nappi PIs) and (AL Frazier PI). Both should provide confident estimates of the operating characteristics of miR371 at various stages of presentations of germ cell malignancies.

However, neither of these large NCTN [National Clinical Trials Network] studies are designed to demonstrate the "proof of principle" aspect of clinical utility and patient benefit. These demonstrations likely will come from two new investigations just opening; the investigation in Australia/New Zealand (C. Conduit and B. Tran) and the MAGESTIC investigation (Multi-Institutional miR371-guided surgical trial in stage II GCT) -- Daneshmand PI, Nappi and Nichols co-PIs.

Read the study here.

Nichols disclosed no conflicts of interest.

Primary Source

Journal of Clinical Oncology

Source Reference:

ASCO Publications Corner

ASCO Publications Corner