Mi oh mi-RNA and ... mi-too: New biomarkers for germ cell tumors
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MicroRNAs — small noncoding RNAs that seem to be involved in epigenetic control of gene expression — have garnered increasing attention as potential biomarkers in the past few years, with interest focused on gastrointestinal malignancy, and now germ cell tumors.
A few months ago, Dieckmann and colleagues produced a particularly interesting report suggesting that microRNA (miR)-371a-3p could be a useful marker of germ cell tumors (GCT) that might be superior to the conventional GCT markers human chorionic gonadotropin (hCG), alpha fetoprotein (AFP) and lactate dehydrogenase (LDH).
Their study, completed in Europe, capitalized on an earlier observation from Murray and colleagues that proposed the potential utility of the miR-371~373 and miR-302/367 clusters in this context. In a comparison of samples from more than 600 patients with all stages of GCT compared with 258 healthy men, they showed specificity and sensitivity for primary diagnosis of germinal malignancy greater than 90% and a positive predictive value of 97%.
In stage I disease, seminomas had lower levels of miR-371a-3p than nonseminomas, but this difference disappeared in the metastatic context. Levels appeared associated with primary tumor size and clinical stage. Patients with metastatic disease in nodes or beyond had significantly higher levels than those with clinical stage I disease. Reduced levels of miR-371 reflected the diminution of tumor mass after chemotherapy, and researchers noted that the half-life for clearance was less than 24 hours. Relapse appeared associated with recurrence of detectable miR-371.
Confirmatory study
I noted the Dieckmann paper and the earlier reports about this marker with interest, but felt that confirmatory information was needed before devoting editorial space to the work.
Here we are approaching year’s end, and I see the requisite me-too study has just hit the press in Journal of Clinical Oncology, this time from Nappi and colleagues in North America.
This small multicenter study assessed the utility of miR-371 among 111 patients with seminoma or nonseminomatous GCT. Obviously, the sample size was much smaller and the trial design less robust than the European study, but the work is worth quoting as it confirms the observations of the earlier study, providing the benefit of earlier validation. I presume that is why the Journal of Clinical Oncology editors accepted it for publication at an early stage of development, also ensuring that a U.S. study was published in the same calendar year as the definitive European trial.
Important observations included no false-positive cases and two (4%) false negatives. The high specificity, sensitivity and positive predictive value were confirmed, and there also was a strong suggestion of a high negative predictive value (notwithstanding a rather modest period of follow-up that will require further scrutiny). Once again, miR-371 outperformed the more conventional GCT markers.
Take-home messages
It seems that miR-371a-3p is a useful marker of GCT, and provides some improved diagnostic specificity and sensitivity compared with AFP, hCG and LDH.
This does not seem to apply to differentiated teratomas, and this will be a trap for the future — the unwise, unwary or inexperienced clinician may well take false comfort in patients who, after completion of chemotherapy, have small residual masses but low levels of miR-371a-3p, and decide against completion surgery because of false reassurance of an absence of residual dangerous tissue. We must not forget the important lesson of the past that unresected residual masses after completion of effective chemotherapy may harbor the potential for intractable transformation into lethal variants of adenocarcinoma or sarcoma that can arise like a phoenix and kill the patient.
We have yet to understand whether undetectable levels of this marker will help us to avoid unnecessary orchiectomy in the patient with a small intratesticular mass on ultrasound or even a palpable lesion on self-examination. Further work will be required to refine further the cutoff levels that reflect normality at the time of diagnosis and for evaluation of the efficacy of treatment, particularly for seminoma. One also should not forget the conundrum posed by an earlier study that suggested tissue levels of this marker are higher in seminoma than in nonseminomatous GCT, which is the reverse of the data from measurements of serum.
Further, one of the helpful prognosticators in the context of poor-risk disease has been the phenomenon of tumor flare and hCG (or occasionally AFP) release after chemotherapy, which can be quite predictive of ultimate outcome. Whether this new marker will afford that prediction also will need to be tested.
‘Another major step’
Forty years ago, when completing my PhD at Ludwig Institute for Cancer Research of Royal Marsden Hospital in London, I had the privilege of working with professors Munro Neville, MD, PhD, MRCPath,Sir Michael Peckham, FMedSci, FRCP, FRCS, FRCR, FRCPath and Eadie Heyderman, MD, studying the strengths and limitations of hCG and AFP in xenografts, tissue culture and young men.
We were able to demonstrate diagnostic sensitivity and specificity well above 50% for nonseminomatous GCT, and showed that AFP is definitively a marker of nonseminoma, that a solid tumor variant of stem cell existed, that adjuvant radiotherapy provided no benefit after orchiectomy for clinical stage I nonseminomatous GCT and could be replaced by active surveillance, and that serial measurements of AFP and hCG were a significant aid to clinical management of patients in follow-up after orchiectomy or when receiving chemotherapy for advanced GCT.
In 2019, it seems that another major step has been taken and that miR-371a-3p will become a useful standard tool in the curative therapy of GCT, notwithstanding a very long time trajectory. Further validation will probably come from one of the new SWOG trials.
That said, the hills to conquer remain poor-risk metastatic disease and the phenomenon of post-chemotherapy residual disease transformation.
References:
Diekmann KP, et al. J Clin Oncol. 2019;doi:10.1200/JCO.18.01480.
Murray MJ, et al. Am J Clin Pathol. 2011;doi:10.1309/AJCPOE11KEYZCJHT.
Nappi L, et al. J Clin Oncol. 2019;doi:10.1200/JCO.18.02057.
Peckham MJ, et al. Br J Urol. 1981;doi:10.1111/j.1464-410X.1981.tb03160.x.
Raghavan D, et al. Br J Cancer. 1980;(Suppl 4):191-4.
Raghavan D, et al. J Clin Pathol. 1981;34:314-319.
For more information:
Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Atrium Health. He can be reached at derek.raghavan@atriumhealth.org.
Disclosure: Raghavan reports no relevant financial disclosures.